TtCI !»>:!: ;r re ssmnw! ,/,!!.:ni>in:<-!ii;siJ»u««K COLUMBIA UNIVERSITY EDWARD G. JANEWAY MEMORIAL LIBRARY THE PITUITARY A STUDY OF THE MORPHOLOGY, PHYSIOLOGY, PATHOLOGY, AND SURGICAL TREATMENT OF THE PITUITARY, TOGETHER WITH AN ACCOUNT OF THE THERAPEU- TICAL USES OF THE EXTRACTS MADE FROM THIS ORGAN Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/pituitarystudyofOObell THE PITUITARY A STUDY OF THE MORPHOLOGY, PHYSI- OLOGY, PATHOLOGY, AND SURGICAL TREATMENT OF THE PITUITARY, TOGETHER WITH AN ACCOUNT OF THE THERAPEUTICAL USES OF THE EXTRACTS MADE FROM THIS ORGAN BY W. BLAIR BELL NEW YORK WILLIAM WOOD & COMPANY MDCCGCXIX -A-fc 5 41 GcrX>> \ PKINTED IN GKEAT BUtTAfN TO MY FRIEND J. ARTHUR SMITH PREFACE In this monograph an attempt has been made to describe and discuss within a reasonable compass our present knowledge with regard to the Pituitary Body, in the belief that a more or less complete summary of the subject is needed by the clinician, if not by the morphologist and physiologist, owing to the com- manding position this organ now occupies in Medicine, Surgery, and Gynaecology, as well as in the other specialities. Descriptions of the Pituitary are to be found in various monographs, such as those of Thaon, Fischer, and dishing, and in the works on the internal secretions of Biedl, Vincent and others ; but in one aspect or another these accounts appear to lack the completeness, manner of presentation, or point of view that is required by the general reader, however well they fulfil special requirements. Our own experimental work — commenced in 1906- was primarily undertaken in order to elucidate the relationship of the Pituitary to the female genital functions, and to determine the physiological and therapeutical importance of extracts made from this organ; but we were led in our investigations further afield, for it was difficult to study comprehensively such special aspects as those mentioned without first obtaining an intimate knowledge of the morphology, and, so Jar as possible, of the pathology of the organ in question. Thus it came about that a considerable amount of material and information was collected from the work of others, and also as the result of our own observa- tions. Our researches have been concerned with the histological anatomy from developmental, physiological and comparative points of view; with the physiological actions of the extracts, the interrelationships between the Pituitary and other organs of internal secretion, the effects of partial and complete removals, the results of experimentally produced infections, the general pathology, and with the therapeutical uses of extracts of the viii PREFACE Pituitary. It is the information and material so obtained that form the subject-matter of this volume. It would be impossible, of course, completely to discuss all the work that has been done in regard to the Pituitary — to do so would mean a compilation of many volumes containing much confirmatory and contradictory evidence. Only the more essential particulars, therefore, have been given ; for at the present time a critical study of the accuracy of our acquired information and an attempt to correlate our knowledge is probably more needed than a mere string of statements. For the same reason a com- prehensive bibliography of the subject has not been attempted, but numerous references to statements quoted and investigations mentioned are given. In these circumstances it is jiossible that valuable work of others has escaped attention, and that our own less important investigations have been given undue prominence. If so, it may be pointed out that this book is not intended to be a mere com- pilation, but, rather, the presentation of an attempt to study the Pituitary from every point of view. Some of the original work contained in the following pages has been published previously ; and it includes that for which the author was awarded the John Hunter Medal and the Triennial Prize by the Council of the Royal College of Surgeons, England, and the Astley Cooper Prize, as well as the substance of a Hunterian Lecture delivered at the Royal College of Surgeons. In addition to my obligation to Mr. Arthur Smith, who has defrayed the laboratory expenses in connexion with my researches, and to whom this work is inscribed, I am indebted to my colleagues Professor J. A. McDonald and Professor E. E. Glynn for laboratory facilities. Miss Miriam Alderson has given me much valuable assistance, especially in regard to the references and in the com- pilation of the index. My laboratory assistant — now Private Walter Plevin, R.A.M.C— has drawn many of the illustrations other than the photographs. Private Fred Holliday, also, has been responsible for some of the pictures. Owing to the difficulty of securing artistic assistance after they had left, a number of photomicrographs have been reproduced ; and at the last moment Miss E. M. Wright kindly drew a few illustrations. All the photo- graphs and drawings, other than those indicated, have been made from my own material. PREFACE ix As this work has been produced at a time of great stress and difficulty, some allowance must be made for imperfections that may be found in regard to publication and authorship. I must, however, thank Mr. W. A. Clowes of Messrs. William Clowes and Sons for the personal interest he has taken in the printing of the book, and Dr. Hubert Armstrong for reading the proofs. W. B. B. 38, Rodney Street, Liverpool, November, 1918. CONTENTS Preface . Introduction PAGE vii PART I THE MORPHOLOGY OF THE PITUITARY § i. Development of the Pituitary § ii. AxATOMY OF THE PITUITARY . Macroscopical anatomy Histological anatomy . - . § iii. Comparative Anatomy of the Pituitary Cyclostomata Pisces . Amphibia Reptilia Aves Mammalia 3 14 14 28 40 4ft 13 4!< ;.i 52 55 PART II THE PHYSIOLOGY OF THE PITUITABT § i. Phtsiologicai In\ i stig ltions Histological Observations Chemical examination of pituitary tissues and body-fluids Chemistry of pituitary . [nfundibulin and the cerebrospinal fluid Injection, ingestion and absorption experiments Immediate results of injections and absorption of extract* Late results of injection and ingestion of extracts 82 82 KM 101 102 1 | 16 105 122 xii CONTENTS PAGE § ii. Pathophysiological Investigations 126 Operations on the pituitary . ........ 126 Destruction of the pituitary . . . . . . . 1 •_'<'» Removal of the pituitary ........ 127 Extirpation combined with implantation of grafts . . . 170 Stimulation of the pituitary in situ ...... 17<» Interrelations between the pituitary and the other hormonopoietic organs 178 Supplementation with pituitary extracts ..... 180 Removal of the other hormonopoietic organs .... 182 Discussion of results of removal of the various hormonopoietic organs 204 Effects of inoculations with bacteria ....... 207 The interpretation of pathological processes affecting the normal physiology 211 § iii. Comparative Physiology 214 PART III DISORDERS ASSOCIATED WITH THE PITUITARY AND THEIR TREATMENT § i. Primary lesions of the Pituitary 218 Hyperpituitarism .......... 218 Acromegaly . 219 Hypopituitarism 238 Polyglandular affections in primary hypophysial lesions . . . 248 Primary lesions of the pituitary producing symptoms neither of excessive nor of diminished secretion ...... 253 § ii. Secondary lesions of the Pituitary . 259 Neighbouring pathological conditions ...... 259 Diseases of the other hormonopoietic organs 262 Metastases 269 Infections 270 Toxaemias of pregnancy . . . . . . . . . 272 § iii. General consideration of the Pathology of the Pituitary . . i'7'i § iv. Treatment of Pituitary lesions 280 Medical treatment of phenomena due to pituitary lesions . . . 280 Surgical treatment of pituitary lesions ...... 282 Surgical anatomy .......... 282 Indications for operation 286 Selection of the route of approach 286 Preparation of the patient 287 Intracranial methods ......... 287 Extracranial methods ......... 291 Results of operations 299 CONTENTS xiii PART IV THE THERAPEUTICAL USES OF PITUITARY EXTRACTS PAGK § i. G-EXKKW. CONSIDERATIONS 301 Methods of manufacture . . . . . . . . 302 Methods of administration ........ 303 General indications for administration ..... 304 General contraindications ........ 305 § ii. Effects produced by Pituitary extb lots ...... 306 Pressor effects of infundibulin ........ 300 Circulatory system 306 Uterus 310 Alimentary tract . . . .">•_' 1 Urinary system .".L'l Mammary glands .......... 322 Spleen 323 Substitution and supplementary effects of pituitary extracts . . 32 1 Antagonistic and metabolic effects of pituitary extracts . . . 327 Ixdex 331 ILLUSTRATIONS PART I PACING PAGE Plate 1. Section of the normal human pars anterior ..... 30 Plate 2. Section of the normal human pars anterior, showing basophil colloid .;] Figure 1. figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 11. Figure 12. Diagram of the earliest stage of development Diagram of the second stage of development Section of head-end of human foetus 4 mm. in length . Section of stomodeum and encephalon of human foetus 9 mm. in length .......... Diagram of the development of the infundibular process Section of pituitary region of human foetus 10 nun. in length Section of pituitary region of human foetus 16 mm. in length Section of pituitary region of human ftetus 16 mm. in length Diagrammatic representations of pituitary in a human fcetu 16 mm. in length ........ Section of the pituitary region of human foetus ?•"> mm. in length Median horizontal section of the adult human pituitary Base of human skull showing sella turcica .... Figure 13 a. Radiograph of normal human sella turcica .... b. Radiograph of normal human sella turcica .... Figure 11. Macroscopical sections of pituitary region in human adults, showing sphenoidal cells in relation to sella- turcica 1 Figure 15. Internal circulation of pituitary of cat . .... Figure 16. Diagram of the external circulation of human pituitary Figure 1". Section of human pars anterior, showing blood-sinuses Figure IS. Section of human pars anterior, showing acini with secretion Figure 19. Section of human par- anterior, showing basophil cells Figure 20. Section of human pars anterior, showing sympathetic fibres Figure 21. Section of human pars intermedia Figure 22. Neuroglial cells and fibres in pars uervosa of cat . Figure 23\ Pituitary of the lamprey Figure 24. Pituitary of the skate Figure 25. Section of distal epithelial portion ..t pituitary of the akate . Figure 26. Pituitary of the cod PACK 4 5 6 7 8 1) HI 11 1^ 13 i:> in 2ii 20 •_':; •_■:. 27 •_'!> :;ii :;i 32 :;» 36 i -J II in XVI ILLUSTRATIONS Figure 27. Pituitary of the eel .... Figure 28. Pituitary of the frog .... Figure 29. Pituitary of the salamander . Figure 30. Pituitary of the lizard .... Figure 31. Pituitary of the tortoise Figure 32. Pituitary of the fowl .... Figure 33. Pituitary of ornithorhynchus Figure 34. Section of pars anterior of ornithorhynchus Figure 35. Section of pars posterior of ornithorhynchus Figure 36. Section of pars nervosa of ornithorhynchus Figure 37- Pituitary of the opossum Figure 38. Section of pituitary of the opossum Figure 39. Pituitary of the ox .... Figure 40. Section of the pars nervosa of the ox . Figure 41. Pituitary of the sheep .... Figure 42. Section of distal epithelial portion of pituitar Figure 43. Section of distal epithelial portion of pituitar Figure 44. Pituitary of the pig .... Figure 45. Pituitary of the guinea-pig . Figure 40. Pituitary of the rabbit .... Figure 47. Pituitary of the cat .... Figure 48. Section of pituitary of the cat Figure 49. Section of pars intermedia of the cat . Figure 50. Section of pars intermedia of the cat . Figure 51. Pituitary of the dog .... Figure 52. Section of pars intermedia of the dog . Figure 53. Section of pars intermedia of the dog . Figure 54. Pituitary of the hedge-hog . Figure 55. Section of pars anterior of the hedge-hog Figure 56. Pituitary of the lemur .... Figure 57. Section of pars posterior of the lemur . Figure 58. Section of pars anterior of the lemur Figure 59. Pituitary of the monkey Figure 60. Pituitary of Man ..... y of sheep y of sheep 47 49 50 50 51 53 55 56 57 57 .">!', 59 61 62 (52 63 64 64 65 0.1 66 67 68 68 69 70 71 72 72 73 74 75 75 76 PART II FACING PAGE of cat after thyroidectomy during Plate 3. Section of pars anterior pregnancy ........... Plate 4. Section of pars anterior of non-pregnant cat after thyroidectomy Plate 5. Section of pars anterior of non-pregnant cat after oophorectomy Plate 6. Section of pars intermedia of non-pregnant cat after oophorectomy Plate 7. Section of pars anterior of non-pregnant cat after removal of suprarenals .......... 186 187 192 193 199 ILLUSTRATIONS xvii PAGE Figure 61. Section of pars anterior of pregnant rabbit 84 Figure 62. Section of pars anterior of pregnant rabbit 84 Figure 63. Section of pars anterior of pregnant guinea-pig .... 86 Figure 64. Section of pars anterior of pregnant woman 86 Figure 65 a. Section of pituitary of non-hibernating hedge-hog ... 88 b. Section of pituitary of hibernating hedge-hog .... 88 Figure 66 a. Section of pars anterior of laying hen 90 I?. Section of pars anterior of non-laying hen . . . . .90 Figure 67. Section of'human pars anterior, showing colloid .... 93 Figure 68. Section of human pars anterior, showing lipoids .... !»4 Figure 69. Section of pars nervosa of cat, showing granular bodies . . I'll Figure 7". Kymograph-tracing showing effect of infundibulin on blood- pressure and uterine contractions ...... 107 Figure 71. Kymograph-tracing showing effect of infundibulin on contractions of distended bladder . ..... Facing page ll'» Figure 72. Kymograph-tracing showing effect of infundibulin on contractions in the empty bladder ..... Facingpage 110 Figure 73. Uterine cannula . . . . . . . . . .Hi' Figure 74. Kymograph-tracing showing defecation caused by infundibulin . 113 Figure 75. Kymograph-tracing showing effect of infundibulin on intestine Facing page 114 Figure 76. Kymograph-tracing showing effect of infundibulin on intestine Facing page 114 Figure 77. Kymograph-tracing showing effect of infundibulin on rate of milk-expulsion . . . . . . . . . .llti Figure 78. Kymograph-tracing showing effect of infundibulin on rate of milk-expulsion . . . . . . . . . .llti Figure 79. Section of adjacent mammae, one of which had been emptied by infundibulin . . . . . . . . . .117 Figure 80. Sections of mammae showing filling of alveoli after injection of infundibulin . . . . . . . . . .118 Figure 81. Apparatus for administration of intra-tracheal ether . . . I"' 11 Figure 82. View of operating-table . . . . . . • .132 Figure 83. View of operating-table . . . . • • • .132 Figure 84. Hitch"- bead showing line of incision for removal of pituitary . L33 Figure 85. Field of operation after bilateral opening has been made . . L34 Figure 86. Radiograph of bitch's head after operation ..... 135 Figure 87. Soft metal spoon-shaped retractor ...... L3o Figure 88. Hooked-knife for incising dura ....... Ki<> Figure 89. Field of operation with pituitary exposed 137 Finnic 90. Angular forceps ...•■••••• 138 Figure 91. Aural forceps .....•••■• 138 Figure 92. Chisel-hook '-'is Figure 93. Watson-Cheyne's dissectoi 139 Figure 94 \. Bitch before control operation ....-•• 14'-' B. Bitch after control operation . ■ • • • • .142 Figure 95. Section showing anterior and posterior lobes removed al operation I 13 Figure 96. Section of base of brain at site of removal of pituitary . . . 143 XV111 ILLUSTRATIONS Figure 97. Section of pars anterior removed by operation Figure 98. Section of pars anterior removed by operation Figure 99 a. Bitcb before partial removal of pars anterior B. Bitch after partial removal of pars anterior Figure 100. Section of pars anterior removed by operation Page 145 148 149 149 150 Figure 10* Fit I'i 108 Figure 101 a. Section of uterus of bitcb before partial removal of pars anterior 151 B. Section of uterus of bitcb after partial removal of pars anterior 151 Figure 102. Section of pars posterior removed by operation .... 152 Figure 103. Section of base of brain at site of removal of pars posterior . 152 Figure 104 a. Bitch before removal of pars posterior ..... 154 B. Bitch after removal of pars posterior ..... 154 Figure 105 a. Section of uterus of bitch before removal of pars posterior . 155 B. Section of uterus of bitch after removal of pars posterior . 155 Figure 10(5. Section showing partial removal at operation of pars anterior and pars posterior .......... 157 Bitch before compression of infundibular stalk . . . 160 Bitch after compression of infundibular stalk .... 100 Bitch before separation of infundibular stalk .... 161 Bitch after separation of infundibular stalk .... 161 jure 109. Bitch opened to show fat-deposit and atrophied uterus after separation of infundibular stalk ...... 162 Figure 110 A. Section of uterus before separation of infundibular stalk . . 163 B. Section of uterus after separation of infundibular stalk . . 163 Section of the pars anterior after compression of infundibular stalk 164 Bitch after insertion of an artificial tumour in neighbourhood of pituitary ........... 17-"> Radiograph showing artificial tumour in situ .... 174 Section showing cyst in pars anterior caused by artificial tumour 175 Radiograph showing artificial tumour in situ .... 176 Section showing displacement of the lobes of the pituitary by an artificial tumour ......... 177 Section of pars anterior of guinea-pig after injections of extract of pars anterior ......... 181 Section of suprarenal cortex after injections of extract of pars anterior ........... 181 Section of pars anterior of pregnant cat after thyroparatbyroid- ectomy ........... 184 Figure 120. Section of pars nervosa of pregnant cat after thyroparathyroid - ectomy ........... 184 Section of pars anterior of puerperal cat after thyroidectomy . 185 Section of pars intermedia of puerperal cat after thyroidectomy 186 Section of pars anterior of cat after thyroidectomy during pregnancy .......... 186 Section of pars intermedia of non-pregnant cat after thyroid- ectomy 188 Section of thyroid of dog after removal of pituitary . . . 191 Section of thyroid of dog after compression of infundibular stalk 191 Figure 111. Figure 112. Figure 113. Figure 114. Figure 115. Figure 116. Fit I'i m 118. Figure 111). Figure 121. Figure 122. Figure 123. Figure 124. Figure 125. Figure 126. ILLUSTRATIONS xix PAGE Figure 127. Section of pars anterior of non-pregnant cat after oophorectomy 193 Figure 128. Section of reticulated portion of pars intermedia after oophor- ectomy ........... 194 Figure 120. Section of pars posterior of non-pregnant cat after oophorectomy 194 Figure 130. Sections of ovaries of bitch before (a) and after (is) partial removal of pars anterior ........ 196 Figure 131 a. Section of ovary of bitch before separation of infundibular stalk 107 B. Section of ovary of bitch after separation of infundibular stalk 1 1)7 Figure 132. Sections of ovaries of bitch before (a) and after («) removal of pars posterior .......... 198 Figure 133. Section of pars posterior of cat after removal of suprarenals . 200 Figure 134. Section of pars nervosa of cat after removal of suprarenal- . 200 Figure 135. Section of pars anterior of cat after removal of suprarenals . 201 Figure 136. Section of pars posterior of cat after removal of suprarenals . 201 Figure 137. Section of thymus of the bitch ....... 204 Figure 138. Section of pars anterior of normal guinea-pig .... 208 Figure 139. Section of the pars anterior of guinea-pig after injections of emulsion of colon bacillus ....... L'Oii Figure 140. Section of the pars anterior of guinea-pig after injections of emulsion of staphylococcus ....... 20!t PART III Figure 141. Radiograph of sella turcica in case of acromegaly . . . 221 Figure 142. Base of skull in case of acromegaly ...... 222 Figure 143. Radiograph of sella turcica in case of acromegaly . . . l'l':'. Figure 144. Radiograph of sella turcica in case of acromegaly . . . l'l'.'! Figure 145. Acromegaly in a woman . . . . . . . . l'2 I Figure 14(5. Radiograph of hand of woman suffering with acromegaly Facing /»i Figure 148. Acromegaly in woman, showing separation of the teeth . . l'l'."> Figure 149. Fields of vision in case of acromegaly ..... L'27 Figure 150. Fields of vision in case of acromegaly ..... 228 Figure 151. Median sections of normal pituitary and pituitary from case of acromegaly . . . . . . . . . .231 Figure 152. Section of pars anterior removed from case of acromegaly . . 233 Figure 153. Case of general infantilism due to pituitary insufficiency . . 237 Figure 154. Radiograph of sella turcica in case of general infantilism . . 238 Figure 155. Case of dystrophia adiposogenitalis ...... 239 Figure 156. Radiograph of sella turcica in case of underdevelopraenl of pituitary 240 Figure 157. Case of dystrophia adiposogenitalis ■ • ■ ■ • . I'll Figure 158. Fields of vision in case of dystrophia adiposogenitalis . . . 242 Figure 159. Left fields of vision in case of dystrophia adiposogenitalis, showing progression towards blindness ....... XX ILLUSTRATIONS Figure 1(50. Radiograph of the sella turcica in case of dystrophia advposo- genitalis ........... Figure 161. Section of the pars anterior from case of dystrophia adiposo- genital ........... Figure 162. Case of Addison^s disease and acromegaly in a man Figure 163. Section of pars anterior of young woman, showing a chromophobe tumour ........... Figure 164. Section of the suprarenal of young woman, showing hyperplasia Figure 165. Radiograph of the sella turcica in case of loss of sight Figure 166. Diagram showing the optic nerves and tracts . . . . Figure 167. Cholesteatoma in neighbourhood of pituitary . . . . Figure 168. Erosion of posterior clinoid process l>y cholesteatoma . Figure 169. Section of pars anterior of cretin ...... Figure 170. Section of pituitary of cretin Figure 171. Section of pars anterior in case of parenchymatous goitre . Figure 17-. Section of pituitary in case of parenchymatous goitre Figure 173. Section of pars anterior in case of exophthalmic goitre Figure 174. Section of pars anterior in case of eclampsia . . . . Figure 175. Section of pituitary in case of eclampsia . . . . . Figure 176. Section of pars posterior in case of eclampsia . . . . Figure 177. Section of pars anterior in case of cortical necrosis of kidneys . Figure 178. Section of pars intermedia in case of cortical necrosis of kidneys Figure 179. Diagrams showing incisions for various operative procedures that have been adopted ........ Figure 180. Sectional measurements in relation to sella turcica Figure 181. Directions of approach in intracranial operations Figure 182. Frazier's orbitofrontal method of approach . Figure 183. Directions of approach in extracranial operations Figure 184. First stage of submucous inferior nasal operation Figure 185. Second stage of submucous inferior nasal operation Figure 186. Third and fourth stages of submucous inferior nasal operation 243 247 250 251 252 254 256 260 261 263 263 265 265 266 273 273 274 274 275 283 285 287 290 292 295 296 297 PART IV Figure 187. Kymograph-tracing showing effect of infundibulin in primary uterine inertia .......... 314 Figure 188. Kymograph-tracing showing effect of infundibulin in secondary uterine inertia .......... 314 Figure 189. Chart showing effect of infundibulin in secondary uterine inertia 316 Figure 190. Kymograph-tracing showing tetanic contractions followed by rhythmical contractions, after an injection of infundibulin . 318 INTRODUCTION After many centuries spent in unprofitable speculation and fruitless investigation, the far-reaching — the vital— importance of the Pituitary has at last come to be fully recognized. To those who have made a study of the history of the sub- ject the extraordinary vicissitudes that have accompanied the acquisition of our knowledge of the Pituitary Body, and the strange lapses into oblivion when recognition of its importance seemed within our grasp, are almost incredible. For ages a subject of curiosity and of strange beliefs — as witness the very name, derived from pituita, meaning phlegm, which by Galen and other ancient writers it was supposed to secrete into the nasal cavity 1 — this structure is now the object of the keenest scientific interest. The Pituitary Body is an organ of internal secretion, and is, as we shall see later, of vital importance to the animal organism. The phenomenon of internal secretion, or hormonopoiesis, is fully recognized in regard to many individual hormonopoietie organs ; but the problem of the correlation of the internal se- cretions of the coordinated system of hormonopoietie organs, of which the Pituitary forms a part, is very complicated, and for the most part imperfectly understood, although it is now acknow- ledged by most authorities that this correlation is a close one, and that the influence of any one of the hormonopoit t ic organs on the metabolism cannot be completely considered aparl from the interaction of the rest. 1 Vieussens, Sylvius, and other ancient writers considered thai the Pituitary was concerned in the formation of the cerebrospinal fluid. Commenting on this view Cushing calls attention to the fact that cerebrospinal fluid, which, following Herring, he thinks receives secretion directly from the Pituitary, m a\ in certain pathological circumstances escape from the nose. Richard Lower, in a tract (Dissertatio tie Origine Catarrhi) published in l .^r. Fig. 8. Section of the pituitary region of a human fcetus 16 mm. in length, serial to but further back than the section shown in figure 7. The infundibular process has descended between the lateral ' horns ' of the isolated Rathke's pouch. (From a section kindly lent by J. E. Frazer.) X60. is seen (fig. 10) to be closely related to a solid neural process. The main part of the hypophysis — that is, the distal epithelial portion, or pars anterior — has a glandular appearance owing to the mode of growth already described ; and the residual lumen of the hypophysis — the remains of Rathke's pouch from which diverticula can be traced, is closely applied on its posterior surface to the neural process. This thin posterior wall of the central cavity of the hypophysis eventually forms the pars 12 MORPHOLOGY A U B Diagrammatic representations of the pituitary of a human foetus 16 mm. in length seen in sections in figures 6, 7, and 8. A. Side-view. B. Back- view. C. Sectional side-view: a, line of vertical transverse section seen in figure 6; b, line of vertical transverse section seen in figure 7 ; c, line of vertical transverse section seen in figure 8. DEVELOPMENT OF THE PITUITARY 13 intermedia, or juxtaneural epithelium (see fig. 5). It will also be observed in the section (fig. 10) that the lateral ' horns ' of the hypophysis have encircled the neck of the infundibulum ; and that the pars anterior extends well in front of the infundib- ular process (compare with figs. 6, 7, 8). ft* v.x% •*■« •'■■■■: I *-- ■...■ S ska Fig. 10. Section of the pituitary of a human foetus 75 mm. in length. X 60. Ultimately in mammals the branching processes of the pars anterior fuse, or become compressed together, to produce a more or less compact structure. In elasmobranchs this tubular, or branching, arrangement is the final state of development. The last stages in the formation of the pituitary in mammals are unimportant developmentally. As we shall see, certain variations of configuration occur in the different orders ; con- sequently the fully developed organ can best be described from anatomical — general and comparative — points of view. §ii. ANATOMY OF THE PITUITARY MACROSCOPICAL ANATOMY The actual conformation of the pituitary and of the bony bed in which it is situated varies considerably in different animals, but in all there is a close relationship between the two so far as their outlines are concerned. General characteristics. — If the fresh pituitary be cut in transverse section the anterior lobe is found to be soft but tough in consistence, and pink or yellowish-pink in colour, in marked contrast with the posterior lobe which is very soft and paste-like, and pearly white in colour. In all mammals the pars anterior, or distal epithelial portion, is much larger than the pars posterior ; but the relationship of the two parts the one to the other varies in the different orders, as we shall see later. In the human subject, the posterior aspect of the pars anterior tits like a cap on the convex anterior surface of the pars posterior (fig. 11) ; the two lobes are separated by a narrow cleft, which, as already stated, represents the residual lumen of Rathke's pouch ; and the pars nervosa is covered in varying degrees in front and laterally by the epithelium of the pars intermedia (juxtaneural epithelium). In man the pars nervosa is solid, the central cavity having disappeared in the process of develop- ment. The anterior and posterior lobes are easily disjoined by coarse dissection. The dimensions and weight of the pituitary. — The dimen- sions and weight of the pituitary vary somewhat in different individuals of the same species, and these variations are de- pendent on the age, and to some extent on general bodily ANATOMY OF THE PITUITARY 15 development. But in spite of this general relationship between the size of the body and the size of the pituitary, the interest- ing and important fact has been noted that the pituitary is relatively larger in adult, parous females, especially in multi- parse, than in nulliparae and in males. In regard to the weight of the pituitary, Caselli 1 found that in fifty men the average weight of the pituitary was 0*667 Fig. 11. Median horizontal section of the adult human pituitary. The pars anterior is below, and the pars nervosa above. X 5. gramme, and in fifty women 0*731 gramme. The material for this investigation was obtained from asylums. Halliburton, Candler, and Sykes 2 found that in eighteen adult males, the average weight of the fresh pituitary was 0*469 gramme, yet in only four cases did the organ weigh more than 0*5 gramme. On the other hand, in twenty-four females the 1 Caselli, A., Studi Anat. e Speriment. Fisiopatologia d. Glandola Pihiitaria. Reggio nell' Emilia, 1900. 2 Halliburton, W. D., J. P. Candler, and A. W. Sykes, Quart. Journ. Exper. Physiol .. 1909, ii, 229. 16 MORPHOLOGY average weight of the fresh gland was 0*567 gramme, and in only four of these cases did the organ weigh less than 0*5 gramme. All the material used in this investigation, also, was obtained from asylums. Erdheim and Stumme 1 , in an extensive study of this question, obtained the following results with regard to the gravimetrical differences in human pituitaries. In males during the second decade of life the average weight was found to be 0*563 gramme ; during the third decade, 0*593 gramme; and during the fourth decade, 0*643 gramme. In the later years of life the weight of the pituitary was observed gradually to decrease. With regard to females, these observers found that in nulliparae the average weight of the pituitary was approximately the same as in men ; and the maximum weight obtained during the reproductive period was 0*75 gramme. In primiparae recently confined the average weight was 0*847 gramme ; whilst in multiparas at the end of pregnancy the average weight was 1 *06 gramme. The maximum weight found in a primiparous woman was 1*10 gramme, and in a multiparous woman 1*65 gramme. Li von 2 , also, has summarized his own investigations and those of previous observers concerning the weights and sizes of the pituitary in Man and in the commoner mammals. Here we are only concerned with these questions in reference to the human subject, for it is usual for scientific investigators to make their own control observations concerning such matters in connexion with their experimental studies. Livon's observations were made on pathological material ; consequently, as he himself points out, they are, possibly, not of much value. This objection, however, obtains in practically all the investigations that have been made on this subject. Further, in the collected statistics given by this author no mention is made of sex-distinctions ; and this omission renders the figures quite valueless in the light of modern knowledge. Schonemann 3 , Comte 4 , and others have noted that the weight of the pituitary in Man varies according to the age ; and 1 Erdheim, J., and E. Stumme, Beitr. z. Pathol. Anal. u. z. Allg. Pathol, 1909 xlvi, 1. 2 Livon, Ch., Marseille Mddical, 1909 (No. 22), 683. 3 Schonemann, A., Virchow's Arch. f. Pathol. Anat. n. Physiol., 1892, cxxix, 310. 4 Comte, L., Beitr. z. Pathol. Anat. u. z. Allg. Pathol, 1898, xxiii, 90. gr. 013 55 0-30 55 0-53 55 0'60 • • 55 0-67 ANATOMY OF THE PITUITARY 17 the approximate figures derived from these studies are as follows : — New-born infant From 1 to 10 years From 10 to 20 ., From 20 to 30 ,, From 30 to 40 „ But in regard to these estimations, also, no allowance appears to have been made for sex-differences, so the figures are of value only in that they show the relative increases of weight with age up to a certain period. After middle life most investigators agree that there is a gradual decline in the average weight of the pituitary. It will be seen that there is some discrepancy between the various sets of figures recorded above, even when sex was taken into consideration ; but it is possible to account for this by assum- ing that the different observers employed different methods for collecting their material. The outstanding fact, however, is the influence of pregnancy in causing an increase in the weight of the organ. We shall have to consider this matter again when studying the histology of the pituitary in relation to its functions. The dimensions, like the weight, of the normal human pituitary appear to vary somewhat. Livon 1 gives the following table of measurements, which was compiled from various sources : — teroposterior diameter. mm. 6-8 8 Vertical diameter. mm. 6-8 6 Transverse diameter. mm. 12 12-15 Authors. Sappey Testut 5-7 5-7 15 Poirier 6-8 6 12-15 Thaon 8 6 12-15 Paulesco 10 5-5 15 Livon Here, again, we find some divergence in the figures, and this is no doubt due to an uneven admixture of the sexes and patho- logical conditions present, and possibly to the employment of different methods of measurement. Erdheim and Stumme 2 , also, record their observations on 1 Livon, Ch., Marseille Medical, 1909 (No. 22), 683. 2 Erdheim, J., and E. Stumme, Beilr. z. Pathol. Anal. u. z. Allg. Pathol., 1909, xlvi. 1. 18 MORPHOLOGY this point. These investigators give the following average figures for adult men : transverse diameter, 14*4 mm. ; anteroposterior diameter, 11*5 mm. 1 ; and vertical diameter, 5 5 mm. In nulli- parous adult women the average measurements were found to be 14*4 mm., 11*5 mm., and 5*9 mm. respectively. These figures show that the dimensions, like the weights, are almost identical in adult men and nulliparous adult women ; but they differ considerably from some of the collected figures given by Livon. The sella turcica and the anatomical relations of the pituitary. — -The fully developed pituitary is an intracranial organ, the epithelial part derived from the ectoderm of the stomodeum having become completely shut off at a very early period from the buccal cavity by the development of the cartilage in which the basisphenoid bone is laid down. In this way the pituitary comes to lie on the body of the sphenoid in a recess known as the ' sella turcica ' (Turk's saddle) owing to its shape : the cavity is hollowed out in the centre from before backwards, and, in the human subject, slopes away at the sides, while the saddle-like appearance is further emphasized by the anterior and posterior clinoid processes which overhang the seat of the ' saddle ' before and behind (fig. 12). It is obvious that the size of the pituitary is definitely related to the dimensions of the sella turcica, but very few accurate observations have been made on the capacity of this fossa. Gibson 2 , in an examination of 107 skulls, found that there are normally very considerable variations in the size, shape, and bony relations of the sella turcica. The average dimensions of this fossa — that is, of one reconstructed from all the fossae examined — were found to be 12 mm. in the anteroposterior diameter, and 6 mm. in the vertical. Cope 3 examined fifty skulls and obtained the following average figures in regard to the size of the sella turcica : the anteroposterior diameter measured 10-94 mm., the transverse diameter 11*02 mm., and the vertical diameter 5 - 82 mm. 1 In the original paper there is a misprint or miscalculation in the average figure, which is stated to be 21*5 mm. This error has been copied by Biedl. 2 Gibson, W. S., Surg. Qyncecol. ObsteL, 1912, xv, 199. 3 Cope, V. Z., Brit. Journ. Surg., 1916, iv, 107. ANATOMY OF THE PITUITARY 19 According to Gushing 1 , the average measurement of the sella turcica as seen in a skiagram — obviously an imperfect method — are as follows : the anteroposterior diameter is about 15 mm., and the depth of the fossa about 9 mm. These measurements Fig. 12. The base of the skull in the human subject with a normal sella turcica. (Photograph.) X ], appear to err on the generous side, for a majority of X-ray photographs show that the sella turcica is of a smaller size (fig. 13a), although the larger may be normal (fig. 13b). X-ray 1 Cushing, H.. The Pituitary Body ami its Disorders, 1912. 20 MORPHOLOGY Fig. 13a. Radiograph of a normal sella turcica in the living human subject, posterior diameter measures 11 mm. (By Thurstan Holland.) The antero- Fig. 13b Radiograph ot a normal sella turcica in the living human subject. The antero- posterior diameter measures 14 - 5 mm. (This excellent photograph was taken recently by Thurstan Holland with a new method of centering.) X}- ANATOMY OF THE PITUITARY 21 photographs, therefore, demonstrate the fact that even in per- fectly normal individuals there is a considerable degree of variation in the size of the sella turcica. Fitzgerald 1 has investigated the dimensions of the sella turcica in over 100 skulls of both sexes, and after making careful measurements he found that the size, and to a less extent the shape, of the pituitary fossa is related to certain measurements at the base of the skull, and that these are uninfluenced by sex. It was observed that if measurements be taken from the tip of the ethmoidal spine to the anterior limit of the optic groove (anterior measurement), and from the opisthion to the middle of the sella turcica (posterior measurement), the length of the pituitary fossa is found to vary directly with the posterior measurement, and inversely with the anterior ; that is to say, a long anterior measurement and short posterior are associated with a short fossa, and vice versa. The following table, to which appropriate headings have been added, of the average measurements of the sella turcica in relation to the average anterior and posterior cranial measurements mentioned, taken from Fitzgerald's paper, illus- trates this point, and also shows the relation of these measure- ments to the shape of the fossa, although the latter is subject to variations. Table I ON ANTERIOR MEASUREMENT Anterior measurements n«i n +«i „„„ „ „ „, * * ,< * basis cranii. Related average measurements of sella turcica Length. Breadth. Front depth. Hind depth. Large (23-27) mm. . . 10-5 mm. 17 mm. 8-5 mm. 7-7 mm. Medium (20-23) mm. 11 mm. 17 -5 mm. 7 mm. 6*5 mm. Small (15-20 mm.) .. 13 mm. 16*5 mm. 8 mm. 7 mm. ON POSTERIOR MEASUREMENT Posterior measurements basis cranii Related average measurements of sella turcica. Length. Breadth. Front depth. Hind depth. Large (above 70 mm.) 14 - 5 mm. 17 mm. 7 mm. 7 - 5 mm. Medium (65-70 mm.) 12 mm. 15 mm. 8 mm. 7 mm. Small (under 65 mm.) 10 mm. 14 mm. 6*5 mm. 6 - 5 mm. The measurements basis cranii are in each part of the table divided into three groups— large, medium, and small. 1 Fitzgerald, D. P., Joum. Anal, and Physiol, 1910, xliv, 231. 22 MORPHOLOGY If we add together the average measurements of the sellse turcica? given in the above tables, we arrive at the following approximate average dimensions for this fossa : anteroposterior diameter, 11-8 mm. ; transverse diameter, 15-1 mm., and vertical diameter, 7*2 mm. It is difficult to explain why such divergent average figures of the measurement of the sella turcica have been obtained by different observers, unless different methods of measurement have been employed. The relation of the sella turcica to the sphenoid bone and to the sphenoidal cells is a matter of considerable anatomical interest, and also of surgical importance as we shall see later when we consider the methods of approach to the pituitary. In the human subject the pituitary fossa is developed in the basisphenoid (postsphenoid) ; but in some animals, such as the pig, and even rarely in man, the presphenoid may take part in the formation of the anterior wall of the sella turcica 1 . The craniopharyngeal canal, which becomes occluded, and so causes Rathke's pouch to be shut off from the oral cavity, passes through the anterior part of the basisphenoid, a fact that has been emphasized by Haberfeld 2 , Cope 1 , and others. The sphenoidal cells are very inconstant in their configuration and their relationship to the pituitary fossa (fig. 14). In early life the sphenoidal sinuses are small, and are limited to the presphenoid 3 . During childhood they enlarge, and gradually the presphenoid becomes hollowed out. The development of the sinuses may stop at this stage, or continue until the postsphenoid is either partly or completely excavated. The sella turcica may, therefore, be situated behind, or partly above and behind, or even completely above, the sphenoidal sinuses. There is, too, considerable variation in regard to the septa which may divide the sphenoidal cells. As a rule, the sinuses are situated mostly in the presphenoid, and are divided by a median anteroposterior septum, but this may be imperfect. If the sinuses should extend back into the postsphenoid, there is 1 Cope, V. Z., Brit, Joum. Surg., 1916, iv, 107. 2 Haberfeld, W., Zeigler's Beitr. z. Pathol. Anat, u. z. Allg. Pathol., 1909, xlvi, 133. 3 Onodi, A., The Accessory Sinuses of the Nose in Children, English translation, 1911. ANATOMY OF THE PITUITARY 23 usually a transphenoidal ridge marking the line of junction of the two parts of the sphenoid ; but horizontal or vertical septa, or both, are sometimes found dividing the sinuses from side to side Fig. 14. Macroscopical sections of the pituitary regions in human adults, showing varia- tions in the conformation of the sella turcica and the related sphenoidal cells. (After Gibson.) (fig. 14). These, as we shall see later, may give rise to confusion in regard to the position of the sella turcica during surgical procedures. 24 MORPHOLOGY The cavity of the sella turcica is lined with dura mater, and it is, also, covered in by a sheet of the same membrane, which is attached to the four clinoid processes and perforated for the passage of the stalk of the posterior lobe. This infundibular stalk arises from the floor of the third ventricle at the site of the tuber cinereum. Various important structures, apart from those just mentioned, are situated in immediate relationship to the pituitary. The circular sinus completely surrounds the organ. This sinus is com- posed of the cavernous sinuses on either side, and of the anterior and posterior communicating channels. The sella turcica itself is situated in the centre of the arterial circle of Willis, which is formed by the anterior communicating arteries joining the anterior cerebral arteries in front, by the internal carotids and posterior communicating arteries at the sides, and behind by the posterior cerebral arteries. The third nerves pass from behind forwards and above downwards on either side in close proximity to the pituitary ; and the third, fourth, ophthalmic division of the fifth, and the sixth nerves are in lateral relationship as they traverse the cavernous sinuses. Above and in front of the pituitary, and in front of the stalk, is situated the optic chiasma. The importance of these relationships is evident when we are called upon to consider the pressure-effects which may be pro- duced by an enlarged pituitary, or to operate upon this organ. Vascular supply of the pituitary.— -This has been studied by Herring 1 and by Dendy and Goetsch 2 , and it is chiefly to these workers that we owe our knowledge of the details concerning the blood-supply of this organ. Herring examined the internal circulations and showed that the main vessels of the pars anterior and of the pars posterior respectively are independent of one another. He found that, if the vessels be successfully injected with carmine gelatine, the pars anterior appears to be a close network of blood-vessels (fig. 15) — previously known to be the case from histological investigations (fig. 17) — and that the arterial supply of the pars anterior is obtained from the internal carotids by means of small arteries 1 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121. 2 Dendy, W. E., and E. Goetsch, Amer. Journ. Anal., 1911, xL 137. ANATOMY OF THE PITUITARY 25 which reach their destination by passing down the stalk. Some of the veins from this part of the pituitary run up the stalk and discharge into the large cavernous sinuses — designated the ' lateral sinuses ' by Herring — on either side of the pituitary ; while other veins appear to pass into the pars posterior (Herring), in which they run beneath the pars intermedia (fig. 15). The posterior lobe, on the other hand, is supplied by a median artery which enters the superoposterior surface (Gentes 1 ; Herring 2 ). This vessel arises from the junction of two symmetrical branches from the internal carotid (Dendy and Goetsch). It may be sug- •.Pars Posterior Pars Nervosa Pars Intermedia Fig. 15. The internal circulation of the pituitary of the cat. Herring of an injected 'pituitary. ) (After a photomicrograph by gested, therefore, that this artery be called the azygos artery to the pars posterior of the pituitary. The veins of the pars posterior are situated beneath the cells of the pars intermedia, and they unite to form venous channels, most of which pass out through the superoposterior surface in con- junction with the azygos artery, and empty into the cavernous sinuses, or into the posterior communicating channels. It is obvious, then, that the vascular arrangement is some- 1 Gentes, L., Soc. Sci. d'Arcachon Trav. des. laborat, Bordeaux, 1907, 129. 2 Herring, P. T., Journ. Exper. Physiol, 1908, i, 121. 26 MORPHOLOGY what peculiar. In the pars anterior the small vessels are sinus- oidal in arrangement and character ; and, so far as the arteries are concerned, they have an origin different from that of the artery to the posterior lobe. On the other hand, there is some connexion between the veins of the two lobes. This vascular distribution is a matter of importance in regard to the physio- logical interdependence of the two lobes — a question which will be discussed at length later. In general terms, the internal circu- lation of the pituitary may be described as being distinctive in regard to the epithelial portions, whereas in the pars nervosa the distribution of the vessels is not very different from that obtain- ing elsewhere on the surface of the brain in the neighbourhood. Dendy and Goetsch 1 studied especially the external connexions of the blood-vessels of the pituitary. They found that the arterial supply to the anterior lobe comes from a large number — often over twenty — small branches of the internal carotids and the anterior communicating arteries of the circle of Willis, and that these arteries converge towards the stalk ; also, that many other vessels, which arise from the posterior part of the circle of Willis, pass over the corpora mamillaria to reach the posterior aspect of the stalk (fig. 16), down which run all the arteries to the pars anterior, as already described. The venous channels from the j3ars anterior take a course very similar to that of the arteries (fig. 16), and pass into the circular sinus — for the most part laterally into the cavernous sinuses ; while the veins from the pars posterior empty, as already men- tioned, into the posterior communicating sinus or into the caver- nous sinuses. It has been stated by Dendy and Goetsch that if a para- hypophysis — which is probably an accessory distal epithelial structure — be present, it has a blood-supply entirely separate from that of the rest of the pars anterior : small independent arteries reach this body from the internal carotids on either side, and, it is said, a single artery, arising in two trunks from the ununited arteries to the pars posterior ot the pituitary proper, enters the posterior aspect. This singular arterial distribution does not correspond with the view usually held that this body is an accessory pars anterior only, 1 Dendy, W. E., and E. Goetsch, Amer. Journ. Anal, 1911, xi, 137. ANATOMY OF THE PITUITARY 27 as is almost certainly the case. The venous blood from this struc- ture is said to be carried away by a single small vein which enters the floor of the sella turcica. If, then, the body be an accessory organ — and almost certainly it is an accessory pars anterior, judg- Fig. 16. Diagram to show the external arterial and venous circulation of the pituitary seen from below, as described by Dendy and Goetsch. ing from the structure of it and its situation over the site of the channel formed by the neck of Rathke's pouch — when it is pre- sent the separate blood-supply might permit the removal of the pituitary proper, wholly or in part, without the production of symptoms ; for the blood-supply of the accessory organ being 28 MORPHOLOGY uninjured, this structure might take on the functions of the parts removed. Nervous connexions with the pituitary. — These are related to the sympathetic system. The evidence concerning their pre- sence in the pituitary is histological, and will, therefore, be dis- cussed more fully presently. HISTOLOGICAL ANATOMY The finer details in the anatomy of an organ, such as the pituitary, are closely related to its functional energies ; consequently only a brief account of the histology of the epithelial cells will be given here. The significance of the histological appearances of the secretory elements will be discussed in con- nexion with the physiological aspect of the subject (p. 82). It has been mentioned that in the mammalian pituitary there are three easily recognizable parts — the distal epithelium, the juxta- neural epithelium, and the pars nervosa — and that the last two together form the pars posterior. Pars anterior (distal epithelium) is composed of well- defined epithelial cells supported by a framework of fine, but tough, connective tissue, and separated into groups by large blood-vessels and sinuses whose walls are lined with a single layer of endothelium (fig. 17). Hannover 1 in 1844 first called attention to the occurrence of more than one type of cell in the pars anterior of the frog and Man. He found that the same structure in the fowl consists almost exclusively of one variety of small cells. No further observations of importance appear to have been made until the year 1884, when Flesch 2 and Dostoiewsky 3 , working independ- ently, described cells of two different types — the chromophil and chromophobe. To Lothringer 4 , however, is due the credit of showing definitely the staining affinities of these dissimilar cells. 1 Hannover, A., Eecherches Microscopiques sur le System Nerveux, 1844, 26. 2 Flesch, M., Tageblatt der 57 Versammlung Deutscher. Nafurforscher und Aerzfe zu Magdeburg, 1884, 195. (Quoted by Dostoiewsky.) 3 Dostoiewsky, A., Arch. f. Mikr. Anal, 1886, xxvi, 592. 4 Lothringer, S., Arch. f. Mikr. Anat., 1886, xxviii, 257. ANATOMY OF THE PITUITARY 29 Many subsequent workers, among whom Rogowitsch 1 , Steida 2 , Pisenti and Viola 3 , Schonemann 4 and Launois 5 were the most prominent, have confirmed and extended these observations. Three varieties of epithelial cells are found in the pars anterior. Whether these cells are distinct varieties or only the same type of cell in different stages of functional activity will be discussed later. At the moment we are only concerned with the general histological appearances. • o . « • e g *e % % - C> a*, " . - Z- ' ' G 1 : > ■ < ft c n -> Fig. 19. Section of the normal human pars anterior, showing groups of basophil cells. X300. as will be explained in discussing the physiological significance of these cells, such well-marked basophils do not surround masses of secretion, although sometimes a dark homogeneous basophil cell is seen in the wall of a vesicle surrounding baso- phil colloid (plate 2) : for the most part the cells surrounding this substance are chromophobe or lightly eosinophil. Colloid material is, too, sometimes seen in the blood-vessels and sinuses (Thaon). Many investigators have described nerve-fibres and cells in 32 MORPHOLOGY the pars anterior, but Berkley 1 was the first to give a complete and accurate account of the distribution of the nervous elements. This investigator found that only sympathetic nerve-fibres from the carotid plexus are present, and that there are no true nerve-cells or fibres in this part of the pituitary. These sympathetic fibres, which are very fine and varicose, come off the main stem approxi- mately at a right angle, cross the sinuses to run an irregular course among the epithelial cells, and finally break up into Fig. 20. Section of the normal human pars anterior, showing sympathetic nerve fibres. {Partly plwtomicrographic.) X300. branching terminations with numerous ball-shaped endings which lie in the intercellular tissue (fig. 20). Thaon 2 states that he has investigated the matter carefully and has failed to find any lymphatics Avhatsoever in the pars anterior. Caselli 3 , however, asserts that lymphatics are abundant, 1 Berkley, H. J., Brain, 1894, xvii, 515. 2 Thaon, P., Uhypophyse, Paris, 1907. 3 Caselli, A., Studi Anat. e Sperhnent. Fisiopatologia d. Olandola Pituitaria. Rea-gio nell' Emilia. 1900. ANATOMY OF THE PITUITARY 33 while Pisenti and Viola 1 and Herring 2 state that there is con- siderable doubt as to whether they exist or not. Edinger 3 believes that lymph-spaces separate the epithelial cells from the blood-sinuses. Most observers, however, agree that lymphatics, if present, must be extremely few in number. Pars intermedia {juxtaneural epithelium). This portion of the pituitary body was first identified and described by Pere- meschko 4 . As we have seen, the juxtaneural epithelium is differ- entiated from the distal epithelium (pars anterior) in the process of development. It is for the most part applied to the surface of the pars nervosa, which abuts on the cleft, and to the region of the neck ; but the extent and distribution of the juxtaneural epithelium varies enormously in different animals. In some, such as the cat and dog, the distribution is very extensive : not only is the epithelium applied to the surface of the pars nervosa, completely enclosing it, and collected in a large mass around the neck, but it extends, also, in a tongue-shaped projection along the base of the brain above the pars anterior (figs. 47 and 51). In these animals, too, the cells in the neighbourhood of the neck and above the pars anterior are arranged in the form of vesicles, which enclose much granular secretion (figs. 48 and 52). In the human pituitary colloidal secretion is sometimes found in the pars inter- media above the cleft, and also in the cleft itself. This secretion in the pars intermedia and cleft of the human pituitary is most frequently seen in the female during and just after pregnancy, and in old age in both sexes. The juxtaneural epithelium, however, in the human subject is very scanty and forms a thin layer covering the pars nervosa where it adjoins a very narrow cleft (fig. 21). At the upper limit of the cleft and around the stalk the cells are more numerous, but never occur in large numbers. The juxtaneural epithelium is usually faintly basophil, or neutrophil, in its staining reactions. The cells are finely granular and polygonal in shape. In those animals, such as the cat, in which there are many layers of epithelium lining the cleft, the 1 Pisenti, G., and G. Viola, Centralbl. f. die Med. Wissensch.. 1890, xxviii, 450. 2 Herring, P. T., Quart. Joum. Exper. Physiol, 1908. i, 121. 3 Edinger, L., Archiv. f. Mikr. Anal, 1911, lxxviii, 496. 4 Pereraeschko (no initial in the original), Virchow's Archiv., 1867, xxxviii, 329. 3 34 MORPHOLOGY distribution is unequal; consequently projections of wedge-shaped epithelial masses are frequently seen dipping down into the pars nervosa. In these circumstances, also, the epithelial elements lining the cleft are often flattened on the free surface and are triangular in shape, with an angle dipping down into the cells beneath ; and the cells which are in contact with the pars nervosa may, also, resemble in shape the foot-cells of the testicle. In many animals— but never in man — supporting spindle-shaped cells £ * %. . » '§> *■<>■• ** o° ° , o. o V ^ ♦ ** - /•'' . ' * ° a „ *L. ° -* «» * f 1 --- CS u * fl J ' « * o" < ?a - $> • *°* * ,5 ~ Q ° ^ oi - * '• " *4* ' * •' / * **> _ ■ »* * ~« ' ' # ». V * * "* • - - a " « r •,»* • « • * a „ * ^^»- '^ * ^ ^v * »***A *»** A »v •" " ,*,'» °"' *. - e ' • V _ f > * ¥*^ • ■»,. ^; Fig. 29. <- Anterior direction. Median sagittal section of the pituitary of the salamander {salamandra maculosa). {After Gentes.) I, infundibular process; PN, pars nervosa; JN, juxtaneural epithelium ; DE, distal epithelium ; C. capillary gland. Fig. 30. <— Anterior direction. Median sagittal section of the pituitary of the lizard {laccrta viridis). {After Gentes.) I, infundibular process ; H, infundibular recess ; PN, pars nervosa; JN, juxtaneural epithelium ; DN, distal epithelium; C, residual cavity. COMPARATIVE ANATOMY OF THE PITUITARY 51 on the hypophysis ; second, the well-defined but limited pars intermedia and the extensive distal epithelial portion in which the cells are closely related to its internal blood -supply. REPTILIA In some of the reptiles — lacerta viridis (Gentes, Herring) ; alligator mississijppiensis (Tilney) — an arrangement similar to '>. ^ w ^^^0^ Fig. 31. Median sagittal section of the pituitary of the tortoise (testiido europoea). (After Gentes.) H, infundibular recess; PN, pars nervosa; JN, juxtaneural epithelium ; DE, distal epithelium ; C, residual cavity. that just described is found in regard to the pars intermedia and pars nervosa, but the ramifications of the latter are greater (fig. 30). In some reptiles the pars ' posterior ' is superior to the pars ' anterior ', which forms as it were, a saucer below it (fig. 31). We shall see that this cup-and-saucer arrangement 52 MORPHOLOGY also obtains in some of the higher mammals. According to Tilney two types of cells are found in the pars anterior of the alligator — acidophils, which are centrally placed, and basophils at the periphery. The residual lumen or cleft is usually quite distinct. In the tortoise (testudo europcea), according to Gentes, the pituitary is more like that seen in birds and mammals than is the case in most other reptiles. There is very little irregularity in the surface of the pars nervosa, and there is an anterior tongue of the distal epithelial portion (fig. 31). Herring 1 , also, has described the histological features of the reptilian (testudo grceca) pituitary. He found that the distal epithelial portion is made up of numerous acini lined with cubical or columnar epithelium and filled with secretion. AVES Gallus domesticus. — In regard to the fowl, which has a type of pituitary common to many birds, investigators have not been entirely in agreement. Hannover 2 and Herring 3 state that the anterior lobe, which is in front of and below the posterior lobe (fig. 32), is made up of undifferentiated cells, and, in consequence, resembles parathyroid tissue. These cells are, they state, small and finely granular and are unlike the cells in the mammalian pituitary. On the other hand, Sterzi 4 , Gentes 5 and Tilney 6 describe chromophil cells in the pars anterior. The last-named also describes basophils which, he says, are situated almost entirely on the anterior margin of the cleft; whereas, according to the same observer, the eosinophils occupy the rest of the pars anterior, some staining lightly, others darkly. Herring was unable to find a cleft, but Tilney describes an " appreciable space or cavity ". In passing, it may be noted that Tilney appears to consider 1 Herring, P. T., Quart. Journ. Exper. Physiol., 1913, vi, 73. 2 Hannover, A., Becherches Microscopiques sur le System Nerveux, 1844, 26. 3 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 261. 4 Sterzi, A. (quoted by Gentes), Atti delV Accad. Sci. Veneto-Trentino-Istriana., 1904, i, 72. 5 Gentes, L., Soc. Sci. cF Arcachon, Travaux des laborat., Bordeaux, 1907, 129. 3 Tilney, F., Memoirs Wistar Instil Anal and Biol, Philadelphia, 1911 (No. 2), 1. COMPARATIVE ANATOMY OF THE PITUITARY 53 cells that would ordinarily be described as ' chromophobe ' as ' basophil '. I have myself examined the fowl's pituitary and have come to the conclusion that the divergence of opinion in regard to the character of the cells in the distal epithelial portion is due to the fact that different observers have examined pituitaries in different physiological states ; that is to say. that if hens be examined the appearance of the pituitary will be found to vary Fig. 32. Anterior direction. Median sagittal section of the pituitary of the fowl (gallus domesticus). (After Herring.) A, distal epithelium ; B, juxtaneural epithelium ; C, third ventricle. with the state of genital activity — a subject I shall discuss more fully in the appropriate place (p. 87). In the cock and in the egg-laying hen I have found that the distal epithelial portions are very similar : there are many eosinophil cells, with small, round, dark nuclei, mixed indis- criminately with neutrophil cells having large nuclei which show a chromatin network— an average field (fig. G6a, p. 90) shows a kaleidoscopical disregard of order and arrangement. It is in the brooding state that the cells assume a uniform type, as we shall see later. 54 MORPHOLOGY I have been unable to detect any cleft, but it is common to see in sections artificial separation of the distal epithelial cells from the neural process. The pars nervosa in the fowl is convoluted and hollow, and opens into the third ventricle. The pars intermedia is very- poorly developed, and is not spread uniformly on the pars nervosa ; the neck, however, is thickly covered. In this short survey of the morphology of the pituitary of creatures below the mammals several important facts have been recorded. First, in the elasmobranchs the pars posterior is not always present. Second, the cells of the pars anterior do not show acidophil and basophil differentiation in the lowest verte- brate forms investigated ; and in some the cells are arranged in acini with capillaries in the lumina. Third, the pars nervosa when present usually shows a hollow, branched or convoluted arrangement ; and, if we were to judge only by appearance, the close application of the pars intermedia cells to these hollow, branching processes, would lead us to the conclu- sion that the partes intermedia and nervosa together form a gland that discharges its secretion into the third ventricle. All these points will lie before us later when an attempt is made to discuss the functions of the pituitary. From this point we may continue our study of the compara- tive anatomy by a consideration of the pituitaries of represent- atives of different orders of mammals, some of which have repeatedly been described not only by the writers already named, but also by Lothringer 1 , Trautmann 2 and many others. It may be mentioned in the first place that there appears to be some relationship not only between the general contour of the pituitary, and the relative positions of the pars nervosa to the epithelial portions, but also between the general shape of the skull and the depth of the pituitary fossa. Thus we find that in long flat-headed animals, such as the dog (fig. 51) and the hedgehog (fig. 54), the pars nervosa is superior or supero- posterior to the epithelial portions, and the fossa is shallow; whereas in the short-headed animals, such as the ornithorhynchus (fig. 33), the cat (fig. 47), the lemur (fig. 56), the monkey (fig. 59) 1 Lothringer, S., Arch. f. Mikr. AnaL, 1886, xxviii, 257. 2 Trautmann. A., Arch. f. Mikr. Anat., 1909, lxxiv, 311. COMPARATIVE ANATOMY OF THE PITUITARY 55 and Man (fig. 60), the pituitary is situated in a deep fossa, and the pars nervosa is more directly posterior to the epithelial portions. MAMMALIA Monotremata. — Of the most primitive mammalian order (monotremata) only two species now exist — the echidna and the ornithorhynchus. I have had the opportunity of examining these animals ; but my material in regard to the echidna was not sufficiently well preserved to enable me to make satisfactory histological examinations. The pituitary of ornithorhynchus anatinus which has not, so far as I know, been described previously, is singularly interesting, in that it shows certain character- istics of the higher fishes and " v \ some reptiles with respect to the pars posterior. The organ is situated in a fairly deep fossa ; : ^. consequently its outline is found ■■■ ■''■':^ to be roundly oval in shape. / The pars anterior is round and convex in front and slightly con- i^l:ii^.- * cave behind. This posterior sur- F IG . 33. face is separated by a cleft from Anterior direction. — > the pars posterior which fits closclv to it (fio; 33) Median sagittal section of the „,.',,, . pituitary of ornithorhynchus. The cells of the pars anterior x 15. are both chromophil and chromo- phobe. The former are for the most part finely granular and eosinophil ; but here and there coarsely granular, spherical cells are to be seen, and these show gradations from a bluish- pink acidophilia to purple basophilia — variations that probably represent transitional phases from acidophilia to basophilia. The nuclei of the large dark cells are eccentric in position (fig. 34). The chromophobe cells are shrunken and ragged and have clear, lightly staining nuclei. Towards the infundibular stalk the cells, here and there, have an acinous arrangement. Granular secretion and colloid material, however, are very scarce. 56 MORPHOLOGY There is a considerable amount of supporting tissue among the cells of the pars anterior, especially towards the periphery, where spindle-shaped, kite-shaped, and long triangular nuclei stand out prominently among the epithelial cells. Blood-spaces are to be seen, but they are not very conspicuous. The cells of the pars intermedia of the ornithorhynchus entirely surround the pars nervosa in a thick layer ; and from the cellular capsule columns of cells pass deeply down and even completely through the pars nervosa (figs. 35 and 36). These t.d *' ■ * • \ Fig. 34. Section of the pars anterior of the orniihorhynchns. X 250. cells are polygonal in outline, are neutrophil in staining reaction and have rounded nuclei ; they appear to have no supporting tissue. A few small masses of granular secretion are to be found among the cells, but there is no evidence of any vesicular formation. The pars nervosa is peculiar in that not only is it channelled by the cells of the pars intermedia, but also it is divided up into lobules by fine, though dense, connective tissue trabecular in which flattened nuclei may be seen. It is noteworthy, also, that the invading columns of cells of the pars intermedia pass down COMPARATIVE ANATOMY OF THE PITUITARY 57 Fig. 35. Section of the partes intermedia and nervosa of omitJwrhynchus, X60. 2> o 9 9 © o 9; T/i 9© & 4$ & Fig. 36. Section of the pars nervosa of omithorhynchus, showing a column of pars intermedia cells passing down. X 400 58 MORPHOLOGY channels denned on either side by a layer of thin, tough con- nective tissue (fig. 36). There is distinct evidence, too, that those trabecular which do not enclose ingrowing columns of intermedia cells are nevertheless channels ; that is to say, the connective tissue is composed of two separate layers. There is, occasionally, some secretion to be found among the epithelial cells enclosed in the trabecular, and not infrequently these cells migrate and invade the neuroglial tissues proper, and even give rise to the formation of the so-called ' secretion-bodies '. As already stated, this invasion of the pars posterior by columns of juxtaneural epithelium recalls the branching arrange- ment of the pars nervosa seen in many fishes and reptiles ; and it represents, no doubt, a structural arrangement whereby an intimate and extensive relationship is established between the pars intermedia and pars nervosa. Marsupialia.— The pituitary of the marsupial has been de- scribed by Tilney 1 in the case of the opossum (didelphys virginiana). I, also, have examined the pituitary of this animal. Median sagittal section of the pituitary of the opossum {didelphys virginiana). X 15. The pars nervosa is situated superiorly, or slightly supero- posteriorly, to the distal epithelial portion (fig. 37). Tilney describes a central cavity in the pars nervosa and a lumen through the stalk leading to the third ventricle. In the specimen examined by me — an old male — there is a slit-like central cavity. 1 Tilney, F., Memoirs Wistar Instit. Anat. & Biol. Philadelphia, 1911 (No. 2), 1. COMPARATIVE ANATOMY OF THE PITUITARY 59 The pars nervosa is composed of neuroglial elements arranged in a peculiar manner ; that is to say, there is a dense band folded on itself like the lutein-layer in the ovary. Between the folds the neuroglial elements are loose. It is possible that the convoluted band is the remains of the edge of a large cavity lined with ependymal cells, which existed in an early stage of development. The juxtaneural epithelium entirely surrounds the pars ner- vosa, and is for the most part composed of one layer only of Fig. 38. Section of the pituitary of the opossum (didelphys virginiana). showing the distal epithelium, below and to the right, separated by the cleft from the pars nervosa which is covered with a single layer of juxtaneural epithelium. (Photomicrograph.) X 250. columnar epithelium, the cells of which have large, oval, central nuclei. Here and there the epithelial investment may be two or three cells in depth, but this is quite exceptional. Tilney, however, describes a layer several cells thick. But in the specimen examined by me the uniformity of the single- cell layer was remarkable and interesting (fig. 38). The cells of the juxtaneural epithelium are neutrophil. The distal epithelial portion is separated from the rest of the organ by a wide cleft ; and those cells which abut on this 60 MORPHOLOGY residual lumen are flattened on the surface and are tightly packed together (fig. 38). The distal epithelium is abruptly divided into two parts by differences in the staining affinities of the cells. In the anterior portion the cells are uniformly lightly basophil or chromophobe. The smaller cells have darkly staining nuclei, and the larger cells clear, round, central nuclei. In the posterior portion brightly staining eosinophil cells with small dark nuclei are mixed indiscriminately with large chromophobe cells containing large, round, clear nuclei. The cells of both parts of the distal epithelial portion are arranged in irregular branching columns. There are numerous blood-spaces, but there is very little intercellular connective tissue. Tilney has described dark basophils and colloid secretion in this part of the pituitary of the opossum. I have been unable to find either darkly staining basophil cells or colloid material. Ungulata.— The commoner domestic species — the ox, the pig and sheep — have probably been examined by numerous observers, but there are very few accounts of the pituitaries of the sheep and pig. The pituitary of the ox (bos taurus) has been described by Lewis, Miller and Matthews 1 , by Herring 2 and others. The whole gland is oval and is placed in a deep fossa with a narrow outlet for the infundibular stalk. The anterior lobe is oval and is separated from the posterior lobe by a cleft. The pars posterior is crescentic in shape — the concave aspect abut- ting on the cleft (fig. 39). The front, the lateral and the lower aspects of the pars nervosa and the entire circumference of the neck, are covered with cells of the pars intermedia, which con- sists of a layer many cells deep. This layer is thickest at the bottom and in the middle of the cleft (fig. 39). The pars nervosa is solid, and there is no invasion or dipping down of the pars intermedia, which forms an unbroken line. The anterior lobe is made up of brightly staining eosinophil cells, mixed indiscriminately with chromophobe, or faintly baso- phil, cells. No dark basophils are to be observed. The general 1 Lewis, D. D., J. L. Miller and S. A. Matthews, Amer. Arch. Med., 1911, vii, 785. 2 Herring, P. T., Quart. Journ. Exper. Physiol., 1914, viii, 245. COMPARATIVE ANATOMY OF THE PITUITARY 61 arrangement of the cells is more or less acinous ; but little or no colloid material is to be found. The pars intermedia consists of the usual faintly basophil cells which may assume an acinous arrangement near the neck. A striking feature of the pars intermedia in this animal is the number of large blood-vessels lying among the epithelial cells. The pars nervosa presents the same characteristic in regard to the blood-vessels, which are extremely numerous and large (fig. 40). In no other pituitary that I have examined has there been such a profusion of vessels through the whole of the nervous process. Fig. 39. Median sagittal section of the pituitary of the ox (bos taurus). X 7 'O. I have been unable to find secretion-bodies in the pars nervosa. Herring states that " they are very pronounced " ; but Lewis, Miller and Matthews assert that they are not a common phenomenon. The pituitary of the sheep (ovis aries) has been described by Peremcschko 1 and Tilney 2 . I, also, have examined this organ. It is stated by Tilney that the " hypophysis " — presum- ably the pars anterior — of this animal is divided and sub- divided by " a rich trabecular system " which gives it " the semblance of a tabulated organ" 2 . Tilney also states that the 1 Pererneschko (no initial in original), Virchoics Arch., 1867, xxxviii, 329. 2 Tilney, F., Memoirs Wistar Instil. Anal, and Biol., Philadelphia, 1911 (No. 2), 1. 62 MORPHOLOGY Fig. 40. Section of the pars nervosa of the ox (bos tavrus). showing many blood-vessels containing blood. X 100. Si Fig. 41. Median sagittal section of the pituitary of the sheep (ovis aries). neural process is seen to the left of the picture. The small X 7-5. COMPARATIVE ANATOMY OF THE PITUITARY 63 pars anterior is composed chiefly of eosinophil cells, each of which appears to have its definite place in the wall of a vesicle. There is no doubt that the pars anterior, especially at the inferior periphery, is subdivided into lobules by wide spaces (fig. 41). I think there is no doubt that these are blood- channels, for they are lined with endothelium (fig. 42). There is a rich vascular system, and the epithelial cells are arranged in a radial fashion around the sinuses (fig. 43). The eosinophils are certainly most prominent, but there are V*. Fig. 42. Section of the distal epithelial portion of the sheep (ovis aries) i showing spaces lined with endothelium. X 150. many faintly basophil, or neutrophil, cells which arc often found in large masses. The pars intermedia, which shows the usually faintly basophil staining affinity, is many layers in depth, and invests the pars nervosa in front and at the sides, and surrounds the stalk. The cells are arranged in columns radiating from the surface of the pars nervosa, and there is much supporting tissue. Colloid s( crction may be found in the cleft. The pars nervosa, which is solid, is very small, and I have 64 MORPHOLOGY been unable to find blood-vessels, except in close relation to the pars intermedia. - - 0' -v^t - - ' *\ . ' -• i ■ - ■. Fig. 43. 9 Section of the distal epithelial portion of the sheep (ovis aries), showing radial arrangement of the cells around a blood-channel. X375. I have, also, examined the pituitary of the pig (sus domesiicus). In this animal the organ is a long oval in shape (fig. 44). The anterior lobe is bluntly rounded anteriorly, and is slightly concave behind to accommodate the pars posterior which is pear-shaped, and is separated from the pars anterior by a cleft. The pars nervosa is entirely surrounded by the pars intermedia, which however does not form a thick layer except in the neighbour- hood of the cleft and around the stalk, which is entirely covered. The pars anterior has histological features exactly similar to those already described in regard to the pituitary of the ox. The pars intermedia shows the usual staining reaction. Here Fig. 44. Median sagittal section of the pituitary of the pig {sus domesiic- us). X7-5. COMPARATIVE ANATOMY OF THE PITUITARY 65 and there wedge-shaped masses of cells dip down a short way into the underlying pars nervosa. The pars nervosa shows a peculiar whorled arrangement of the fibres, the -general trend of which is towards the stalk. A number of blood-vessels is to be observed in this structure, but not so many as in the case of the ox. A few granular bodies may be seen in the neighbourhood of the pars intermedia. Rodentia. — Tilney 1 states that in rodents generally, the pars nervosa lies above the rest of the pituitary. Such, however, is certainly not the case in the guinea-pig and the rabbit. This author also states that in the rat (mus decumanus) the cells of the distal epithelial portion |v;\ are basophil in the neighbourhood k of the narrow cleft, and eosinophil : ' in the rest of the distal epithelial portion, and that the juxtaneural epithelium forms a deep layer of • 45, faintly basophil cells. In my ex- Median sagittal section of the pituitary perience, however, deeply staining of the guinea-pig (cavia familiaris). , , ., , . , 1 J x j 5 basophils are not seen in the pars anterior of the rabbit (Upus cunic- ulus), the guinea-pig (cavia familiaris) or the dormouse (mus- cardinus avellanarius), nor is granular secretion or colloid material to be observed. Faintly ba- sophil — really chromophobe — cells are fairly numerous, but most of the epithelial cells of the pars anterior are lightly eosinophil. In the guinea-pig the whole pituitary is somewhat elongated, and there is- a well-defined cleft (fig. 45). In the rabbit the cleft is ^ G - 46 - extremely narrow, so much Median sagittal section of the pituitary of so that the very regular the rabbit (lepus cunicuhs). X !£)• and thick pars intermedia appears to lie almost directly on the pars anterior (fig. 46). 1 Tilney, F., Memoirs Wistar Inslit. Anat. and Biol., Philadelphia, 1911 (No. 2), 1 5 66 MORPHOLOGY The pars intermedia (juxtaneural epithelium) thickly covers the pars nervosa. These cells stain faintly with basic dyes— a staining reaction that is universal in regard to the cells of the pars intermedia of all mammals. Carnivora. — Of this mammalian order the two most com- monly investigated types are the domestic dog {canis familiaris) and cat (felis domestical). These animals, however, present in their pituitaries widely different characteristics. ' "-" ' '-" •',"'' Fig. 47. Median sagittal section of the pituitary of the cat (felis domestica). The part enclosed in the white lines is shown more highly magnified in figure 48. X 15. In the cat the pituitary is situated in a very deep fossa ; consequently the pars nervosa is placed posteriorly, and the whole organ is almost round in shape (fig. 47). Probably the best description of this pituitary has been given by Herring 1 , who has directed special attention to the hollow space to be found in the pars nervosa and the opening through the neck which connects the cavity with the third ventricle. This space and the channel are lined with ependymal cells. Curiously, no 1 Herring, P. T., Qtoart. Journ. Exper. Physiol, 1908, i, 121. COMPARATIVE ANATOMY OF THE PITUITARY 67 mention is made of this cavity by Tilney in his description of the cat's pituitary, and his account is singularly poor in other respects, for, contrary to his statement, there is usually a considerable amount of secretion in the particularly well- developed acini in the neighbourhood of the neck (fig. 48). This acinous formation often extends along the base of the brain, under the third ventricle, in a most definite manner ; and the acini, in this region, are widely separated from one Fig. 48. Section of the pituitary of the cat (felis clomestica), showing more highly magnified the part enclosed in white lines in figure 47. X 50. another by an exceeding vascular connective tissue stroma (ng. 49). The juxtaneural epithelial cells (pars intermedia) in the cat completely surround the pars nervosa and the neck, and in some places the cells form wedge-shaped masses projecting in- wards (fig. 47). These juxtaneural cells stain rather more deeply than usual with the basic dyes. Supporting spindle- shaped cells are always found in this situation (fig. 50). The pars anterior is extremely vascular, and the epithelial 68 MORPHOLOGY ^,-y ^ctftfi* ft - vV* -> • in Fig. 49. Section of the reticulated portion of the pars intermedia of the cat (felis domestica), showing the vesicular arrangement of the cells which are lying in a loose connective tissue stroma containing large blood-vessels. X250. © o © & Fig. 50. Section of the pars intermedia of the cat (felis domestica) where it abuts on the cleft, showing supporting spindle-shaped cells. X 700. COMPARATIVE ANATOMY OF THE PITUITARY 69 cells form cither an arrangement of short branching columns, resembling the disposition of heart-muscle, or a more distinctly acinous grouping. The cells are for the most part eosino- phil, but many show a hazy, moderately deep basophilia, and it is not uncommon to see groups of quite definite basophils, although their colour-affinity is not so pronounced as in the human subject. Here and there, granular secretion may be found among the acini. Pale chromophobe cells with large, clear nuclei are plentiful. As in practically all mammals in which the pars intermedia is well developed, the cells of the distal epithelial part bordering on the cleft are closely packed and resemble the cells of the juxtaneural epithelium in appear- ance and staining reaction. . "/ ■' '■ ■'■■ t**?.* v 'r^^Hi'*"-, Fia. 51. Approximately median sagittal section of the pituitary of the dog (canis familiar is). The part enclosed in a white ring is shown more highly magnified in figure 52. X 15. In the pars nervosa of this animal the so-called 'secretion- bodies ' are frequently seen. The importance of these bodies will be discussed later (p. 97 and following). In the dog the pituitary is situated in a very shallow fossa at the base of the skull ; consequently the pars nervosa lies superiorly to the epithelial portions. The pars nervosa is solid, but there is a slight ventricular depression in the neck. There is a wide, irregular residual lumen or cleft, and the pars inter- media covers unevenly the whole of the neural process, while the distal epithelial part extends below the cleft like a saucer, with the largest mass of cells anteriorly (fig. 51). 70 MORPHOLOGY The ' anterior ' lobe is very vascular and there is but little supporting tissue. The cells are arranged in cords, and are, for the most part, faintly staining both with acid and basic dyes, more especially with the acid. Where the cells of the pars 'anterior' merge with those of the pars intermedia they assume a more acinous arrangement, become faintly basophil and secrete a granular substance. I have not found the deeply staining basophils, in specific areas in the distal epithelial portion, as described by Tilney 1 . tf > Fig. 52. Section of the pars intermedia of the dog (canis familiaris), showing more highly magnified the part enclosed in a white ring in figure 51. X200. The cells of the juxta neural portion are very interesting in this animal. As is shown in figure 51, they invest completely the pars nervosa and form wedges dipping into it, as in the cat. A peculiar feature, also, in this animal is the extensive acinous arrangement of the pars intermedia which is found in every part of it, and on either side of the cleft at the neck (fig. 52). In no other animal that I have examined, not ex- cepting the cat, is so much secretion found, not only in the 1 Tilney, R, Memoirs Wistar Instil Anat. and Biol, Philadelphia, 1911 (No. 2), 1. COMPARATIVE ANATOMY OF THE PITUITARY 71 epithelium applied to the pars nervosa, but also in that which is distant from the cleft — in what may be described as the re- ticulated portion of the pars intermedia. In this last mentioned area the granular, faintly basophil secretion is found not only in the acini but also quite indiscriminately in diffuse masses among the cells (fig. 53). No mention is made of this secretory activity of the pars intermedia of dogs by Tilney. 0$ e, % © « °1 o e Q * o ® © <-." © Fig. 53. Section of the pars intermedia of the dog (canis familiaris), showing secretion diffused among the cells. X500. Insectivora. — I have examined pituitaries from the hedgehog (erinaceus europceus) — hibernating and non-hibernating — but have found no other description in the literature. The organ is very flat and lies in a very shallow depres- sion in the base of the skull ; consequently the pars nervosa lies superiorly to the epithelial portions (fig. 54). There is a definite cleft (residual lumen) which is placed below the pars 'posterior', or pars superior as it really is. The pars nervosa is solid, and is covered with a nearly even layer of pars intermedia, lying from four to eight cells deep. 72 MORPHOLOGY In the non-hibernating animal — the phenomenon of hiberna- tion will be discussed presently (p. 85) — we find that in the distal epithelial portion the cells are arranged in an acinous Fig. 54. Anterior direction — >. Median sagittal section of the pituitary of the hedgehog (erinaceus europcetis). X 15. manner. The cells are of three types : first, finely granular, lightly eosinophil cells with large, round, faint nuclei are found to be the most numerous ; second, many deeply eosinophil coarsely Fig. 55. Section of the distal epithelial portion of the hedgehog (erinaceus europceus), showing irregularly shaped, darkly staining nuclei. (Photomicrograph.) X 500. granular cells with peculiar very darkly staining — almost ma- hogany- coloured— nuclei of irregular shape (fig. 55) ; third, a few chromophobe, or faintly basophil, cells with large clear COMPARATIVE ANATOMY OF THE PITUITARY 73 nuclei — a familiar characteristic of this type of cell — may be seen. Blood-vessels and blood-spaces are very numerous, and there is a considerable amount of supporting connective tissue. The cells of the pars intermedia (juxtaneural) resemble very closely the cells of the distal epithelial portion, being for the most part faintly basophil and having large clear nuclei ; yet here and there eosinophil cells with dark nuclei are to be found — a most unusual phenomenon. There are numerous large blood-vessels immediately below the cells of the pars intermedia among which are to be seen a few supporting spindle-shaped cells. It will be noticed that in figure 54 the cleft extends down- wards posteriorly into the cells of the distal epithelium. The cells on the posterior aspect of this extension resemble those of the juxtaneural epithelium. Primates : Lemuridce. — Next in an ascending scale we may consider the lemurs, which, possibly, represent the common ancestors of the higher apes and man. Of this family, I have examined the ring-tailed lemur (lemur catta), which is nocturnal in its habits. I have been unable to find any account of the hormonopoietic organs of this animal in the literature. Before describing the pituitary, I may mention that in the animal examined (only one living specimen was obtained) the thyroid resembled in its histological features that seen in exophthalmic goitre in human subject. This interesting fact becomes more striking when it is remembered that the animal has a natural condition of exophthal- --r mos, possibly to enable it to see well when roaming about at night. The structure of the pituitary, £ too, shows peculiarities for which it is difficult to account. In the lemur this organ is situated Fig. 56. in a deep fossa ; consequently it is Median sagittal section of the oval in shape, and the pars nervosa pituitary of the lemur {lemur is situated posteriorly (fig. 56). The cells of the pars intermedia cover the pais nervosa in front, beneath and at the sides, and in front of the stalk. Where these cells are applied to the body of the pars nervosa, which is 74 MORPHOLOGY solid, they show a tendency to dip down, and appear to form islets of cells, as shown in cross-section, among the neuroglial elements (fig. 57). The pars intermedia cells stain rather more deeply with basic dyes than is usual in mammals — except, perhaps, in the cases of the dog and cat. Numerous supporting cells are found among the epithelial elements in this region, and groups of cells are enclosed by dense connective tissue. © "- * *.*■*.->•# 8 Fig. 57. Section of the pars posterior of the lemur (lemur caita), showing apparent islets of pars intermedia cells in the pars nervosa. X 250. The pars anterior in the animal under consideration shows most pronounced and interesting features. The eosinophil ele- ments are very bright and prominent, and in places are arranged in branching columns after the manner of heart-muscle. The only other type of cell seen is the active chromophobe cell (fig. 58). These chromophobe cells are large, stain very faintly with basic dyes, and appear to be almost confluent in places. This pseudosyncytial appearance of chromophobe cells was first described by Lannois and Mulon 1 as occurring in pregnancy ; it 1 Lannois, P. E., and P. Mulon, Compt. Rend, de Soc. Biol, 1903, i, 448. COMPARATIVE ANATOMY OF THE PITUITARY 15 is also seen in pathological conditions — notably after removal of the thyroid — indeed, plate 4 (facing p. 187), showing the effect W$B&$* . ■'.. * > "- l/° -^ ° » ." ■-- £* i^ "- ° « vi i „& ; O P O c o ? . ..o GC a o , C s Fig. 58. .Section of the pars anterior of the lemur (lemur catta), showing dark eosinophil cells and light chromophobe cells. X250. on the pars anterior in the cat of experimental removal of the thyroid, almost illustrates the normal appearance seen in the lemur examined, which was a young non- pregnant female. This phe- nomenon is curious when considered in conjunction with what has already been said about the structure of the thyroid in this animal. Simiidce. — - In monkeys FlG - 59 - the pituitary is situated in Median sagittal section of the pituitary a deep fossa; it is, there- oi the monkey (macacus rhesus). fore, roundly oval in shape, and the pars nervosa is posterior in position (fig. .V.)). It is 76 MORPHOLOGY probable that the pituitaries of the different species are very similar. I have examined macacus rhesus. Herring 1 and Tilney 2 also have examined this organ in monkeys. Tilney examined the baboon (cynocejjhalus babuin), but Herring does not state the species described by him. The pars intermedia forms an investment varying in depth, but usually thin, over the front and sides of the pars nervosa and along the front, and, in some cases, around the stalk. The pars nervosa is solid, and is comparatively large (fig. 59). The pars anterior appears to be composed chiefly of eosino- phil cells, although some faintly basic staining — really chromo- Fig. 60. Median sagittal section of the human pituitary. X5. phobe — cells may be seen. My observations coincide with those of Herring rather than with those of Tilney, in regard to the absence of basophils ; but this may be explained by the fact that Herring and I examined the same species, while Tilney examined a species that may differ from macacus rhesus. Blood-spaces are numerous, but there is little other supporting tissue. The cleft is very narrow, and in this respect and in the limitation of the pars intermedia the pituitary of the monkey approaches in appearance that seen in Man (fig. 60), in whom the pars intermedia is of very slight extent, as already described. 1 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121. 2 Tilney F., Memoirs Wistar Instil Anal ami Biol, Philadelphia, 1911 (No. 2), 1. COMPARATIVE ANATOMY OF THE PITUITARY 77 In this brief study of the comparative features of the pituitary a few facts stand out as being of considerable im- portance. Their importance is related to the elucidation of the physiological functions of this organ. We have found in one of the lowest vertebrates the complete absence of a pars nervosa ; we have observed its sudden develop- ment to, apparently, an organ of considerable physiological signific- ance, if we may attach functional importance to morphological structure, which is, however, always a dangerous procedure. In bony fishes the maximum surface of nervous tissue is exposed, by a series of branching processes, to the epithelial covering ; and this phenomenon obtains to a considerable extent in reptiles and even in the monotreme mammals. Then, apparently, this feature disappears, except for the evidence of epithelial ingrowths in the pars nervosa, such as are seen in the cat and lemur. In the opossum and in the cat we find another interesting morphological characteristic, namely, a cavity within the pars nervosa which is continuous with the third ventricle ; and this has been held by Herring 1 , dishing 2 and others to constitute a factor of prime importance from a physiological point of view. In the amphibians and ungulates we have seen that blood-vessels are very numerous in connexion with the pars posterior. This, too, may be a point of some moment in regard to the physiology of this part of the pituitary. We have, moreover, observed that the histological evidence of activity of the pars intermedia differs in different mammals, and that it appears to be greatest in the cat and dog so far as the actual production of an obvious secretion is concerned. In the monkeys and in Man the pars intermedia and the pars nervosa appear to be of small significance. The comparative structure of the pars anterior likewise affords us some food for reflexion. In certain fishes and reptiles the cells are arranged in acini with blood-vessels in the lumina — a disposition which facilitates the passage of the secretion of the cells directly into the blood-stream. In no case do we see quite so well-defined a differentiation in eosinophils, basophils and chromophobes as in the normal pituitary of Man. There is, however, no doubt that in the lower vertebrates differentia- 1 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121, 161. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 78 MORPHOLOGY tions do exist, but they are not pronounced in most of the mammals, nor, indeed, in Man till puberty. In the lemur there are extremely interesting histological features which we shall discuss again later, for use will be made of this compara- tive study in discussing the peculiar problems associated with the physiology and pathology of the pituitary. PART II THE PHYSIOLOGY OF THE PITUITARY PART II THE PHYSIOLOGY OF THE PITUITARY In order to obtain information concerning the normal func- tions of an organ, we have definite and well-recognized methods of investigation. These are either purely physiological or patho- physiological ; and before proceeding to discuss the application of them to the study of the pituitary body it will be useful to summarize the methods themselves. I. Physiological Methods (a) Histological investigations.- — These enlighten us as to the nature of the structure with which we have to deal, and also enable us to discern the character of its functional processes in various circumstances. We learn by differential staining the chemical affinities of the different cells of the tissues investigated, and the various phases of their activity. {b) Chemical examination of the body-tissues and excreta. — By this means we are sometimes able to discover the chemical nature of a secretion, and to trace in the blood or other body- fluids its rate of production and disappearance. By this method, also, we are able to observe changes in the metabolism. (c) Injection, absorption, and ingestion experiments. — In these investigations extracts of the organ concerned are in- troduced into the body of the experimental subject, and obser- vations are then made in the following ways in regard to the immediate and remote effects produced. i. Immediate effects of injections are noted by means of various physiological recorders ; of absorption by placing the structures to be tested in Ringer's solution contain- ing the extract, and by means of the implantation of freshly excised organs. 80 PHYSIOLOGY ii. Late effects of daily injections or ingestions into a pre- viously normal animal, are noted in regard to the meta- bolism and to the structure of various other organs. It is generally conceded that these methods of investigation are open to few objections ; but we must bear in mind that in our experiments under the third heading we are usually ex- hibiting quantities of an organic extract considerably in excess of those which the animal could receive from the same organ in normal circumstances and in the same period of time. II. Pathophysiological methods (a) Operative procedures. — i. Partial or complete extirpation, destruction or injury of the organ in situ. — -There is no doubt that partial or complete extirpations are greatly to be preferred to destruction with the cautery and with other agents ; for it is difficult with destructive methods to limit the amount of necrosis effected, or to estimate the damage done to adjacent portions of the organ and the surrounding tissues. By extirpation experiments we are able to produce cessation of, or insufficiency in, the functions of an organ. ii. Extirpation or destruction follozved by substitution therapy by means of injections, feeding, or grafting. — By these means we are often able to learn whether our deductions, based on extirpation or destruction alone, are correct, for substitution may mitigate the effects produced. By this method of investigation, however, positive results alone are of value. iii. Stimulation of the organ in situ. — This is accomplished by electrical impulses applied indirectly through the func- tional nerves, or by electrical currents or other methods of irritation, such as the pressure of a foreign body, applied directly ; also, by the injection of exciting sub- stances (hormones) into the circulation. (b) Removal of, or injury to, correlated organs. — In this way we may become acquainted with the relationships between various structures, such as the organs of internal secretion. (c) Injection of bacteria or toxins into the blood-stream, PHYSIOLOGY OF THE PITUITARY 81 peritoneal cavity or subcutaneous tissues. — By this method, which, possibly, is a form of stimulation, we learn the behaviour of the organ to infections or toxaemias — a matter requiring consideration apart from stimulation by hormones. (d) Interpretation of pathological processes affecting the normal physiology of the organ concerned.— Many patho- logical processes in an organ give rise to excessive or diminished function in varying degrees. From these so-called ' experiments of Nature ' the physiologist may find much evidence to support or disprove conclusions reached in other ways. In these methods, then, if they be properly carried out, we have the means of investigating fairly completely the functions of an organ such as the pituitary body. It will be obvious, moreover, that sometimes combined experiments, such as those described above under II (a) ii, may be especially useful ; and in this connexion it must be pointed out that the full ap- preciation of the results of many of the methods mentioned depends on the completeness of the investigation. For instance, in extirpation experiments we must not be satisfied with ob- serving whether the animal dies or survives ; we must learn, if possible, the actual effect of the experiment on the correlated organs and structures, and on the metabolism generally. Un- fortunately, this completeness of investigation is rarely possible to the ordinary investigator, for he is not usually an expert in surgery, histology, chemistry and general medicine, and at the same time able to devote his whole time to experimental work ; and, on the other hand, the pure physiologist is not always sufficiently acquainted with the technique of surgery, and with the possible applications of his results to medical and surgical practice. It is, therefore, at present only by combining the results of many workers that we are able to view a subject such as that which we are at present discussing from a more or less comprehensive standpoint. No doubt the time will come when hospital laboratories will be established in this country in which complete investigations can be carried out under the same roof by the combined efforts of many workers, each of whom is a specialist in his own sphere of action. PHYSIOLOGICAL INVESTIGATIONS HISTOLOGICAL OBSERVATIONS In its histological features the pituitary body is one of the most puzzling structures in the animal organism. It has, therefore, been the subject of much careful study ; and however imper- fectly we can connect the physiological functions with the special structure, we are at least now thoroughly familiar with the latter in the human adult. Nevertheless, a careful investigation into the differences seen at the different periods of life is urgently needed ; for, although it may be possible for an experienced observer to recognize the pituitary of the child by the com- parative uniformity in the staining reactions of the cells of the pars anterior, and that of elderly persons by the amount of pig- ment found in the pars nervosa, these distinctions are only rough and approximate. So, too, further observations concerning the structural alterations associated with various physiological and pathological conditions are required before we can completely understand the significance of such changes. The general structure and the relationship of the different portions of the pituitary have already been described. The same combination of the parts is common to all mammals, with slight differences in regard to the extent of the pars anterior, the differentiation of the cells of the pars intermedia, the solidity or hollowness of the pars nervosa, and the relation of this nerv- ous process to the epithelial portions. The pars nervosa always directly underlies the third ventricle, and this, as we shall see, has been held to be a matter of some importance in con- nexion with the pathology as well as the physiology of the pituitary. We have seen, too, that in most animals and in the human subject the anterior lobe is separated by a cleft (the original cavity of Rathke's pouch) from the posterior lobe. HISTOLOGICAL OBSERVATIONS 83 Having thus got our bearings we may proceed to an ex- amination of the different parts of the pituitary under high magnifications in order to determine the connexions of the various elements with the functions of the organ as a whole. It will be remembered that each part — the pars anterior, the pars intermedia and the pars nervosa — presents specific and dis- tinct morphological characteristics ; so it will be advisable to consider them separately, in spite of the fact that the pars anterior and the pars intermedia have a common origin. Pars anterior — As already described, this portion of the pituitary is composed of epithelial cells arranged in a more or less branching or tubular fashion. Granular secretion may be seen in the lumen of the acini (fig. 18, p. 30) or in the blood- sinuses which are large and numerous. It is, therefore, believed that the secretion of the pars anterior is poured directly into the blood-stream or stored in the form of colloid. We have noted, too, that in adults among the higher animals the epithelial cells of the pars anterior show differential staining affinities, in consequence of which the various types have been described as being chromophil and chromophobe — they stain well or indiffer- ently. Of the chromophil cells some are acidophil and show considerable avidity for eosin, while others are basophil and stain deeply with hsematoxylin. The chromophobe cells are tinged very lightly with basic dyes (plate 1, facing p. 30). Many in- vestigators have sought to place these different types of cells in regular situations in the anterior lobe ; but, beyond the facts that the basophils are most numerous at the periphery and that the eosinophils surround the blood-sinuses, there seems to be little justification for such descriptions, and my own experience is that no two pituitaries in any animal or human being are alike in this respect. There are certain important normal histological phenomena associated with physiological states, which require special con- sideration. Pregnancy. — Comte 1 first, and later Erdheim and Stumme 2 , noticed that in pregnancy the anterior lobe enlarges considerably. 1 Comte, L., Zeiglers Beitr. z. Pathol Anal. u. z. Allg. Pathol., 1898, xxiii, 90. 2 Erdheim, J., and E. Stumme, Zeighr's Beitr. z. Pathol. Anaf. %i. z. Allg. Pathol., 1909. xlvi. 1. 84 PHYSIOLOGY I ( V * % •4 • Fig. 61. Section of the pars anterior of the pregnant rabbit, showing eosinophilia of the cells. (Photomicrograph.) m i „ X500. . % *> fc! Fig. 62. Section of the pars anterior of the pregnant rabbit, showing large chromophobe ('pregnancy') cells. (Photomicrograph.) X 500. HISTOLOGICAL OBSERVATIONS 85 This increase in size is stated by Erdheim and Stumme to be due entirely to changes in the chromophobe (' neutrophil ', ' principal ', or ' chief ') cells, which now develop and become slightly more chromophil (' pregnancy cells ') ; that is to say, there is during pregnancy a condition of excessive activity in regard to these cells. Siguret 1 observed in rabbits a diminution in the number of the chromophobe cells and an increase in the number of eosinophil. This author also found that the change was as marked at the commencement as at the end of gesta- tion. Lannois and Mulon 2 were the first to describe the con- fluence of the chromophobe cells in pregnancy, and this they designated ' syncytial'. My own observations have impressed me with the fact that considerable variations may be found during pregnancy both in animals and women. Usually in rabbits there is, as Siguret has stated, an increase in the degree of eosinophilia — that is to say, the lightly stainiig eosinophil cells, which predominate in the pars anterior of this animal, stain more deeply (fig. 61). Never- theless, I have seen extremely pronounced chromophobia in this situation during pregnancy in the rabbit (fig. 62). In women the chromophobe cells are usually plentiful in these circum- stances, but this is not always the case. The essential change, however, in the pars anterior of all animals during pregnancy is towards greater activity, and this may be represented by increased eosinophilia of the epithelial elements or by chromophobia. The chromophobe cells in these circumstances often assume a lobulated or an adenomatous arrangement (figs. 63 and 64). Hibernation, too, produces striking changes in the histological appearances of the pituitary, and these occur in the epithelial elements of the partes anterior and intermedia — the secretory cells of this organ. Gemelli 3 first called attention to this phenomenon, and lie came to the conclusion that hibernation is a condition of pluriglandular inactivity. He found in the pars anterior that the cells arc entirely undifferentiated in this physiological state. 1 Siguret, A., L l hypo2)hyse pendant la gestation, Paris, 1912. 2 Lannois, P. E., and P. Mulon, Compt. Rend. Soc. de Biol, 1903, i, 448. 3 Gemelli, A., Arch. p. le Sci. Med., 190G, xxx, 341. 86 PHYSIOLOGY .?#e Fig. 63. Section of the pars anterior of the pregnant guinea-pig, showing the tabulated arrangement of chromophobe cells. (Photomicrograph.) X 250. ft' 'i *&< ■ Fig. 64. Section of the pars anterior of the pregnant woman, showing the tabulated arrangement of chromophobe cells. (Photomicrograph.) X 125. HISTOLOGICAL OBSERVATIONS 87 Cushing and Goetsch 1 came to a similar conclusion regarding the condition of the pituitary during hibernation. Further, these observers have suggested that physiological sleep may be associated with temporary inactivity of the pituitary. In sup- port of this hypothesis they refer to the torpor usually seen in animals from which a large portion of the pars anterior has been removed, and to the drowsiness seen in advanced pituitary disease associated with diminished secretion — that is, in the syndrome dystrophia adiposogenital. They have called par- ticular attention to a case of pituitary tumour in which the patient became comatose and had a low body-temperature. Cushing operated and found a cyst in the pars anterior which he evacuated. There was no general intracranial pressure. Pituitary extract made from the whole gland improved the condition, and permanent relief was obtained by the implant- ation of the pars anterior from a stillborn child into the subcortical tissue of the brain of the patient. Whatever changes occur elsewhere, there is no doubt that definite alterations are found in the pituitary during hibernation. In the hedgehog and dormouse, which I have examined, during the summer the cells of the partes anterior and intermedia are active — they are swollen and blurred, and the nuclei stain faintly (fig. 65a) ; but during the period of winter-sleej^ they become shrunken and discrete, and their nuclei stain deeply (fig. 65b). Associated with these changes in the hibernating animal there is an enormous deposition of fat —just as there may be in experimentally produced or patho- logical insufficiency of the pituitary secretion : I have seen the subcutaneous layer of fat in the hibernating hedgehog one inch in thickness. Brooding in hens, as already indicated (p. 53), is associated with varying degrees of pituitary insufficiency that can be recognized histologically. In the non-laying hen that is not brooding the pituitary appears less active than that of the laying hen, but more active than that of the brooding hen. The adult cock's pituitary resembles that of the laying hen. Observations concerning these physiological variations in hens do not appear to have been recorded previously. I have been unable to conduct my investigations on a large scale at the present time, 1 Cushing, H., and E. Goetsch, Journ. Exper. Med., 1915, xxii, 2~>. 88 PHYSIOLOGY J j ?'*»', *$ ft ^ °0 'J ', •J?s JK-^V pa ? Fig. 65a. Section of the pituitary of the normal non-hibernating hedgehog, showing the distal epithelium on the right and the juxtaneural epithelium covering the pars nervosa on the left. X 125. ft* «^ *','»' *'* " V *« •* s». ??X*. '>:-.•*» 5J-i Fig. 65b. Section of the pituitary of the hibernating hedgehog, showing the inactive shrunken cells of the distal epithelium on the right, and of the juxtaneural epithelium on the left. X 125. HISTOLOGICAL OBSERVATIONS 89 but there appeared to be no doubt whatever as to the cause and effect in the birds examined. In the pars anterior of the laying hen there are many large eosinophil cells, mixed with chromophobe cells in an irregular manner ; and the cells look blurred and swollen (fig. 66a). In the brooding hen the cells are almost all small and chromophobe ; they appear shrunken and inactive, and they form definite acini, many of which contain granular secretion, enclosed in a con- nective tissue meshwork (fig. 66b). The appearances of the pituitary in these physiological states — pregnancy, hibernation and brooding — throw much light on the normal physiology of the pituitary in relation to its struc- ture ; but it is improbable that this organ alone is affected in these circumstances. Gemelli's statement that hibernation is pluriglandular in origin is probably correct ; and we know that all the organs of internal secretion are altered during the period of gestation, so it is probable that brooding also is associated with pluriglandular inactivity. It is a little more difficult to deduce facts of physiological import from the comparative morphology of the pars anterior of the pituitary, and we must reserve some of the points worthy of consideration for a short discussion later of the comparative physiology of this organ. It may, however, be mentioned that among the mammals we find considerable variation in tinctorial affinities. In the ornithorhynchus all varieties of cells are found in the pars anterior, and especially wc may observe several stages in the formation of the deeply staining basophil cells. In the rodents, such as the rabbit, true basophils are very rare, and in no animal below the monkey have I observed basophil colloid. This is a matter of some interest, and it probably explains the fact that eosinophilia is the most im- portant phase of activity in these animals. We are now in a position to consider the significance of the different types of cells found in the pars anterior. There is some divergence of opinion on this question, and two views are held : first, some authorities, of whom Gcmelli 1 is the chief advocate, believe that the different types of cells have different functions; second, there are many who think with Saint-Remy 2 1 Gemelli, A., Folia Neurobiol, 1908, ii, 167. 2 Saint-Remy, G., Compl. Rend, de V Acad, des Sci. 1892, cxiv, 770. 90 PHYSIOLOGY Fig. 66a. Section of the pars anterior of the laying hen, showing large eosinophil cells mixed indiscriminately with chromophobe cells. X 125. - - . , • » Fig. 66b. Section of the pars anterior of the brooding hen, showing shrunken chromophobe cells divided into acinous groups by connective tissue. X 125. HISTOLOGICAL OBSERVATIONS 91 and Benda 1 that the apparently different types of cells represent the same structure in different stages of activity. As this is a point of considerable interest and importance, as well as of doubt, I shall state my own views on the subject. In general, my observations lead me to support the second view ; and I feel able to put my conclusions into a more definite form than has hitherto been attempted. In the first place it must be emphasized that in no part of the anterior lobe in normal circumstances — excluding pregnancy, brooding, and hibernation — can one find positive evidence of the presence of any one type of cell to the exclusion of the others ; that is to say, at the most important points of observation all varieties are seen to be mingled together (plate 1, facing p. 30). This fact alone is significant, for it is what one would expect to find where different stages of secretory activity are in progress at the same time ; and it appears to me to dispose of Erdheim's 2 argument for the opposite view, namely, that cells of the same kind may be found in clusters in abnormal circum- stances. With regard to the disposal of the secretion of the anterior lobe, it appears that for the most part this is carried away in the blood-channels. Thaon 3 and others have drawn attention to the fact that granular secretion may actually be seen within the blood-sinuses. Nevertheless, there can be little doubt that the secretion is chiefly taken into the blood-stream in infinit- esimal quantities. In exceptional circumstances, however — influenced, no doubt, by metabolic conditions — the secretion is stored. This storage secretion, unlike the normal thyroid secre- tion 4 , usually stains with haematoxylin (basophil) rather than with eosin (acidophil), although abnormally an acidophil affinity is sometimes seen. The secretion has a granular appearance when eosinophil or neutrophil, and only resembles homogeneous colloid when distinctly basophil. This basophil affinity of the formed colloid secretion gives us valuable evidence as to the 1 Benda, C, Berl. Klin. Woch., 1900, xxxvii, 1205. 2 Erdheim, J., Frankf. Zeilschr. f. Pathol, 1910, iv, 70. 3 Thaon, P., L'hypophyse, Pans, 1907. 4 It should be stated, however, that thyroid secretion may, in apparently normal circumstances, show a faintly basophil tendency. 92 PHYSIOLOGY parts played by the different cells in regard to the secretory products of the pars anterior. In attempting to describe the secretory phases I shall con- sider first the eosinophil cells. These cells are the elements which produce the internal secretion of the pars anterior in normal circumstances. It is possible to observe differing degrees of staining affinity in various eventualities, and always it is the granules within the cells that stain most deeply. The eosinophil cells lie against the walls of the blood-channels, and their secretion is taken up by the blood-stream. If the secre- tion is not removed from these cells, chemical changes occur which alter the tinctorial affinities of the secretory products : gradually the acidophilia diminishes, and basophilia, at first slight, becomes more and more pronounced until the typical, darkly staining, basophil cell is produced. It will be remembered that in the eosinophil cell the nucleus is central and is surrounded by an extensive cytoplasm con- taining eosinophil granules, and that in the deeply basophil cell the nucleus is eccentric. Several phases may be observed in the basophils : first, they are translucent and contain granules ; later, they become opaque and homogeneous, and in the transition the nucleus is gradually displaced to the periphery of the cell. Eventually, the basophil cell disgorges dark basophil colloid. This colloid is surrounded by cells most of which are small chromophobe ele- ments with large clear nuclei and little cytoplasm — the exhausted remains, in fact, of the basophils that have extruded their colloid material (fig. 67). These chromophobe cells regenerate, and in normal circumstances become eosinophil, and pour their secretion into the blood-vessels ; or they change once more into the basophil cells, and store their secretion until such time as again they extrude it in the form of colloid. In those cases in which there is an immediate and urgent demand for the secre- tion of the pars anterior, as in pregnancy, the small chromophobe cells, and even some of the young eosinophils, increase in size but remain chromophobe, and yield up their secretion as soon as it is formed ; indeed, it is not unusual to see bubble-like collections of secretion among the cells, especially in abnormal circumstances, such as occur after removal of the thyroid. The phases just described may be summarized in a few words : HISTOLOGICAL OBSERVATIONS 93 the small chromophobe cells are exhausted cells ; the eosino- phil cells are the active secretory cells in normal circumstances ; the basophil cells form a storage secretion ; and the large chromo- phobe cells, which develop from the small exhausted chromo- phobe cells or the young eosinophils, are formed only when there is an urgent and immediate need for the secretion of the pars anterior. fY- Fig. 67. Section of the normal human pars anterior, showing basophil colloid surrounded by chromophobe cells, one or two of which are becoming eosinophil. (Photomicrograph.) X500. Thaon 1 , Erdheim and Stumme 2 and others have directed attention to the lipoid particles that may be demonstrated in the epithelial elements of the pituitary. These bodies stain with sudan III, scharlack R and osmic acid. They are, of course, soluble in ether and alcohol. My own material is not sufficient from which to draw con- clusions, but there can be no doubt that the amount of lipoid material demonstrated by staining methods varies enormously in different pituitaries, and probably in different circumstances. 1 Thaon, P., L'hypophyse, Paris, 1907. 2 Erdheim, J., and E. Stumme, Zeigler's Beitr. z. Pathol. Anal. u. z. Allg. Pathol. 1909. xlvi, 1. 94 PHYSIOLOGY In some the amount is large (fig. 68) ; in others there is very- little. The stained lipoid bodies vary in size from dust-like particles to globular masses considerably larger than the nuclei of the cells. I have been unable to detect lipoid substances in the granular secretion found in the acini. According to Erdheim and Stumme, chromophobe cells — including pregnancy cells — are poor in lipoids, while the chromo- phils — that is to say, eosinophils and basophils — may contain large quantities of these substances. But in my experience the Fig. 68. Section of the normal human pars anterior stained with osmic acid, showing lipoids in the cells. (Photomicrograph.) X 125. lipoids, as made evident by staining methods, vary in quantity, even in cells of the same character ; consequently I feel that we are not in the possession of enough information to draw satisfactory conclusions as to their exact nature and import. The fact that there are sympathetic nerves in the pars anterior is probably of significance from a functional point of view. Pars intermedia. — -As already indicated, this portion of the pituitary is derived from the pouch of Rathke and becomes HISTOLOGICAL OBSERVATIONS 95 slightly differentiated from the rest of the anterior lobe with which it is continuous. For the most part it is closely attached to the pars nervosa and infundibular stalk. The pars intermedia usually invades the pars nervosa to a slight extent. We have seen that in Man and the higher mammals the invasions are superficial in normal circumstances, but that in some of the lower animals the pars nervosa is divided up by columns of cells. It is frequently to be observed that in the part which is in relation to the stalk there are many vesicles which may contain granular secretion. This is usually neutrophil, but in conditions to be mentioned later it may be eosinophil. Sometimes the secretion appears homogeneous like colloid, and in these circum- stances it is usually basophil in its staining affinity. Occasionally, secretion is found in the cleft, and is no doubt derived from the cells of the pars intermedia. It has been shown that in different animals there are different degrees of secretory activity in the pars intermedia, so far as we can judge from the formation of obvious secretion ; and that in Man there is little evidence of the production of secre- tion other than the colloid so frequently found above, and in, the cleft. In abnormal conditions experimentally produced in animals a certain blurring and fusing of the cells of the pars intermedia appears to be coincidental with increased secretion. The relationship of the pars intermedia to the production of infundibulin will be discussed directly in connexion with the functions of the pars nervosa. Pars nervosa. — -We have seen that this portion of the pituitary is chiefly composed of neuroglial cells and fibres, and that there are occasionally to be found a few ependymal cells included at the neck in those animals in which the pars nervosa is solid. When there is a central cavity, such as is seen in the cat, this is lined with ependymal cells the fibres of which run longitudinally upwards (Herring 1 ). Further, we have considered the question of the nerve-supply of the pituitary, and have noted that most investigators have failed to find true nerve-fibres, 1 Herring, P. T., Quart. Jowrn. Exper. Physiol. 1908, i, 121. 96 PHYSIOLOGY and that it is doubtful whether sympathetics are present in this part of the pituitary. We must now consider the histological and accessory evidence at our disposal concerning the secretion formed by the pars nervosa itself, or by the pars intermedia in conjunction with the pars nervosa. Later, we shall study the physiological prop- erties of the extract made from these parts of the pituitary, which together form the posterior lobe and are so closely conjoined as to be inseparable on rough dissection. Whether this extract is the same as the normal secretion we need not discuss, beyond saying that it is usually believed to be so. We have already seen that vesicles are nearly always to be found in the pars intermedia, and these contain a substance said by Biedl to resemble in appearance thyroid colloid, but in my experience it is more usual to find in animals a neutrophil granular secretion. It is most probable that this material represents the normal secretion of the pars intermedia. Osborne and Swale Vincent 1 found that by careful dissection they could separate the central portion of the posterior lobe from the epithelial investment, and that whereas an extract of the former gave the typical effects of infundibulin, an extract made from the epithelial portion gave much less definite results. Further Osborne and Vincent 2 have shown that extracts of other nervous tissues do not possess the same physiological activity as an extract of the posterior lobe. Herring 3 has recently confirmed the results obtained by Osborne and Vincent to the extent of finding that although both extracts stimulate muscle -contractions, the one made from the pars nervosa is from two to five times more powerful than the extract of the pars intermedia. Herring also found that an extract of pars intermedia in strengths of 0*5 per cent, and less has no specific action on the blood-pressure or renal excre- tion ; whereas an extract of the pars nervosa in so low a strength as 0*005 per cent, produces the characteristic pressor and diuretic effects (see pp. 105 and 109). 1 Osborne, W. A., and S. Vincent, Brit. Med. Jounu, 1900, i, 502. 2 Osborne, W. A., and S. Vincent, Joum. Physiol, 1899-1900, xxv, 9. 3 Herring, P. T., Quart. Journ. Exper. Physiol.. 1915, viii, 245 and 267. HISTOLOGICAL INVESTIGATIONS 97 Miller, Lewis and Matthews 1 , on the other hand, maintain that it is the cells of the pars intermedia which produce infund- ibulin, and that the pars nervosa is inactive in this respect. These observers also found that it was impossible to obtain pressor effects from an extract of the stalk, and they conclude that " there is, therefore, a distinct interruption in the path of secretion of the pressor substance from the pars nervosa to the ventricle ". This is opposed to Herring's view concerning the passage of secretion from the pars nervosa to the third ventricle. Evidence as to the different actions of extracts of the pars intermedia and pars nervosa must be carefully received ; for, in the first place, it is practically impossible to remove all the epithelial elements from the surface of the pars nervosa, especially in the region of the stalk, and, in the second, islets of pars inter- media cells may be found in the pars nervosa. A glance at some of the illustrations in the section on comparative anatomy (p. 40 and following) will make these difficulties obvious. Miller, Lewis and Matthews 1 obtained pressor effects from the contents of a cyst in the pars intermedia. Herring 2 was unable to obtain any definite effect from the contents of the cleft. Hamburger 3 , likewise, found that the contents of the cleft were devoid of any pressor action. Herring 4 was the first to describe what he called ' hyaline ' bodies in the pars nervosa. He considers that they represent the active secretion of the cells of the pars intermedia, which is passed into the pars nervosa. Further, he believes that these bodies stream upwards towards the neck, or infundibulum, and that finally they pass into the third ventricle, and so into the cerebrospinal fluid. Herring also found that they are very much more numerous in the pars nervosa after thyroid- ectomy. Cushing and Goetsch 5 subsequently investigated the question, and on the main points they agree with Herring. But these 1 Miller, J. L., D. D. Lewis, and S. A. Matthews, Amer. Journ. Physiol. (Proc. Amir. Physiol. Soc), 1910-1911, xxvii, xvii. 2 Herring, P. T., Quart. Journ. Exper. Physiol, 1915, viii, 245 and 267. 3 Hamburger, W., Amer. Journ. Physiol, 1904, xi, 282. 4 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121. 5 Cushing, H, and E. Goetsch, Amer. Journ. Physiol, 1910, xxvii, GO. 7 98 PHYSIOLOGY writers also came to the conclusion that some of the ' hyaline ' bodies represent degenerated wandering cells, and that other ' hyaline ' bodies consist of secretion which has escaped or has been forced from the vesicles of the pars intermedia. They state that whereas the secretion in the pars intermedia is basophil, these ' hyaline ' bodies are faintly eosinophil. They also assert that they found the colloid from the vesicles physiologically inactive ; but they do not state how they obtained their material. Last, these investigators found in the cerebrospinal fluid an active substance resembling infundibulin in its physiological actions. From this they conclude that it is proved beyond doubt that the active principle of the posterior lobe or pars intermedia is passed directly into the third ventricle. Now, if this method of secretion prove to be indisputable, it represents a most remarkable train of events, and one which has no parallel in the animal economy. But, although I have myself observed all the histological details mentioned by these authors, I would hesitate to conclude that to histological features so unusual in connexion with secretory activity is to be assigned the representation of a novel method for the distribution of an internal secretion. The very fact that some so-called ' hyaline ' bodies are without nuclei and others contain them indicates the true nature of these bodies (fig. 69). They are cells undergoing degeneration, which may in the process disperse their contents. Again, it must be noted that they are always very granular, and are not hyaline in structure nor do they re- semble the homogeneous colloid seen in the vesicles of the pars intermedia in the sightest degree ; but they do resemble exactly the granular secretion-cells and masses (fig. 53) and the granular collections in the vesicles (figs. 49 and 52) seen in the pars inter- media of cats and dogs. On histological evidence I originally formed the opinion that the cells of the pars intermedia alone produced the pressor sub- stance which I called 'infundibulin' 1 . The work of Miller, Lewis and Matthews 2 is directly opposed to the view of Herring, for they found that an extract of the stalk had no pressor action. They believe that the cells of the 1 Bel], W. Blair, BriL Med. Journ,, 1909, ii, 1609. 2 Miller, J. L., D. D. Lewis, and S. A. Matthews, Amer. Journ., Physiol. (Proc Amer. Physiol. Soc), 1910-1911, xxvii, xvii. HISTOLOGICAL INVESTIGATIONS 99 pars intermedia alone are concerned in the production of infund- ibulin. This whole question is undoubtedly a difficult one, but I feel that the idea of a secretion actively moving towards the third ventricle is disproved by the fact that these ' bodies ' must be degenerated cells, since they sometimes possess the remains of nuclei. Yet this point appears to have been noted by Herring, for he says : " Secretion goes on either by emptying of material from the cells into the lymph, or possibly by a breaking down Fig. 69. Section of the pars nervosa of the normal cat, showing granular bodies, some with nuclei, some without. (Photomicrograph.) X500. and destruction of the whole cell. The latter, indeed, is the more probable fate of isolated epithelial cells, and seems to occur at times in the epithelial investment itself" 1 . It is, moreover, a fact of some importance that one rarely sees many of these granular bodies in normal circumstances ; and after thyroidectomy I have not always seen a great increase in their number. My present opinion is that the secretion of the pars intermedia 1 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121. 100 PHYSIOLOGY and of the posterior lobe is taken up by the blood-stream. In support of this view attention may be called to the morpho- logical facts that there is a network of blood-vessels beneath the pars intermedia, and that in some animals, such as the ox, the pars nervosa has a very rich internal blood-supply. At the .same time I am quite aware that the cells of the pars intermedia wander into the pars nervosa, and there degenerate (fig. 69). Any secretion they contain is, no doubt, absorbed by the capillary vessels. It seems quite possible, also, that the cells of the pars intermedia both store their secretion in the form of colloid and, like the anterior lobe, pass some of it directly into the blood- stream. In order to reach the blood-vessels the secretion may pass through the pars nervosa. If this be so, as seems certain, it is possible the pars nervosa in some way alters the character of the secretion before it reaches its destination; this view 1 , which' I believe to be correct, whatever the final destination of the secretion may be, is supported by Herring 2 . We shall, directly, consider more fully the evidence con- cerning the question of the presence of infundibulin in the cerebrospinal fluid. 1 Bell, W. Blair, Arris and Gale Lectures, Lancet, 1913, i, 937. 2 Herring, P. T., Quart. Journ. Exper. Physiol, 1914, viii, 245. CHEMICAL EXAMINATION OF THE PITUITARY TISSUES, AND THE EVIDENCE REGARDING THE PRESENCE OF INFUNDIBULIN IN THE BODY-FLUIDS CHEMISTRY OF THE PITUITARY Very little work has been carried out in regard to the chemistry of the pituitary body. An examination of the whole gland shows that it is rich in calcium and phosphorus, but this may be on account of the nervous elements in the pars nervosa. Schnitzler and Ewald 1 have described the existence of iodine in the anterior lobe, and concluded that it is probably in the same form as in the thyroid gland. Halliburton, Candler and Sikes 2 , and Wells 3 have failed to confirm this observation. Biedl 4 states that the colloid in the anterior lobe is in- soluble in water, alcohol and ether. This substance is unlike mucin in that it swells with acetic acid, and afterwards dissolves. The secretion of the posterior lobe is soluble in water, and is not destroyed by boiling; consequently the active principle is not a protein. It has been found to be dialyzable, and it has certain important physiological actions that will be described later. Suprarcnin, which is probably of a quite different chemical composition, has been made synthetically, but up to the present time the actual chemical composition of infundibulin 1 Schnitzler, J., and K. Ewald, Wien. Klin. Woch., 1896, ix, 657. 2 Halliburton, \V. D., J. P. Candler, and A. \V. Sikes, Quart. Journ. Exper Physiol, 1909, ii, 229. 3 Wells, H. G., Journ. Biol. Ghem., 1909 1910, vii, 259. 4 Biedl, A, Innere Sekretion, 2nd ed. 1913. 102 PHYSIOLOGY has not been definitely determined, although Aldrich 1 has obtained a crystalline pier ate and sulphate which have a pressor action. Houssay 2 , also, claims to have obtained infundibulin in a crystalline form. Recently Fuhner 3 has placed on the market a substance called ' hypophysin '. This is stated to contain several different substances, one of which acts on the uterus alone. It is said that Fuhner 's preparation can be made from both the anterior and posterior lobes. Dale 4 has produced evidence to show that infundibulin is not one of the groups of bodies to which belong suprarenin, the active principles of ergot and the pressor substance that is found in putrid meat. The same investigator has also shown that whereas ergotin annuls the effect of suprarenin subsequently given, yet it in no way affects the action of infundibulin on arterial and uterine contractions. Schafer and Herring 5 believe, from their experiments, that pepsin destroys the pressor effect of infundibulin, but docs not interfere with its diuretic action. They state, also, that trypsin has no effect whatever on the extract. Dale 4 , however, ob- served exactly reverse effects in regard to the actions of pepsin and trypsin ; and he gives some very convincing tracings of his results. Pepsin, he states, does not change infundibulin at all, whereas trypsin entirely destroys it in a few hours, so far as its physiological activity is concerned. INFUNDIBULIN AND THE CEREBROSPINAL FLUID dishing and Goetsch 6 , following the suggestion of Herring 7 concerning the passage into the cerebrospinal fluid of the so- called ' hyaline ' bodies which may be seen in the pars nervosa, 1 Aldrich, T. B , Amer. Journ. Physiol. (Proc. Amer. Physiol. Soc), 1908, xxi, xxiii. 2 Houssay, B. A., Revist. Soc. Med. Argent., Buenos Aires, 1911, 268 (Reprint). 3 Fiihner, H., Zeitschr. f. d. Ges. Exper. Med., 1913, i, 397. 4 Dale, H. H., Biochem. Journ., 1909, iv, 427. 5 Schafer, E. A., and P. T. Herring, Proc. Boy. Soc. Biol, 1906, lxxvii, Ser. B, 571. 6 Gushing, H., and E. Goetsch, Amer. Journ. Physiol., 1910, xxvii, 60. ' Herring, P. T., Quart, Journ. Exper. Physiol, 1908, i, 121. INFUNDIBULIN AND THE CEREBROSPINAL FLUID 103 endeavoured to prove that the cerebrospinal effusion contains infundibulin. Further. Weed and dishing 1 state that injections of infundibulin increase the rate of cerebrospinal secretion. They inserted a graduated and calibrated needle into the third ventricle of the dog, with the skull and meninges intact except for a small perforation equal in size to the diameter of the needle. The drops of cerebrospinal fluid were taken as an indication of the secretory rate. These investigators, believing the formation of cerebrospinal fluid to be secretory, make the surprising statement that in response to an injection of infund- ibulin " a prolonged flow from the ventricle may continue even after death, and may reach an amount apparently in excess of the normal content of the ventricles ". This seems an extra- ordinary post-mortem phenomenon, and one which requires extensive confirmation before it can be seriously considered. Carlson and Martin 2 criticize the hypothesis of Herring and the observations of Cushing and Goetsch regarding the passage of infundibulin directly into the cerebrospinal fluid. These authors say : "It is obvious that the conclusions drawn by Cushing and Goetsch from their experiments are open to a number of grave objections. The cerebrospinal fluid used in most of the experiments was pathological, and was concentrated 20 to 25 times, and the intravenous injections were made into another species. Finally, no control experiments were reported on blood or serum from the same individuals yielding the cerebro- spinal fluid ". Carlson and Martin found that the haemodynaniic action of the cerebrospinal fluid was solely due to the quantity injected, as is the case with defibrinated blood or Ringer's solution : there is, in fact, no evidence of a specific pressor or depressor effect. These observers are careful to state, however, that their negative results do not prove that cerebrospinal fluid is free from pituitary secretion ; but, as they say, we have as yet no satisfactory test for this secret ion in the fluids of the body. When such tests have been worked out Carlson and Martin think that the distribution of pituitarj secretion in the body-fluids will prove to be similar to that of all the other internal secretions so far 1 Weed, L. H., and H. Cushing, Amer. Journ, Physiol., 1915, xxxvi, 77. 2 Carlson, A. J., and L. M. Martin, Amer. Journ. Physiol, 1911, xxix, 64. 104 PHYSIOLOGY studied, the concentration being greatest in the blood and least in the cerebrospinal fluid. With these statements I entirely agree. Cow 1 , apparently under the impression that the cerebro- spinal fluid has definitely been proved to contain infundibulin, asserts that the infundibulin content of this secretion is increased after injections of extracts of the duodenal mucous membrane, which he believes contains a hormone that excites activity in the pituitary. 1 Cow, D., Journ. Physiol., 1915, xlix, 441. INJECTION, INGESTION AND ABSORPTION EXPERIMENTS IMMEDIATE RESULTS OF INTRAVENOUS INJECTIONS, OF ABSORP- TION OF EXTRACTS IN SOLUTION AND OF GRAFTS Probably the most important and fruitful work carried out in connexion with the pituitary has been concerned with the physiological results of injections of the extracts into the living animal : certainly these results have been the most far-reaching in their application to morbid conditions. In this place I shall describe the physiological actions of the extracts on the different organs and systems as obtained in the laboratory, and shall merely indicate the practical application of them, for this aspect of the subject will be discussed in more detail later. Circulatory system In 1895 Oliver and Schafer 1 described the action of an extract of the whole pituitary upon the blood-pressure. These observers were, at the time, investigating the physiological effects of extracts made from chief organs of internal secretion, and they also gave an account of the pressor effect of suprarenal extract — that is, of the medullary portion of this organ. They stated, however, that the suprarenal extract is more powerful in this respect than that made from the pituitary. As the result of these observations and statements, the suprarenal product obtained clinical recognition, while the physiologically active principle of the pituitary remained in obscurity. 1 Oliver, (;., and E. A. Schafer, Journ. Physiol., 1895, xviii, 277. 106 PHYSIOLOGY In 1898 Howell 1 made some further observations. First, he found it is the extract of the posterior lobe alone— that is. of the pars nervosa and the pars intermedia, which come away together when the pituitary body is divided at the cleft — that has the pressor action. In this respect he found the extract of the anterior lobe to be inactive — an observation subsequently confirmed by many other investigators. Second, he observed that the cardiac rhythm is consider- ably retarded, and that the heart-beat is increased in force by the injection of an extract of this portion of the pituitary (fig. 70). This effect is believed by Dale 2 to be partly due to a direct action on the heart-muscle, and partly to a retardation of the flow in the coronary vessels. Third, Howell noticed that second and subsequent injections of infundibulin, if given soon after the first, produce little or no effect until the first has all been destroyed or excreted by the organism. In the following year Hedbom 3 found that the rate of beating in the isolated mammalian heart is considerably decreased on perfusion with infundibulin in Ringer's solution. Cleghorn 4 in the same year obtained results similar to those described by Hedbom. Also in 1899, Schafer and Swale Vincent 5 verified these experi- ments on the heart, and showed, further, that the slowing of the pulse is not constant — an observation I have myself confirmed in regard to the human subject — but that when present the effect is not abolished by atropine or by section of the vagi. These observations prove, therefore, that the action of the extract is peripheral in its effect. Schafer and Vincent noticed, too, that a fall in the blood- pressure follows the second and subsequent doses, if they be given soon after the first. Osborne and Vincent 6 subsequently found that this effect is produced by the depressor substance found in most organic extracts. It is certain, moreover, that it 1 Howell, W. H., Journ. Exper. Med., 1898, iii, 245. 2 Dale, H. H., Biochem. Journ,, 1909, iv, 427. 3 Hedbom, K., Skand. Arch. /. Physiol, 1899, \iii, 147. 4 Cleghorn, A., Amer. Journ. Physiol,, 1899, ii, 273. 5 Schafer, E. A., and S. "Vincent, Journ, Physiol,, 1899, xxv, 87. 6 Osborne, W. A., and S. Vincent, Brit. Med. Journ., 1900, i, 502. INJECTION EXPERIMENTS 107 -z £ a a o3 — a> £' O •= ■Z - ^ 2 1 os J, 50 •-« o-g * 05 — .3 S G 2 _~ m § "o « £ g © ~ _r — t- S -+a =:-- C t! t-t M O 1, PR — - £ © o so 00 g 3d rt DO © g 32 .o (U — ■+3 £- c3 cS o - C r. G to _o •3. 4£ +3 bC g Jj ,Q ^ ^ - □ °C _o 7. "^ - d t-i — bC C3 o © - — >» •I. M r. © © — _= — 108 PHYSIOLOGY is usual to see a preliminary fall of blood-pressure before the rise occurs (fig. 70). Mummery and Symes 1 , and Hick and I 2 independently observed that the blood-pressure is maintained at a high level for a much longer period of time than is seen after an injection of suprarenin. We also observed, as others had done, that a second dose has little or no effect until some time has elapsed since the administration of the first dose. We shall sec directly that it has been stated that infund- ibulin has a specific effect in regard to the renal vessels, but this point is best discussed in regard to the production of diuresis. Dale 3 and de Bonis and Susanna 4 have shown that con- traction is produced in the pulmonary arteries and arterioles by infundibulin. This is interesting in view of the facts, demon- strated by Brodic and Dixon 5 , that the muscular coats of the smaller arteries of the lung are not under the control of the sym- pathetic nervous system, and that suprarenin does not produce vaso-constriction in them. The coronary arteries, also, are thought by some 67 to be independent of sympathetic control ; but, like the pulmonary arteries, they are affected by the pressor action of infundibulin 3,4 ' 8 . Spleen Magnus and Schafer 9 have shown that infundibulin causes contractions in the muscular coat of the spleen, producing a decrease in the volume of the organ. Dale 3 has confirmed this observation. We shall see that advantage may be taken of this effect in certain affections of the spleen. 1 Mummery, P. L., and L. Symes, Brit. Med, Journ., 1908, ii, 786. 2 Bell, W. Blair, and P. Hick, Brit. Med, Journ., 1909, i, 777. 3 Dale, H. H., Biochem. Journ., 1909, iv, 427. 4 Bonis, de V., and W. Susanna, Zentralbl. fur Physiol, 1909, xxiii, 169. 5 Brodie, T. G., and W. E. Dixon, Journ. Physiol, 1904, xxx, 479. 6 Schafer, (quoted by Dale 3 ) Arch, de Sci. Biol, de St. Petersburg, 1904, 251. 7 Elliott, T. R, Journ. Physiol, 1905, xxxii, 401. 8 Pal, J., Zentralbl. fur Physiol, 1909, xxiii, 253. 9 Magnus, R, and E. A. Schafer, Journ. Physiol, 1901-1902, xxvii, 9. INJECTION EXPERIMENTS 109 Respiratory system Mummery and Symes 1 observed that a diminution in the amplitude of the respiratory movements is produced by an injection of infundibulin — an effect that may have some con- nexion with the action of infundibulin on the pulmonary circul- ation, already described. This is a matter of clinical importance. Urinary system Kidneys. — -In 1901 Magnus and Schafer 2 published experi- ments to show that the extract of the posterior lobe produces diuresis. Further, they stated that whereas all the other arteries in the body are constricted by the active principle of the extract, the arteries of the kidney are dilated, and that there is an increase in the kidney-volume. Subsequently, Schafer and Herring 3 found that diuresis occurred even when the arteries in the kidney failed to dilate, and when the general vasocon- striction was absent after repeated doses of the extract ; con- sequently they came to the conclusion that there must be direct stimulation of the secretory cells of the kidney during the excre- tion of a specific active principle. Herring 4 has recently stated that it is only an extract from the pars nervosa that produces diuresis and an increase in the kidney-volume. An extract made from the pars intermedia, like that of the pars anterior, is inactive in this respect. The view of Schafer and Herring that there is stimulation of the secretory cells of the kidney by the extract of the pars nervosa has found support in the experiments of Dale 5 , who has observed that infundibulin is excreted in the urine. Further, Dale does not believe that there are two active principles, but, rather, that there is one which has both a pressor and a diuretic effect. Gushing believes that the pars posterior contains both glycogenolytic and diuretic substances. 1 Mummery, P. L., and L. Symes, Brit, Med. Joum., 1908, ii, 786. 2 Magnus, R., and E. A. Schafer, Joum. Physiol., 1901-1902, xxvii, 9. 3 Schafer, E. A., and P. T. Herring, Proc. Roy. Soc. Biol., 1906, lxxvii, Ser. B, 571. 4 Herring, P. T., Quart. Joum. Exper. Physiol., 1915, \ iii, 215 and 267. 5 Dale, H. H., Bio-chem. Jowrn., 1909, iv, 427. 6 Gushing, H., Boston Med. and Surg. Joum., 1913, clxvhi, 901. 110 PHYSIOLOGY Cow 1 has recently endeavoured to prove that the pituitary is activated in regard to its diuretic function by a hormone from the gastrointestinal tract which is absorbed along with ingested fluids. Hashimoto 2 had previously stated that the diuretic effect of extracts of the duodenal mucous membrane is entirely due to their saline contents. Cow, however, disputes this point of view, and adduces arguments in favour of the specificity of duodenal extract in the respect mentioned. Bladder. — Frankl-Hochwart and Frohlich 3 first described the effect of infundibulin on the bladder. They state that strong contractions are always produced. Dale and Laidlaw 4 were unable to obtain the same result, and in our earlier experiments 5 we did not observe any definite action on the vesical musculature. Subsequently, I found that in the presence of considerable distension — such as could be produced by the use of the cannula and manometer apparatus, to be described presently in connexion with the recording of uterine contractions — expulsive contractions can usually be produced by the intravenous administration of infundibulin (fig. 71). I found, too, that, after the bladder had apparently been emptied with a catheter and only an occasional drop of urine was following, an intravenous injection of infundibulin caused the immediate evacuation of the residual urine in a series of rapid drops, and that shortly after the bladder had been completely emptied a further rapid outflow of drops occurred (fig. 72). The second flow probably represented increased secretion from the kidneys — that is, a diuretic effect. Wc shall see later that in clinical practice infundibulin is very unreliable in regard to the evacuation of the bladder. 1 Cow, D., Journ. Physiol., 1915, xlix, 441. 2 Hashimoto, M., Arch. f. Exper. Pathol, u. Pharkamol, 1914. Ixxvi, 367. 3 Frankl-Hochwart, L. von, and A. Frohlich, Arch. /. Exper. Pathol, tt. Phar- makol, 1910, lxiii, 347. 4 Dale, H. H., and P. P. Laidlaw, Journ, Pharmacol, and Exper. Therap., 1912, iv, 75. 5 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, i, 777. Kymograph -tracing shfhere is an immediate expulsion of residual urine, and [To face page 110. Kyi!Mi:r:L|>h-tr;u-iiiL' ^ho\\ »ia euntn-irtiuns nt l In- i.li>tviuli-il Madder of the cat after an inject iuii \\ mil: tin c-tk-t-l nf infimdibnlin c nediate expulsion of residual urine, and [Tofacfpage 110. INJECTION EXPERIMENTS 111 Uterus In 1907 we were engaged in investigating uterine contrac- tions in the rabbit 1 . Extracts of all the ductless glands were employed, and among them an extract of the posterior lobe of the pituitary obtained from the ox. We found that although the resting — that is, the non- pregnant and non-cestrous — uterus in the rabbit did not react, the menstruating and pregnant uterus contracted very violently in pithed animals, when an intravenous injection was given. We noticed, also, that the range of action was considerably longer and more powerful than was the case when suprarenin had been injected. Before this date Dale 2 had illustrated incidentally the effect of an extract of the pars posterior upon the uterus, but the illus- tration with no comment in the text was buried in a paper on the action of ergot, and was quite unknown. It is possible that other laboratory workers may have used infundibulin for comparative tests. In a later paper Dale 3 criticized the negative results obtained on the resting uterus of the rabbit, and he stated that the resting uterus of the cat will always react to the extract. It must be remembered, however, that the resting uterus of the rabbit undergoes marked seasonal changes, in the winter especially, when there is a considerable degree of atrophy. Dale made the valuable observation that whereas the effect of suprarenin on the uterus is negatived by a previous injection of ergotine, the action of infundibulin is not affected in the same way. In estimating the degree of contraction we employed a new method whereby a special cannula (fig. 73) full of saline solution was passed up the vagina, and, under guidance through a small incision in the abdominal wall, into a uterine horn in which it was tied with a woollen ligature. The cannula was then con- nected with a manometer containing saline solution and attached to an air-bellows with a recorder. By this means we obtained 1 Bell, W. Blair, and P. Hick, Brit. Med, Journ,, 1909, i, 777. 2 Dale. H. H., Journ. Physiol, 1900, xxxiv, 163. 3 Dale. H. H.. Biochem. Journ., 1909, iv, 427. 112 PHYSIOLOGY a record of the total expulsive effect. Figure 70 shows a tracing of the effect produced on the uterine contractions, as well as on the blood-pressure, by an intravenous injection of infundibulin in a pregnant cat. Further, we found that the isolated uterus suspended in Ringer's solution contracts on the addition of infundibulin — an effect that indicates that the action of infundibulin on the uterus is peripheral. Fig. 73. Uterine cannula for recording the expulsive contractions of the uterus in animals. Alimentary tract Intestines. — During the course of our work on uterine con- tractions we discovered that the infundibular extract may produce a remarkable pressor effect on the intestinal muscles. Our attention was first called to this phenomenon by the observation that on several occasions actual defecation was produced at regular intervals in a pithed rabbit. At each evacuation there was a sudden rise in the blood-pressure (fig. 74). Records of the intestinal movements are, however, best obtained by tension-sutures attached to a piece of isolated bowel suspended in Ringer's solution, and connected with a lever. In many cases we find that on the addition of infundibulin INJECTION EXPERIMENTS 113 to the solution there is relaxation, and cessation of the normal contractions (fig. 75) ; but that often this is preceded by a powerful contraction (fig. 76). Ott and Scott 1 , Houssay 2 and others have confirmed these results. Bayer and Peter 3 found that in the isolated intestine after an initial diminution in the movements there is a marked increase in their amplitude. These observers consider the first effect to be due to stimulation of the sympathetic fibres which inhibit the muscular contractions, and that the second is the result of the stimulation of the nerve-fibres connected with Auerbach's Fig. 74. Kymograph -tracing showing rises in the elevated blood-pressure corresponding to acts of defecation (D) in the rabbit after an injection of infundibulin. plexus. Bayer and Peter think that there are two active prin- ciples responsible for these opposite effects. Young 4 , also, has recently shown that infundibulin has a well- marked action on the intestine of the cat, raising the tone and causing the development of large oscillations ; but he points out that the watery solution of the extract must be fairly strong — not less than 2 per cent. 1 Ott, I., and J. C. Scott, Proc. Soc. Exper. Biol, and Med., 1911, viii, 48. 2 Houssay, B. A., La Ciencia Med., Buenos Aires (Reprint. Xo date); Revist. Soc. Med. Argent., Buenos Aires, 1911, 268 (Reprint). 3 Bayer, G., and L. Peter, Arch. f. Exper. Pathol, u. Pharmakol., 1911, lxiv, 204. 4 Young. A. W., Quart. Journ. Exper. Physiol, 1915, viii, 347. 8 114 PHYSIOLOGY Dale and Laidlaw 1 working with dogs were unable to obtain any increase in the intestinal movements. As we shall see, there is little doubt as to the power of infund- ibulin to produce contractions in the atonic intestinal muscles of the human subject — a condition occasionally seen after abdominal operations. It may be mentioned here that we have found that com- paratively the greatest range of action both in regard to the blood-pressure, intestinal movements, and uterine contractions can be obtained when there is loss of tone in the muscles concerned. Stomach. — In 1910 I recommended infundibulin for the treatment of postoperative atony and dilation of the stomach 2 . The effect obtained clinically was subsequently confirmed experi- mentally by Houssay 3 — the pressor effect being observed on the isolated stomach. This investigator 4 has also noted that injec- tions of infundibulin cause an increase in the flow of gastric juice, due to stimulation of the secreting cells. Mammary glands In 1911 Ott and Scott 5 announced that infundibulin acts as a galactogogue on the actively secreting mammary gland. MacKenzie 6 subsequently confirmed this finding. This is an unexpected, and at present not satisfactorily explained, phenom- enon. The effect is so rapid that it would seem improbable that the active principle is excreted by the mammary glands, and in its passage stimulates the secreting cells. Hammond 7 states that the effect is not brought about by the expulsion of milk which is stored in the cells and would have been obtained at the next milking, but rather by stimu- lation of the mammary epithelium. Nevertheless, Hammond found only a slight increase of the daily yield of milk. Further, 1 Dale, H. H., and P. P. Laidlaw, Journ. Pharmacol, and Exper. Therap., 1912, iv, 75. 2 Bell, W. Blair, The Principles of Qynoecology, 1910. 3 Houssay, B. A., La Ciencia Med., Buenos Aires (Reprint. No date). 4 Houssay, B. A., La Sem. Med., Buenos Aires, 1913 (No. 46) p. 5. 5 Ott, L, and J. C. Scott, Proc. Soc. Exper. Biol, and Med., 1911, viii, 48. 6 MacKenzie, K., Quart, Journ. Exper. Physiol., 1911, iv, 305. 7 Hammond, J., Quart. Journ. Exper. Physiol., 1913, vi, 311. Normal bowtl contractions relaxation after addition of Infundibul ' of 'in/undibuiin ioRi ngtr's i olution " Fig. ograph-tracing showing the effect of infundibulin on the cat's isolated small intestine suspended in I olution. In this case there was relaxation (upward release of the lever) without previous contractic ] Infundibulin added to Ringer's solution Fig. 76. Kymograph-tracing showing the effect of infundibulin on the cat's isolated small intestine suspent ger's solution. There was an immediate forcible contraction (downward pull on the lever) follow xation. [To face pa INJECTION EXPERIMENTS 115 Hammond states that the quality of the milk procured by the injection of infundibulin is normal except for an increase in the percentage of fat. It was found, however, that in the subse- quent milkings there was a drop in the fat-percentage, the other constituents remaining normal. There is no evidence that the increased secretion is due to elevation of the blood-pressure, for it is said by Schafer and MacKenzie 1 and by Hammond 2 , that expulsion of milk occurs, although in lessened quantities, after repeated doses of the ex- tract, in which circumstances the blood-pressure is not raised. Hammond, and Simpson and Hill 3 state that there is a rapid de- crease in the quantity of milk to be obtained after the first increase. . I have found that if one gland, from which the nipple has been amputated, be exhausted after an intravenous injection (fig. 77), and the nipple from another mamma on the same animal be amputated fifteen minutes later, there will also be an im- mediate, rapid outflow of milk from this organ, as the result of the intravenous injection of infundibulin administered in the first instance (fig. 78). This is interesting in connexion with the fact 4 that an histological examination of adjacent mammary glands, one of which has been incised and emptied by the ad- ministration of infundibulin, shows that in the exhausted gland the alveoli are empty and their walls are retracted, while in the adjacent mamma the alveoli are distended with milk (fig. 79). Hammond's and MacKenzie's experiments appear to some extent to negative the view that infundibulin acts on muscular tissue in the breasts, and thus leads to the mechanical expulsion of milk. Schafer 4 , however, in a recent paper, opposes the view that the infundibular hormone stimulates the secretory epi- thelium of the mammae, and expresses the opinion that the increase in the milk obtained is due to contraction of plain muscle- lil>res in the alveoli. It appears to me that all the experimental facts accord best with this view, that the increase in the rate of expulsion is due to a single pressor effect upon the muscle-fibres in the walls of the alveoli — a view held by most physiologists. 1 Schafer, E. A., and K. MacKenzie, Proc. Roy. Soc. Biol, 1911, Lxxxiv, Ser. B. 16. 2 Hammond, J., Quart. Journ. Exper. Physiol., 1913, vi, 311. 3 Simpson, S., and R. L. Hill- Quart. Journ. Exper. Physiol, 1915, viii, 377. 1 .Schafer, E. A., Quart. Journ. Exper. Physiol, 1915, viii, 379. 116 PHYSIOLOGY .2 ■- CD *** £ ce Ph " d -■a " -i - d o o - CD o -d CO cS CO s cS O - © +3 © +2 on eS eS i-i — O ■"C rd '5- s c« d U d © oa ^5 g8 INJECTION EXPERIMENTS 117 Apart from the effect of infundibulin, just mentioned, on the mammae of the lactating animal — due partly to the natural elasticity of the walls of the alveoli, and partly to the con- traction of the unstriped muscle to be found therein — the epithelial cells in the alveoli may be emptied of their milk contents during the process. I have, however, been able to obtain but slight evidence that the secretion in the cells is added to that in the alveoli already distended and unable to evacuate their contents. An histological examination of the mammas of a lactating animal removed before and after the administration Fig. 79. Section of the edges of adjoining mammae in the guinea-pig, showing below alveoli emptied after an intravenous injection of infundibulin and excision of the nipple, and above the alveoli of the adjacent unemptied mamma. X 125. of infundibulin shows a slight difference in the size of the alveoli in the different circumstances (fig. 80). I have, also, made experiments, hitherto unrecorded, which bear on the question of the stimulation of mammary secretion. Strictly speaking, they concern the late, rather than the im- mediate, action of the pituitary hormones, but I shall consider them here rather than under the next sub-heading. 118 PHYSIOLOCxY I was anxious to discover whether the mammary epithelium of the virgin animal could be stimulated into any semblance of secretory activity by injections of pituitary extracts. In all cases one mamma was first removed to serve as a control to the subsequent histological examinations of the remaining mammary glands at the conclusion of the experiments. Fig. 80. Sections of mamrnSe from a guinea-pig. On the left are shown the alveoli of a mamma removed for control. On the right are the alveoli of the corresponding mamma of the opposite side, from which the milk was not allowed to escape after an intravenous injection of infundibulin. It will be noticed that there is apparently a slight filling of the vesicles after the administration of infundibulin. X 125. 1. Three adult virgin guinea-pigs received injections of a saline extract of the pars anterior. Of these two received 20 injections of 0*5 c.c. of this extract (equivalent to 0*25 gramme of fresh pars anterior substance) on alternate days ; and one only 7 injections, when it died. 2. Six adult virgin guinea-pigs received injections of a saline extract of the pars posterior. Of these three received 18 injections of 0*1 c.c. (equivalent to 0*02 gramme of fresh pars posterior substance). They were all found dead on the day after the last injection, and on the same date. The INJECTION EXPERIMENTS 119 other three animals each received 27 daily injections, and remained well. The mammae, removed from the animals in both experi- ments, after they had died or had been killed, were carefully examined, but in no case was any change observed which could be construed into an indication of secretory activity. It seems probable, therefore, that extracts of the pituitary cannot of themselves arouse activity in the breasts. At the same time, it is not possible to assert on the evidence of these experi- ments, which were concerned with virgin animals, that infund- ibulin does not affect the secretion of mammae already lactating. It may be stated, then, that the problem of the cause of the immediate increase in the flow of milk in a lactating animal, which is very definite, is still not completely solved. Dilator muscles of the iris In 1908 Cramer 1 showed that infundibulin produces dilatation of the pupil in the enucleated eye of the frog. On the other hand, Dale 2 states that no such effect can be obtained on the mammalian eye. Pancreatic secretion There is one more interesting study of the effects of the injections of extracts to which allusion must be made. I refer to the action of infundibulin on the secretion of the pancreas. Pemberton and Sweet 3 have done the most important — indeed, the only important — work on this subject. These observers found that the pancreatic secretion is inhibited by injections of infundibulin. This result is produced repeatedly, even when the blood-pressure fails to rise after subsequent injections. Inhibition is also caused when the pancreas is stimulated by the normal excitant — hydrochloric acid — in the duodenum. 1 Cramer, W., Quart. Joiirn. Exper. Physiol., 1908, i, 189. 2 Dale, H. H., Biochem. Journ., 1909, iv, 427. 3 Pemberton, R., and J. E. Sweet, Arch. Int. Med., 1910, v, 466. 120 PHYSIOLOGY Immediate results of absorption from grafts This has long been a recognized method of proving that certain tissues possess an internal secretion, and grafts of most of the hormonopoietic glands have been successfully implanted, and have continued physiologically active for a time. It is, of course, a method of local absorption. We have already noted the effect of infundibulin in Ringer's solution on the uterus and other involuntary muscles — a method of local absorption utilized to test the mode of action of the extract on these muscles. By the method of grafting we may obtain the normal effects of the internal secretion of the organ concerned. From the work that has been done on this subject we know that certain conditions and circumstances greatly assist or modify the results of this procedure. Thus, it is almost an universal rule that autoplastic transplantation — that is, the removal of an organ or a portion of it from, and reimplantation into, the same individual — is far more successful in the immediate and late results than homoplastic grafting, in which the organ of one individual is transplanted into another of the same species, or of heteroplastic substitution from another species. Halsted 1 laid down that for really successful transplantation there must be considerable insufficiency of the internal secretion in question — in other words, the whole or a large portion of the particular organ must be removed if implantations of the same structure are to be successful. I have tested this statement in regard to the grafting of ovaries — one ovary being removed and after suitable treatment reimplanted, and the other left. It was found subsequently, at various periods, that the grafts were in an active condition in spite of the existence of one normal ovary. My investigations, therefore, do not entirely support Halsted's view. It is a most important question, for, if a successful reimplantation can be carried out — as I believe — before the total removal of an organ of internal secretion, a patient's life may in this way be secured from serious disturbances or from jeopardy. Further, it is, of course, essential in all cases of grafting that the implantation should be made where there is a good blood- supply. I have never favoured the peritoneal cavity or equally 1 Halsted, W. S., Jovrn. Exper. Med., 1909, xi, 175. ABSORPTION FROM GRAFTS 121 avascular sites, because in such situations the graft is often smothered by a dejjosit of lymph, and perishes before vascular connexions can be established. Implantation into the kidney has been practised with considerable success in the case of the ovary ; but grafts appear to do equally well when placed in muscle, a situation which, at any rate in the case of the human subject, is the safest and most convenient. Moreover, the grafts must be thin : it is useless to attempt to implant large blocks of any organ, for the central portions under- go necrosis before the blood-supply can be established. Last, it is hardly necessary to add that perfect asepsis is essential to success. Very few observers seem to have studied the question of the implantation of the pituitary body. Crowe, Gushing and Homans 1 , as we shall see later, were able to prolong the life of some of their dogs by previous or simultaneous implanta- tion of the anterior lobe, but in no case was a permanent effect obtained. Schafer 2 failed to secure good results. He employed homo- plastic and heteroplastic grafts in animals from which the pituitary had not been removed. Both of these circumstances may have militated against success, although, in spite of Halsted's dictum, I do not think the existence of a normal pituitary would do so. Schafer also tried the effect of grafts from the posterior lobe, and observed a temporary and moderate polyuria. As the graft disappeared so did the increase in the quantity of urine secreted. No doubt so long as any infundibular secretion remains to be extracted from the graft the effect mentioned may be observed, if the extract of the pars nervosa causes diuresis : but when all this is absorbed there will be a return to the previous state. Allusion has already been made to Cushing's apparently successful implantation of a homoplastic graft in the human subject. It is, however, clear that the small amount of work which has been done on implantation of the pituitary has not proved satisfactory ; but it is also apparent that various necessary 1 Crowe, S. J., H. Gushing, and J. Homans, Bull. Johns Hopk. Hosp., 1910. xxi, 127. 2 Schafer, E. A., Proc. Boy. Soc. Biol, 1909, lxxxi, Ser. B. 442. 122 PHYSIOLOGY conditions, already mentioned, have not always been carefully observed. The subject is an important one, for in the future the success of some of the surgical procedures practised in connexion with the pituitary body may depend on satisfactory implantations. LATE RESULTS OF INJECTION AND INGESTION Schafer 1 has investigated the effects of feeding with anterior lobe, and Cerletti 2 of injecting an emulsion into the peritoneal cavity. Schafer's experiments were not very conclusive, but they tended to show that there is more rapid increase in the weight of animals receiving an extract of* the anterior lobe than of the controls. Cerletti found retardation in the growth of bones in the animals to which the extract was administered ; but his control experiments have been considered unsatisfactory. Metabolism experiments under these conditions have been carried out by various observers, but the results obtained have been most conflicting. Oswald 3 administered an extract of the whole gland by the mouth to dogs, but observed no effect on the nitrogen and phosphorus excretions. Malcolm 4 in a series of experiments came to the following conclusions. The administration of dried pars anterior causes retention of nitrogen and phosphorus. Dried pars nervosa (? posterior lobe) produces the same effect. Fresh entire gland produces an opposite effect in regard to the nitrogen. The dried partes anterior and nervosa (? posterior) both cause an increased output of calcium ; but the former also brings about a large excretion of magnesium in the fasces, while the pars nervosa does not do so to the same extent. The same investigator found that the fresh gland has no influence on the calcium output when the animal is on a calcium-poor diet, but rather a tendency in the opposite direction. The excretion of magnesium, however, is increased. 1 Schafer, E. A., Proc. Roy. See. Biol, 1909, lxxxi, Ser. B. 442. 2 Cerletti, U., Arch. Hal. d. Biol, 1907, xlvii, 123. 3 Oswald, A., Virchow's Arch., 1902, clxix, 444. 4 Malcolm, J., Journ. Physiol, 1904, xxx, 270. LATE RESULTS OF INJECTION AND INGESTION 123 Franchini 1 observed that there is a reduction in the calcium, magnesium, and phosphorus metabolism in animals fed with an extract of the whole gland. Wasting, intestinal ulceration and cardiac hypertrophy were also seen. Thompson and Johnson 2 found that whole-gland pituitary extract stimulates the metabolism in the dog in an increasing degree even when the dose is not increased. This is shown in the output of nitrogen, urea and the phosphates, and also by the loss of body-weight. Schafer and Vincent 3 found that subcutaneous injections given over a length of time produce marked toxic effects : there is quickened respiration and increased pulse-rate, associated ultimately with paralysis beginning in the hind legs. Glycosuria and diuresis are almost constant symptoms in rabbits ; and Thaon 4 has recorded hematuria as a late result. Carraro 5 observed that hepatic degeneration with necrosis of the liver-cells occurs after long continued injections of infundib- ulin. Conti and Curti 6 state that the toxic symptoms following injections of pituitary extracts are ameliorated by the previous injection of thyroid extract or of an extract of the pituitary itself. Rosalind Wulzen 7 found that the growth of a young fowl is retarded by the addition to the diet of fresh unmodified anterior lobe of ox's pituitary. This was shown in the body- weight and the diminished growth of the long bones. She also noted involution of the thymus. All these changes were more marked in males than in females. The results obtained appeared to be dependent to some extent on the dosage employed. With regard to the renal excretions, Carlson and Martin 8 , referring to the work of Borchardt 9 and of Goetsch, dishing 1 Franchini, G., Berl. Klin. Woch., 1910, xlvii, 613, 670, and 719. 2 Thompson, W. H., and H. M. Johnson, Journ. Physiol, 1905-6, xxxiii, 189. 3 Schafer, E. A., and S. Vincent, Journ. Physiol, 1899-1900, xxv, 87. 4 Thaon, P., Lliypophyse, Paris, 1907. 5 Carraro, A., Arch. p. le Sci. Med., 1908, xxxii, 42. 6 Conti, A, and O. Curti, Boll. Sci. Med. di Bologna, 1906, viii, 629. 7 Wulzen, R., Amer. Journ. Physiol, 1914, xxxiv, 127. 8 Carlson, J., and L. M. Martin, Amer. Journ. Physiol, 1911, xxix, 64. 9 Borchardt, L., Zeitsch. f. Klin. Med., 1908, Ixvi. 332. 124 PHYSIOLOGY and Jacobson 1 , which seemed to show that injections of the posterior lobe may cause hyperglycemia and glycosuria, assert that cerebrospinal fluid, which according to Gushing and others contains infundibulin, has no such effect in meat-fed dogs. Carlson and Martin also state that intravenous injections of large quantities of extracts of both lobes of the pituitary do , not give rise to sugar in the urine — even though pushed until toxic symptoms, such as vomiting and purgation, appear. Goetsch 2 has quite recently made some extensive investiga- tions concerning the influence of feeding with pituitary extracts upon growth and sexual development ; and he has come to the following conclusions. A dried and powdered extract of the posterior lobe causes failure to gain in weight, loss of appetite, increased peristalsis with enteritis, muscular tremors and weakness of the hind limbs. The same effects are observed after the administration of ex- cessive doses of whole-gland preparations, owing to the extract of the pars posterior contained therein. The administration of dried and powdered pars anterior causes an increase in the rate of growth, and early sexual develop- ment in the young animal. I myself have investigated the late effects on a few adult female animals of injections of extracts made from the pars anterior and the pars posterior ; but no metabolism experiments were carried out. I obtained the following results. Two guinea-pigs which received on alternate days 20 in- jections of 0*5 c.c. of an extract of the pars anterior lost a little weight : one animal weighing 300 grammes was found to weigh 270 grammes at the end of the experiment ; and the other, which originally weighed 310 grammes, ultimately weighed 290 grammes. Such slight losses in weight may have been due to the general disturbance caused by the injections. A third animal, which was found dead after the seventh injection, weighed 500 grammes at the beginning of the experiment, and only 450 grammes at the end. Three guinea-pigs which received 0*1 c.c. of infundibulin all gained in weight. One weighing 430 grammes ultimately 1 Goetsch, E., H. Gushing, and C. Jacobson, Bull. Johns Ilopk. Hosp., 1911, xxii, 165. 2 Goetsch E., Bull. Johns HopL Hosp., 1916, xxvii, 129. LATE RESULTS OF INJECTION AND INGESTION 125 weighed 500 ; another of 300 grammes increased to 330 grammes ; and the weight of the third rose from 280 grammes to 300 grammes. Three other animals died on the same date after receiving 18 injections each, and in all probability they died of some intercurrent affection. These three guinea-pigs, also, had increased in weight : the first from 270 to 280 grammes ; the second from 400 to 420 grammes ; and the third from 220 to 240 grammes. In no case were the doses pushed to lethal quantities ; but with the quantities used, which were not small in proportion to the body-weight, no other definite changes were detected in the condition of the animals, nor were obvious symptoms produced. In one case a virgin guinea-pig was fed daily with 0'5 gramme of pars anterior for 45 days, then with 1*0 gramme for 14 days, and finally with 2'0 grammes for 50 days. This animal increased in weight from 390 grammes to 420 grammes. In all cases complete post-mortem examinations were con- ducted on the animals, whether they died or were killed ; and special attention was directed to the histological appearances of the reproductive organs and of the hormonopoietic glands. Only in the case of the pituitary was any definite change observed. This occurred in the two guinea-pigs that received 20 injections of an extract of the pars anterior. In both cases the pars anterior of the pituitary showed only chromophobe cells, which were arranged in acinous formation. In all the other cases, including the animal which was fed with dried anterior lobe, the pituitaries were normal in regard to the differential staining of the cells. It is, perhaps, also worthy of mention that colloid was some- what excessive in quantity in the thyroids of the animals which received injections of, and of the one which was fed with, extract of the pars anterior. § ii. PATHOPHYSIOLOGICAL INVESTIGATIONS OPERATIONS ON THE PITUITARY Of the two methods of eradication — destruction in situ and removal — the latter is preferable, for it is impossible in applying the actual cautery or caustics to limit the sphere of action, or exactly to destroy different parts of the pituitary body. Even when complete destruction is desired it cannot be said with certainty, although the pituitary may have been destroyed, that the lesion is confined to that organ. DESTRUCTION OF THE PITUITARY Destruction of the pituitary in situ has been attempted many times by means of the actual cautery, by caustics, such as chromic acid (Marienesco 1 ; Vassale and Sacchi 2 ; Fichera 3 ), and by ' needling ' (Lomonaco and Rynberg 4 ; Gaglio 5 ). The oral route through the basisphenoid has been the method of access usually employed in the former procedures, and occa- sionally the vertical route for destruction of the pituitary by needling. A more interesting — if equally doubtful — method of destruc- tion was that of Masay 6 who used a cytotoxic. He thought 1 Marienesco, G., Compt, Rend, Soc. Biol, 1892, xliv, 509. 2 Vassale, G., and E. Sacchi, Riv. Sper. di Freniat., Reggio-Emilia, 1892, xviii, 525. 3 Fichera, G., Sper. Arch, di Biol, 1905, lix, 739. 4 Lomonaco, D., and R. van Rynberg, Atti Accad. dei Lincei, 1901, x, 117, 212 and 265. 5 Gaglio, G, Arch. Ital d. Biol, 1902, xxxviii, 117. 6 Masay, F., Uhypophyse, Bruxelles, 1908. REMOVAL OF THE PITUITARY 127 a specific reaction was obtained as the result of his experi- ments, associated with histological changes in the pituitary ; but as the group of symptoms produced included wasting, it can hardly be conceded that specific pituitary insufficiency was pro- duced, for it has been almost conclusively proved that this state is associated with adiposity. REMOVAL OF THE PITUITARY The first experimental removals were undertaken by Victor Horsley 1 ; but most of the animals died soon after opera- tion, and very little information was obtained. Later Caselli 2 , Friedmann and Maas 3 , Vedova 4 and many others — too numerous to mention — attempted extirpation by various procedures and routes, but were unsuccessful in obtaining satisfactory results. The methods of access employed were generally either the temporal route, or more commonly the oral. In the former the temporal bone was widely removed and the temporal lobe of that side raised, in order that the operator might reach the base of the brain. In the oral route the basisphenoid was per- forated and the pituitary body scraped out with a spoon. At- tempts have also been made to deal with the pituitary in animals by reaching it through the frontal fossa. In this method the frontal lobe is raised, much in the same way as that adopted for the temporal lobe in the lateral operation. It is quite obvious that in animals the anterior route has incomparably less advantage than the lateral, and that the oral route through the basisphenoid — apart from creating an open door for sepsis — is somewhat of a shot in the dark, for the operator can have no possible idea of what he is actually removing. These remarks concerning the basisphenoidal route refer to experimental work, and do not apply to operations on the human subject, in whom decompression alone through the floor of the sella turcica by the nasal (not oral) route 1 Horsley, Victor, Lancet, 1886, i, 5. 2 Caselli. A., Biv. Sper. di Frt nidi., Beggio-Emilia, 1900, xxvi, 176 and 486. 3 Friedmann, F. F., and O. Maas, Bert Klin. Wnch., 1900, xxxvii, 1213. 4 Vedova, Dalla, Boll. Accad. Med. di Boma, 1903, xxix, 150; idem l!i<>4, xxx, 137. 128 PHYSIOLOGY may produce satisfactory results in certain lesions of the pituitary. All the earlier experiments were, therefore, more or less com- plete failures ; and it was not until the more recent work of Paulesco 1 who, with the aid of a surgical colleague, evolved the procedure known as the bitemporal method, that successful operations were accomplished, and reliable results obtained. Nevertheless, the published accounts of operations experimentally performed on the pituitary by the newer method of approach are still surprisingly few. It is probable that, apart from the investigations of Paulesco (1908), of Harvey Cushing and his colleagues (1909, 1910), and possibly also of Silbermark (1910), Biedl (1910) and Ascoli and Legnani (1912), no successful work has been carried out. Further, although Victor Horsley (1886) was certainly the first to perform extirpation experiments in this country, and probably in the world, there do not appear to have been any attempts either by surgeons or physiologists, in Great Britain — apart from later experiments 2 by the operator just mentioned — to conduct investigations on these lines until those recorded in the year 1917 3 . My experiments were concerned not only in an attempt to gain further information in regard to the experimental pathology of the pituitary, but also in testing the correctness or otherwise of the experiments of Paulesco 4 , and of Cushing and his fellow- workers 4,5 . I shall first give a somewhat full account of my own work, as this has only recently been published and as so little has been done on the subject, also in the hope that my experiences may assist others to conduct fresh investigations which are urgently needed. Afterwards, I shall discuss together all the results obtained by the improved methods of technique since Paulesco entered this interesting field of investigation. 1 Paulesco, N. C, Dhypophyse du cerveau, Paris, 1908. 2 Handelsmann (no initial in original), and V. Horsley, Brit. Med. Journ., 1911, ii, 1150. 3 Bell, W. Blair, Quart. Journ. Exper. Physiol, 1917, xi, 78. 4 Reford, L. L., and H. Cushing, Bull. Johns Hopk. Hosp., 1909, xx, 105. 5 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hopk. Hosp., 1910, xxi, 127. REMOVAL OF THE PITUITARY 129 Operative technique In my experiments 27 bitches were subjected to operation, and of these two died as the result of the operative procedures, as distinct from the actual lesions produced in the pituitary. Only one of the deaths could be attributed to faulty surgical technique, and in this case the operation was abandoned owing to haemorrhage from which the animal succumbed shortly after- wards. The other immediate death was due to an overdose of ether before the completion of the operation. Another animal died soon after total extirpation of the pituitary from some unknown cause — possibly from an overdose of the anaesthetic. All the other cases did well so far as the operative procedures were concerned. Excluding, then, the two bitches that died before the com- pletion of the operation, 25 cases are left for consideration (tables II-X). Most of the animals used were from four to seven months old, but a few were a little older. The younger the dog is, the easier the operation, owing to the thinness of the skull and lesser risk of serious intracranial haemorrhage. Preliminary procedures. — For ten days previously to the principal operation the animal received daily 10 grains of forma- mine in the food, in order that the cerebrospinal fluid might be rendered antiseptic, as advised by Crowe 1 . Anaesthesia was produced with ether by the ' open ' method a few days before the operation on the pituitary, and a small portion of one uterine horn together with part, or the whole, of the ovary on the same side were removed through a lateral abdominal incision for the purpose of control observations in connexion with subsequent changes in the genitalia. At the conclusion of this operation the whole of the top of the head and back of the neck was closely shaved, in order to lessen the time occupied at the second operation. In those cases in which a fatal result was anticipated — except in the case of bitch no. 19 — the removal of portions of the genitalia was not practised, but the preliminary shaving was always effected. Method of producing ancesthesia. — In view of the difficulty of working aseptically and comfortably (hiring the operation on 1 Crowe, S. J., Bull. Johns Hopk. Hosp., 1909, xx, 102. 9 ISO PHYSIOLOGY the pituitary in close proximity to the administrator, if the anaesthetic were given in the ordinary way, I decided to use an intratracheal method for the administration of ether. This was found to be ideal after we had overcome the initial diffi- culties, which caused us to lose certainly one and possibly two out of the first three animals submitted to operation. In all Fig. 81. Apparatus for the administration of intratracheal ether. (Photograph.) A, tube from bellows ; B, indicator of three-way tap ; C, tube to ether-container ; D, ether- container ; E, tube from ether-container ; F, tube to mercurial pressure- valve ; G, mercurial pressure- valve ; H, pressure-manometer ; I, tube to catheter ; K, catheter. the subsequent cases the anaesthesia was smooth, uninter- rupted and safe, and the animal was easily restored to conscious- ness as soon as the operation was completed by the administra- tion of air alone through the intratracheal tube. In figure 81 the apparatus used is illustrated. It is an easily made adaptation of the more complicated machines in REMOVAL OF THE PITUITARY 131 general use for the intratracheal administration of ether to the human subject. Practice may be required in passing the soft rubber catheter into the trachea. The size of the catheter is determined by the diameter of the animal's trachea, which the catheter should never fit closely. The insertion of the catheter was effected after the animal had been anaesthetized with ether by the ordinary ' open ' method. During the intratracheal administration of the anaesthetic the animal rarely received concentrated ether-vapour : it was usually sufficient, once the animal was fully anaesthetized, to continue the anaesthesia with a mixture of air and ether-vapour, regu- lated by means of a three-way tap to which an indicator was attached (fig. 81, B). By this means ether, ether and air mixed, or air alone could be pumped into the lungs under uniform and limited pressure. The anaesthetist sat at the side of the table opposite to the operator with his hand underneath the covering cloth and rest- ing against the side of the animal, in order to judge of its con- dition : quiet, deep and slow respiration indicated perfect anaes- thesia ; rapid, shallow breathing too deep anaesthesia ; while insufficient anaesthesia was shown by jerky and spasmodic respiration, or even by the animal coughing. The heart-beat also gave an indication of the condition of the subject. Surgical procedures. — The animal, completely under the influence of ether-vapour administered intratracheally, was placed on its belly on an electrically heated table with the chin resting on a V-shaped depression cut out of a solid block of wood (fig. 82). The legs were fixed to the sides of the table, and the ears were tied together across the throat by means of a silk suture passed through the tips. Next, the eyes were carefully protected with dabs while the previously shaven scalp was thoroughly purified with iodine dissolved in chloroform or spirit. The animal was then entirely covered with a sterilized sheet, in which there was a small aperture through which the opera- tion was conducted (fig. 83). The special sliding instrument- table attached to the operating-table (fig. 82) was also com- pletely covered with a sterilized cloth (fig. 83). A long incision, extending backwards from the root of the nose in the mid-line over the vault of the skull as far as the occipital protuberance, was carried downwards and laterally 132 PHYSIOLOGY View of operating-table, showing also the sliding instrument-table, the V-shaped block for animal's head, and the tube leading to the ether apparatus. {Photograph.) Fig. 83, View of operating-table and sliding instrument-table covered with sterile cloths, as at the commencement of the operation. {Photograph.) REMOVAL OF THE PITUITARY 133 behind the ear on the side from which the approach to the pituitary was to be made (fig. 84). This incision was found to be better than the Y-shaped incision which was adopted by dishing and others, and which I, also, employed in the first few operations. Next, the skin over the right temporal region was turned Fig. 84-. view of a bitch's head, showing the line of incision. (Photograph.) xi down, and the temporal muscle and pericranial fascia were carefully reflected from the underlying temporal bone, which was removed widely with a trephine and rongeur. The dura mater was opened with a triradiate incision, care being taken to avoid the vessels (fig. 85). The muscle-flap was then loosely replaced together with the overlying skin, and attention was turned to the other side from which the major portion of the 134 PHYSIOLOGY operation was to be conducted : in my experiments this was always on the left side of the animal. The skin overlying the temporal region was raised on this side until the zygomatic arch was exposed. This structure was excised, together with the overlying aponeurosis, with a pair of bone-cutting forceps. The temporal muscle was reflected as on the right side, and the temp- oral bone widely removed with a trephine and rongeur (fig. Fig. 85. View of the field of operation at the stage when the bilateral openings have been made in the skull. 85). On this side, however, care was taken that the aperture made extended down as far as possible to the base of the skull. If there were any bleeding from the bone on either side it was readily stopped with bone-wax. In figure 86 is seen a skiagram of the skull of one of the animals taken during life a few weeks after operation : the large aperture made on the left side is clearly shown. REMOVAL OF THE PITUITARY 185 . Fig. 86. Radiograph of bitch's head taken during life some weeks after operation, showing the large aperture made in the left side of the skull. (By Thurstan Holland.) Fig. 87. Soft metal spoon-shaped brain-retractor. (Photograph.) x|. 136 PHYSIOLOGY A head-light was now required ; and the next steps of the operation were conducted by the operator single-handed, for it was necessary to manage the brain-retractor with one hand, while the manipulations in connexion with the pituitary were carried out with the other. It will be evident, therefore, that as no assistant is really required for the initial and later stages, these operations can easily be performed without help ; but, in order to expedite matters, such as the cutting of ligatures, an assistant is desirable. The brain — that is, the temporal lobe on the left side — was carefully elevated with the special spoon-shaped retractor (fig. 87) recommended by dishing. As soon as the temporal fossa had been crossed a thickened ridge of dura mater attached to the inner limit was seen. This marks the outer edge of the sella turcica, or rather the fossa to the edge of which the dura is attached, and of which the sella turcica is the most dependent part. The long, hooked knife (fig. 88) was then taken, and a slit made in the dura mater above the lower attachment just mentioned. Care was taken to carry the incision forwards rather than backwards in order to avoid wounding a large vessel frequently encountered in the dura mater. When the tip of the retractor was passed through the opening thus made, a white glistening ridge or strand of rein- forced dura was disclosed, and, when the beak was tilted upwards, the third nerve Long, hooked knife passing from behind forwards and above for incising the dura downwards was brought into view, and in mater. (Photograph. ) b x f front of this the carotid artery. Between these two structures, but further in, the pituitary body was exposed (fig. 89). This organ was easily recognized by its typical apricot-like colour, which is due to the extreme vascularity of the anterior lobe. All blood and Fig. 88. REMOVAL OF THE PITUITARY 137 cerebrospinal fluid was now mopped out with small dabs of wool held in forceps bent at an angle (fig. 90). As soon as the field was dry the rest of the operation planned was carried out. Most of my operations consisted in the removal of portions of the pituitary. I used for this purpose a special pair of aural Fig. 89. View of the field of operation at the stage when the pituitary is first exposed. The circle of light from the head-lamp is seen in the centre of the field. forceps (fig. 91), which I found very convenient. It was im- possible to obtain, or have made, an instrument with spoon- beaks which were large enough to contain the pituitary body and which at the same time could be opened widely. With the instrument mentioned I was able to remove in several frag- ments most of the anterior lobe, and practically the whole of the posterior lobe intact. To remove the entire pituitary I 138 PHYSIOLOGY Fig. 90. Angular forceps for holding wool dabs with which the cerebrospinal fluid and blood are mopped. {Photograph.) Xf. Fro. 91. Aural forceps for removing portions of the pituitary. (Photograph.) Xi. Fig. 92. Author's chisel-hook for cutting through the stalk of the pituitary. (Photograph.) REMOVAL OF THE PITUITARY 139 had a special instrument made : this consists of a lower blade terminating in a blunt hook in which the stalk of the pituitary is caught ; the upper blade, which is formed like a chisel but is blunt, can be pushed in, so as to cut through the stalk caught in the hook (fig. 92). The lower attachments of the pituitary were always first separated with a fine blunt Watson-Cheyne's dissector (fig. 93), before the stalk was cut through ; after this the pituitary could be lifted out with a pair of bent forceps. This freeing of the lower attachments of the pituitary was found advisable in all operations except those in which the stalk was separated or clamped, or in which an artificial tumour was in- troduced. The operation was completed by the sewing of the temporal muscles in place and the closure of the incision through the skin. Alarming haemorrhage sometimes occurred during the operation, especially in the older animals, but in all except one case this was controlled without difficulty ; and probably there was a little carelessness in the case that was lost, for we had been accustomed easily to check the haemorrhage with plugs of wool, and had come to regard it as of small consequence. Nevertheless, the operation was found to be much less for- midable .than the previous descriptions of it led us to expect. The average time occupied by the actual operations was 39 minutes. The final determination of the character of the operation in the extirpation experi- ments was made in every case by a careful comparison of the tissue removed at operation with the post-mortem histological findings. As it seems hardly worth while reduplicating the illustra- tions which show more or less identical results, only those have / Pig. 93. Watson -Cheyne's dis- sector. (Photograph.) 140 PHYSIOLOGY been reproduced which illustrate most clearly the findings that may be considered typical and important. Postoperative symptoms. — In no case were there severe com- plications, such as serious sepsis and paralyses, as the result of the operative procedures ; but sometimes there was an escape of cerebrospinal fluid from the wound. Generally, the animals drank milk within a few hours of the operation, and seemed little affected the next day, when they ate meat, and were able to get out of their beds and walk about. Of the genera] symptoms following operations on the pituitary, polyuria and glycosuria are not infrequent 1 — except after imme- diately lethal procedures when there may be anuria— and these phenomena are probably due to the action of glycogenetic and diuretic substances liberated from the pars posterior. With respect to the cachexia said by Cushing to be specific in connexion with certain pituitary lesions, I have been unable to verify his conclusions, and I am of the opinion that the supposed typical posture attributed to the so-called ' cachexia hypophyseopriva ' (see fig. 112, p. 173) is merely an attitude of weakness, which is always seen in dogs in an advanced stage of emaciation and debility from any cause whatsoever. I shall discuss later the curious somnolence which may over- take the animals after some of these operations. Control experiments These were two in number, and in both cases the bitches were submitted to the same general procedures as those adopted in the other experiments, even to the previous removal of a portion of the uterus and ovary. The pituitary body was exposed at the second operation, but no part of it was removed ; instead, small pieces of tissue were excised from the base of the brain in the neighbourhood. Neither of these animals showed any symptom until shortly before death, when one of them died with convulsions. This animal was probably poisoned, for another bitch which was chained up next to her died with convulsions at the same time. In both cases death occurred many months after operation, and in neither was any causal lesion found in the brain. 1 Cushing, H., Boston Med. and Surg. Journ., 1913, clxviii, 901. REMOVAL OF THE PITUITARY 141 In table II are given the details of these control experiments. One of the bitches (no. 9) before and 152 days after operation is shown in figures 94a and 94b. There was no change in the animal except some increase in size corresponding with the increase in age. Table 11. — Control Experiments. 2 si s o o — o 5 ■ •till "rt S P.M. findings. as "0 a> 2 a S3 <— p. 3 ■§ £ 2 i -i ~ i Z — j Pi a a - o £ ■°.2£ •3 & Macro- Micro- < 12 5 P. 6 ° 0Q sco pical. scopical . Pituitary 6 1 9 mos. Mar. 31 Sections Died 166 days None until Nothing show Sept. last 48 hrs. abnormal normal small 13 of life, piece of when fits brain occurred 9 Q 1 - Apr. 28 Sections show small piece of brain Killed Sept. 27 152 „ None Nothing abnormal Pituitary normal Total extirpation of the pituitary This operation (figs. 95 and 96) was effectually performed on six animals. In all cases a few cells of the reticulated portion of the pars intermedia must necessarily be left at the base of the brain, otherwise the third ventricle will be opened and part of the brain removed. The first animal died shortly after the completion of the operation — so soon that it is possible that death was due to an overdose of ether which was used too freely during the experi- ment. Of the other five all died within a short time — that is to say, within periods ranging between 22 and 36 hours. In all these five cases the animals recovered from the anaesthetic, and were able to take nourishment freely. Before long, however. 1 This animal and bitch no. 2 were kept side by side in the animal house. Both died with convulsions within a few hours of one another man}- months after operation. Strychnine poisoning was suspected, but the examination of the stomach of this bitch gave a negative result. No lesions were found in the brains of these animals that would account for the convulsions. 142 PHYSIOLOGY Fig. 94a. Bitch 9 before control operation. (Photograph-) Fig. 94b. Bitch 9, 152 clays after control operation. (Pliotograjrft. REMOVAL OF THE PITUITARY 143 Fig. 95. The anterior and posterior lobes of the pituitary removed at operation from bitch 1. (Photomicrograph.) X 15. < « (: I "-k; ' Sm Fig. 96. The base of the brain a1 the site of removal of the pituitary from bitch 1. [Photomicrograph.) X 15. 144 PHYSIOLOGY Table III. — Total, or Almost Total, Removal of the Pituitary. 23 27 30 S . •sa g s 3, p. 7 mos, 7 mos. 3 mos, 29 3i mos. 4 mos, o.o 9 | Feb. mos. I J 7 Apr. 7 Sept. Sept. 30 Nov. 9 Nov. 10 roscopical stigation of es removed operation. ■6 o '•3 Eh O val between ration and death. ■% & =>^- ^ a .2; M 3 a 5 Sections Died Died a show total Feb. short anterior 17 while and post- after erior lobes opera- tion Sections Died 24hrs. show total Apr. anterior 8 and post- erior lobes Sections Died 22 „ show total Sept. anterior 9 and post- erior lobes Sections Died 36 „ show total Oct. anterior 2 and post- erior lobes Sections Died 36 „ show total Nov. anterior 11 and post- erior lobes Sections Died 36 „ show post- Nov. erior lobe 12 only P.M. findings. "3 3 O Q Macro- scopical. Did not recover conscious- ness Dullness and re- fusal of food; finally coma. Respira- tions 10. Pulse 140 Coma. Respira- tions 13 Dullness ; then coma Dullness and re- fusal of food ; finally coma Coma No haemo- rrhage ; small blood-elut only Small blood-clot in sella turcica Small blood-clot in track of opera- tion Small blood-clot in sella turcica Small blood-clot in sella turcica Small blood-clot in sella turcica Micro- scopical. Stalk with ? Anses- a few pars thetic intermedia cells at- tached Stalk with a few pars intermedia cells and blood-clot attached Removal of pituit- ary Nothing but Removal small blood- of pituit- clot the size ary of pituitary A few pars intermedia cells with cysts below 3rd ven- tricle, and a small blood-clot A few de- generated pars inter- media cells lying in blood-clot below 3rd ventricle A few pars intermedia cells along base of brain. No sign of anterior or posterior lobe Removal of pituit- ary Removal of pituit- ary Removal of pituit- ary REMOVAL OF THE PITUITARY 145 they became somnolent, and, although it was sometimes possible to rouse them from this condition and to get them to stand and take food, they quickly became somnolent again as soon as they were left alone. After a few hours the respirations became very slow and coma set in ; finally death supervened. The details of these operations are shown in table III. No observable changes occurred in the genitalia in the few- hours of life subsequent to operation, nor were any definite changes found in the other hormonopoietic organs in these circumstances. I anticipated finding hyperplasia in the thyroid, for dishing is \ ery definite on this point, but in no case was any change to be discovered. Partial removal of the pituitary Removal of the Anterior Lobe. — (a) Total removal of the pews anterior. — In only two experiments was the anterior lobe Fig. 97. Section showing large portions of the pars anterior removed at operation from bitch 5. {Photomicrograph.) X 15. almost completely removed (table IV). It seems practically impossible to remove the entire anterior lobe without damaging 10 146 PHYSIOLOGY the posterior. In figure 97 are shown the portions of the pars anterior removed at operation from bitch no. 5. In both cases death followed the extensive removal of the pars anterior within a few hours. Nothing abnormal was observed in the other hormonopoietic organs after operation. Table IV. — Total or Almost Total Removal of the Anterior Lobe. 05 a> a . ■a «» S Ml o *■ a o o n>'-g Microscopical investigation of tissues removed at operation. ■6 eg ■3 O val between 'ration and death. H 3 o o a a 3 I P.M. findings. •a rS Macro - Micro- ■s 05 o s -go CG scopical. scopical . a ■s 5 7 Apr. Sections Died 70 hrs. April 7, Nothing Blood-clot in Removal mos. 6 show total anterior lobe Apr. 9 none. April 8, none. April 9, extreme drowsi- ness ; finally coma abnormal and around of ant- infundib- erior ulum. As lobe far as can be seen the pars ant- 1 erior has been re- moved en- tirely 8 5* Apr. Sections Died 32 „ Dullness Nothing No pars ant Removal mos. 9 show two Apr. and re- abnormal erior to be of ant- large pieces 11 fusal of found. erior of anterior food ; Poor section lobe lobe then coma of region The genitalia, too, showed no changes in the short period of time that elapsed between the operation and the death of the animals. (b) Partial removal of the pars anterior. — It has been mentioned that complete removal of the pars anterior alone is practically impossible, and that the removal of nearly all of it is usually fatal. Nevertheless, it is quite easy safely to remove large (figs. 98 and 100) or small portions of the anterior lobe ; consequently observations of the effects produced by these operations should be reliable. In table V are shown the results of removals of the pars anterior. There were five experiments, and in all the animals survived. It will be noticed that the results are not completely harmonious in regard to the details. REMOVAL OF THE PITUITARY 147 Table V. — Partial Removal of the Anterior Lobe. o 3 2 . Si « ft o.o *a - croscopical Bstigation of ues removed operation. -3 a a> 2 ?! o o a 3 £> o d © iS-d P.M. findings. 8 Z-2 -d | «.§ Macro- Micro- «< ■S-t= ~ "3 a t-i «i «o £ scopical. scopical. grm. grm. 3 4 Mar. Sections Killed 210 days March 11, 6680 5200 Uterus, Partial re- mos. 10 show large Oct. none. ovaries and moval of portion of 6 March 12, mammae pars ant - anterior drowsy. atrophied. erior lobe March 13, very Thyroid small drowsy. March 14, improved. Recovered 13 ? May Sections Killed 60 „ Drank Uterus, Partial re- 4' show fairly July some milk ovaries and moval of large piece 3 1 hour mammae pars anterior of anterior after slightly lobe operation. No symp- toms. Re- atrophied covered 15 6 June Sections Killed 9 „ None. Re- Nothing ab- Pituitary mos. 2 show small portion of anterior lobe June 11 covered normal. (Period too short be- tween ope- ration and death) much dis- turbed. Much hyper- plasia of ex- isting cells of pars an- terior mixed with blood - clot 19 G July Sections Killed 108 „ Drank 4850 5350 Nothing ab- Most of pars mos. 5 show very large Oct. 21 some milk 1 hour normal ; but no anterior re- moved. Pars amount of after control of posterior in- anterior operation. genitalia tact lobe July 6, drowsy. July 7, drowsy. July 8, improved. Recovered taken at a previous operation 24 4 Sept. Sections Killed 10 .. Animal Uterus, Most of the mos. 22 show very Nov. \ ery weak ovaries and pais anterior large 1 through- mammae removed. amount of out whole very Pars pos- anterior period slightly terior in- lobe atrophied. Thyroid very large tact 148 PHYSIOLOGY In no case in this series of experiments was there any observ- able increase in weight. Unfortunately only two bitches were weighed before as well as after operation, and of these no. 3 — shown before and 210 days after operation in figures 99a and 99b — lost weight subsequently to operation ; the other (no. 19) increased in weight in accordance with its normal increase in growth. Some of the animals when recovering from the opera- tion showed the peculiar condition of somnolence already de- scribed in connexion with total removal of the pituitary. As recovery progressed this state gradually passed off. Fig. 98. Section showing large portion of pars anterior removed from bitch 3. (Photom icrograph. ) X 15. Changes in the hormonopoietic organs other than the gonads were not found except, possibly, in the case of the thyroid from bitch no. 24. In this animal the thyroid was observed macroscopically to be considerably enlarged, but on histological examination the organ was found to be normal. The variability in the results would not be difficult to understand if it were only in the case of the removal of small portions of the pars anterior that no symptoms were produced, while excision of large amounts produced changes in the general REMOVAL OF THE PITUITARY 149 Fig. 99a. Bitch 3, before operation. (Photograph.) Fig. 99b. Bitch 3, 210 days after removal of a large portion of pars anterior. (Photograph.) 150 PHYSIOLOGY condition of the animal, in the genitalia and in the other hormonopoietic organs. But these were not the results that were obtained ; and it is difficult to understand why the removal of large portions (fig. 100) from one animal — no. 19 — should give rise to no ill effects, while the removal of smaller pieces, as in some of the other animals, should cause definite changes in the genitalia. In three out of the five cases in which portions of the pars anterior were removed the uterus (figs. 101a and 101b) and ovaries Fig. 100. Section showing large amount of pars anterior removed from bitch 19. {Photomicrograph. ) X 15. were definitely atrophied. In these circumstances we find in regard to the uterus that there is first of all atrophy in the muscular coats, and that this is soon followed by atrophy in the endometrium. The changes in the ovaries will be described later (p. 195). In two cases nothing abnormal was noted, but in one of these the length of time — nine days — that had elapsed between the operation and the post-mortem examination was probably not sufficient to permit atrophic changes to take place in the genitalia. In the remaining case no control was taken before REMOVAL OF THE PITUITARY 151 Fig. 101a. Section of the uterus of bitch 3 before operation. (Photomicrograph.) X40. T -V'' : . r '->" • "'■■-. - ■• v Fig 101b. Section of the uterus of bitch 3, 210 days after partial removal of pars anterior. (Photomicrograph. ) X40. 152 PHYSIOLOGY . Fio. 102. Section showing posterior lobe removed at operation from bitch 16. {Photomicrograph. ) I X 15. *l . V- '"'.' •% Fig. 103. Section showing the site of the pituitary after removal of the pars posterior from bitch 16. It will be seen that a small portion of the pars nervosa at the neck was left behind. (Photomicrograph.) X 15. REMOVAL OF THE PITUITARY 153 the operation on the pituitary, as it was intended that a fatal quantity should be removed. This, however, was not effected at the operation, although a large amount was excised (fig. 100). The uterus and ovaries showed no change from the normal after an interval of 108 days. Naturally, in any case, a considerable lapse of time must occur subsequently to the operation if definite changes in the genitalia are to be expected. Removal of the Posterior Lobe. — (a) Total removal of the pars posterior. — In only one case was total removal of the posterior lobe effected (figs. 102 and 103). The details of this case are shown in table VI. Table VI.- -Total Removal of THE Posterior Lobe. "§ s ■J Killed Oct. 00 Interval between O- operation and 4; death. "a 5 .2 © m 9 a £d P.M. findings. Macro- scopical. Micro- scopical. 16 7 111 OS. June 1 Sections show total None grm. 4700 grm. 5100 Nothing ab- normal. The Shows ab- sence of the posterior lobe 7 uterus, mam- mae, and ovaries had de- veloped since the operation pars pos- terior, ex- cept the neck The animal (no. 16) — shown before and after operation in figures 101a and 104b — had no symptoms whatever. There was some increase in weight, but only in accordance with the growth of the animal. The uterus (figs. 105, A and b) and ovaries (see fig. 132, p. 198) continued to develop, and no changes were observed in the other hormonopoictic organs. (b) Partial removal of the pars posterior. — Ol this experiment, also, there was only one case. The bitch died 199 days after operation with convulsions (table VII, p. 156). It has already been suggested that the animal may have been poisoned, for this and a control animal, mentioned above, both died within a few hours of one another with the same symptoms. So far as could be discovered no changes in the genitalia or elsewhere had been caused by this operation. 154 PHYSIOLOGY Fig. 104a. Bitch 16 before operation. {Photograph. Fig. 104b. Bitch 16, 128 days after removal of the pars posterior. {Photograph.) REMOVAL OF THE PITUITARY 155 Fig. 105a. Section of the uterus of bitch 16 before operation . ■ X60. Fig. 105b. Section of the uterus, which has developed, of bitch 16 128 days after total removal of the pars posterior. X 60. 156 PHYSIOLOGY Table VII. — Partial Removal of the Posterior Lobe. S . '3 4; 2 * o o c-g « ?! 1=1 ft croscopical jstigation of ue removed operation. o a) rval between ^ration and death. it CD O si Ha a — . £-d P.M. findings. Macro - Micro- _: P.M. findings. n a& llil .343 c • 'Q ■°.2il '3"!* » on 1° z l. -t- — '. s o '5 Macro- scopical . Micro- scopical. grm. grm. 17 6 June Sections show Killed 172 days None. 7350 8550 Rather Sections mos. 25 almost total posteriorlobe and a small amount of Dec. 14 Animal came on heat, and had coitus fat show a large amount of anterior lobe and anterior lobe without becoming very little posterior pregnant lobe 25 5 Sept, Sections show Killed 61 „ None 5000 5500 Nothing Poor section mos. 15 almost total Nov. (on ab- of region posterior 5 Oct. 1 normal. lobe with a after medium oper- amount of ation) anterior lobe v 1 See footnote on p. 141. REMOVAL OF THE PITUITARY 157 Combined Partial Anterior and Posterior Lobe Removals. —In both the cases of this experiment (table VIII) large portions of the pars posterior and small amounts of the pars anterior (fig. 106) were removed. In neither case were any symptoms or post-mortem appearances noted which could be ascribed to the operation. Both animals put on weight, bitch no. 17 becoming rather fat ; this animal, moreover, came on heat and " Fig. 106. Section showing portions of the pars posterior (on the right) and a small portion of the pars anterior (on the left) removed from bitch 17. (Photomicrograph.) X 15. had coitus, but did not become pregnant. The genitalia con- tinued to develop, and no changes were noted in the hormono- poietic organs. The absence, then, of specific symptoms following the simul- taneous removal of small portions of the pars anterior and large amounts of the pars posterior corresponds with the state of affairs obtaining after similar removals separately conducted on different animals. 158 PHYSIOLOGY Compression and Separation of the Stalk The details of these operations are shown in table IX. The results which they produce are probably identical, although it is possible that absolute severance of the stalk may produce more sudden and lasting effects than compression. These experiments, as I shall indicate more fully when dis- cussing the results obtained by others, are of considerable interest, for in all three cases there was an increase in weight and in two (nos. 12 and 14) the condition of dystrophia adiposogenitalis was produced. By no other operation was I able to obtain this result. In figures 107a and 107b bitch no. 14 is shown before and after operation, and in figures 108a and 108b bitch no. 12, before and after operation. In the second case, especially, an extreme condition of adiposity is to be seen : the body-weight of this animal increased 66 per cent, in 51 days. In figure 109 this bitch is shown laid open at the post-mortem examination. The appearance of a dog with dystrophia adiposogenitalis is remarkable, and no photograph does justice to the extra- ordinary degree of adiposity which may occur. In general ap- pearance the animal becomes strikingly seal-like : the head and limbs look too small for the body, the fur becomes erect and the breadth of the back causes it to become flattened on top. The young animal remains somatically infantile. Both of the animals which showed considerable increase in weight also showed complete atrophy of the uterus (figs. 110a and 110b), and of the ovaries and mammae. Histological examination of the pituitary region shows that at the line of separation and compression there is a formation of new fibrous tissue, and that the cells of the underlying pars anterior are atrophied and widely separated (fig. 111). In disposition the animal is lethargic after recovering from the postoperative somnolence which is pronounced: it sleeps a great deal. Moreover, when standing it has a typical appearance : the tail and ears droop, and the animal appears to be only half-awake (figs. 107b and 108b). In one case (no. 14) the thyroid was found to be very large indeed, and when examined histologically the vesicles were seen to be enormously distended with colloid (see fig. 126, p. 191). COMPRESSION AND SEPARATION OF THE STALK 159 Table IX. — Compression and Separation of Stalk. Compression of the stalk. 4> 71 a . CM £ • died 5 P.M. findings. 5 11 — a < "3 5 3 s — J3 "? != 5" ^2 r g « a - % z ^ S3 tg: Macro- scopical. Micro- scopical. grm. grm. li 7 May Killed L29 days Drank 6000 7100 Large amount Sections show mos. 18 Sept. milk 1 (on July of subcutan- whole pituitary, 24 hour after 28w.= eous fat. but cells stain operation. 7200) Uterus, badly, are separat- Fair ovaries and ed from one amount of mammae another in the adiposity, infantile. pars anterior, and i.e. 20 % Thyroid are shrunken increase in very large (atrophied). The weight in stalk is severed 71 days and replaced by new fibrous tissue. Thyroid vesicles distended with colloid Separation of the stalk. 12 1 °2 May Killed 128 days For first 3 3000 5i m i Uterus, Sections show line mos. 19 Sept. days ex- (same ovaries and of cleavage below 24 tremely drowsy ; afterwards became abnorm- ally fat. Increase in weight, 66 % in 51 days weight on Jul. 9) mammae intensely atrophied : very large amount of subcutaneous fat patch of normal pars intermedia cells. The rest of the pituitary is embedded in fibrous tissue 21 6£ Aug. Killed 80 „ Increased 740(1 8100 Nothing ab- Poor section ; mos. 31 Nov. 19 in weight normal, except the mammae, which are tissues badly fixed infantile 1 This specimen (fig. 109) is now in the Museum of the Royal College of Surgeons, England. 160 PHYSIOLOGY Fig. 107a. Bitch 14 before operation. (Pit olograph.) Fig. 107b. Bitch 14, 129 days after compression of the infundibular stalk. {Photograph.) SEPARATION OF THE STALK 161 Fig. 108a. Bitch 12 before operation. {Photograph.) Fig. 108b. Bitcli 12, 51 days after separation of the infundibular stalk. (Photograph.) 11 162 PHYSIOLOGY Fig. 109. Bitch 12 laid open at the post-mortem, 128 days after separation of the infundibular stalk. The enormous deposits of fat can be well seen, also the two horns of the atrophied uterus. {Photograph.) SEPARATION OF THE STALK 163 Fig. 110a. Section of the uterus of bitch 12 before operation. (Photomicrograph.) X 40. ;■:-••:; w&& h ::&- ^pRi'" Fig. 110b. Section of the uterus of bitch 12, 128 days after separation of the infundibular stalk. (Photomicrograph.) X 40. 164 PHYSIOLOGY DISCUSSION OF RESULTS OF EXTIRPATION OF THE PITUITARY AND OF SEPARATION AND COMPRESSION OF THE STALK It will now be of interest to see how far the foregoing experiments confirm or contradict the work of others. In this connexion it will be sufficient to consider the pioneer work of Paulesco 1 , and the subsequent experiments of Cushing and his colleagues 23 and of Biedl 4 and his associates. The work of Aschner 5 is less reliable, for although this investigator was able to produce certain of the abnormal Z o*» *■ ° * - "Ns v / .-^- -^ *~- W *-£* : - ■ ■^» -> een. X 500 (Direct colour photomicrograph). Faring page 187.] PLATE 4. Section of the pars anterior of the non-pregnant cat 79 days after thyroidectomy, showing many large chromophobe cells lying among strongly staining eosinophils. X 500 (Direct colour photomicrograph >. EFFECTS ON PITUITARY OF THYROIDECTOMY 187 Pars nervosa. Hyaline or granular bodies are not dis- cernible ; but the pars nervosa seems to be invaded by cells from the pars intermedia ; and at the neck the secretion of the cells is collected as if about to be passed into the nervous portion. Experiment III. — Thyroid removal : Cat, pregnant about 20 days. June 19th. Thyroid removed. June 29th. Two premature kittens born. October 24th. Animal killed with chloroform. Interval between operation and death : 130 days. Histological examination of the pituitary : Anterior lobe. Under a low magnification the anterior lobe appears to be extensively vacuolated (fig. 123). The cells are chiefly chromophobe (plate 3), but there are a few scattered eosinophils. The condition of ' vacuolation ' is seen to be due to excessive secretion, in some places in the cells, and in others between the cells ; and in the latter case the secretion is often surrounded by a vesicular arrangement of the neighbouring cells. The cells of the pars intermedia are well defined and not much fused. Pars nervosa seems to be teased out, but there is no unusual invasion by pars intermedia cells. Experiment IV. — Thyroid removal : Cat, non-pregnant. June 12th. Thyroid removed. August 30th. Animal killed with chloroform. Interval between operation and death : 79 days. Histological examination of the pituitary : Anterior lobe. This is largely composed of eosinophil cells ; but there are many active chromophobe cells to be seen (plate 4). Pars intermedia. There is considerable activity in the cells of the pars intermedia, and faintly staining basophil (neutrophil) secretion can be seen in the cleft (fig. 124). Pars nervosa. This portion of the pituitary is finely reticulated, but there is no invasion by cells of the pars intermedia. It appears, therefore, that, while there is undoubtedly an 188 PHYSIOLOGY increase in the activity of the pituitary body after thyroidectomy, the changes observed are greater in the pituitary of the pregnant animal than in that of the non-pregnant. Further, while the changes observed, if correctly interpreted, all indicate an increase of activity after thyroidectomy, the appearances vary according to the extent of thyroparathyroid insufficiency, as indicated by the immediate effect on the animal, by the length of time between the operation and death, and probably also according to the period of pregnancy. • I "*\ v is- FlG. 124. Section of the pars intermedia of the non-pregnant cat 79 days after thyroidectomy, showing secretion in the cleft. (Photomicrograph.) X500. The alterations in the pituitary as the result of thyroidectomy, as I have observed them, may be summarized as follows : — Anterior lobe. Contrary to the opinion expressed by Herring who operated upon (? non-pregnant) dogs, cats and rabbits, I believe that definite changes do occur in the anterior lobe. These changes appear to vary from an increased eosinophilia of the cells, with scarcity of basophil cells and the presence of numerous neutrophil cells (plate 4), to a condition of great activity when the thyroid is removed during pregnancy, and the animal survives for a long period (plate 3). In the last-named circumstances EFFECTS ON PITUITARY OF THYROIDECTOMY 189 the cells of the anterior lobe become filled with secretion which may give rise to an appearance of vacuolation ; and they are, also, large and for the most part chromophobe. Pars intermedia. We find that there is considerable activity in the cells which line the cleft and in the reticulated groups at the base of the third ventricle. The cells in the reticulated portion appear always to remain discrete, and to produce neutro- phil secretion, as in normal circumstances ; while the cells of the pars intermedia lining the cleft secrete faintly staining granular material either into the cleft (fig. 124), or on the surface of the pars nervosa. In conditions of great activity the cells themselves always seem to fuse (figs. 119 and 122)— the nuclei appearing to lie among a mass of secretion. The pars nervosa may contain much granular secretion in degenerating cells, or free. I have been unable to confirm Herring's observations as to the increased activity of the ependymal and neuroglial elements. Noav, it will have been noticed that while the appearances described above all indicate a condition of increased activity, exactly the same appearances are not seen in all the instances described and illustrated ; but, as I have already pointed out, I have selected examples in which the circumstances as to rela- tive insufficiency, length of life and so on, varied. I would, however, emphasize the fact that I have found with similar conditions and in similar circumstances practically the same appearances always produced. The interpretation of my results does not appear to be very difficult ; and I hope in the explanation to throw some light on that least understood of all the problems in connexion with the pituitary — the relation of the anterior lobe to the pars inter- media and the pars nervosa. It will have been noted that in no ease were all three parts of the pituitary found in a state of excessive activity at the same time. In experiment II we have the nearest approach to this, and in this animal no granular or other secretion-masses are to be seen in the pars nervosa. In experiment III the activity of the anterior lobe is most marked ; while the cells of the pars intermedia are not very active, nor is there secretion in the pars nervosa. In experiment I, in which there was acute thyroid (including parathyroid) insufficiency, as indicated by death with 190 PHYSIOLOGY convulsions in 48 hours, there was considerable activity in the pars intermedia and pars nervosa, without excessive activity in the pars anterior. These facts all seem to point to the conclusion that the pituit- ary body is one organ ; and that the functional activity of the posterior lobe is dependent on the functional activity of the anterior. Further, it appears that the action is not necessarily continuous in every portion at the same time — indeed, the reverse appears to be more common. Later, I shall adduce patho- logical evidence in support of this hypothesis — showing that the function of each portion is dependent on the integrity of the whole. Effects on the thyroid of partial and complete removal of the pituitary Owing to the fact that the number of operators who have successfully excised the pituitaries of animals is very small, observations concerning the effects of removal of the pituitary upon the thyroid are limited. Allusion has already been made to this question in connexion with experimental operations on the pituitary, but for the sake of completeness the observations recorded may be briefly enumerated here. Crowe, Cushing and Homans 1 observed a hyperplasia in the first forty-eight hours after complete removal ; and, if the animal survived the complete or nearly complete extirpation of the pituitary, a ' functional involution ' of the thyroid, with accumu- lation of colloid in the vesicles was noted. I was unable in my experiments to detect the hyperplasia mentioned by Cushing. When any abnormality was noted in the thyroid it was of the nature of excessive accumulation of colloid. In figure 125 is seen the thyroid — apparently normal, or with only slight excess of colloid — 70 hours after complete removal of the pars anterior of the pituitary. According to Cushing there should have been hyperplasia. Figure 126 shows the excess of colloid found in a case of dystrophia adiposogenitalis 129 days after the compression of the 1 Crowe, S. J., H. Cushing, and J. Hoinans, Bull. Johns Hopk. Hosp., 1910, xxi, 127. EFFECTS ON THYROID OF PITUITARY REMOVAL 191 k:;.. M. y~\ "VW-. » ,- "Ysr- 1 V~ r.-- —-i ■ -*- -« w «£J /-■a "N • , - Fig. 125. Section of the thyroid of the bitch 70 hours after total extirpation of the pars ancerior. There is no departure from the normal. &r X60. - &~^-. ■ " Fig. 126. Section of the thyroid of the bitch 129 days after compression of the stalk of the pituitary. There is an abnormal amount of colloid in the vesicles. X 60. 192 PHYSIOLOGY infundibular stalk. In this case the size of the thyroid was observed to be twice that of the normal organ. Neither removal of the whole pituitary nor of the posterior lobe produces any change in the thyroid that can definitely be pronounced to be abnormal. Effects on the pituitary of removal of the ovaries That there is a close interrelation between these two members of the internal secretory system has long been known, and many interesting hypotheses have been formed. Mayer 1 and others believe that the pituitary is able to act vicariously for the ovaries, since it enlarges in pregnancy and after castration. It has even been suggested that the enlarge- ment of the hands and lips sometimes observed in pregnancy is due to excessive pituitary secretion following ovarian in- sufficiency. So, too, hcmianopia, which on rare occasions is seen in pregnancy, has been attributed to the pressure of the enlarging pituitary on the optic tract. As we have already noted, the hyperplasia that occurs during gestation is chiefly due to large chromophobe cells of the anterior lobe. Degener and Livingston 2 have not found any increase in the weight of the pituitary after castration. I have castrated many female cats, and many months sub- sequently have examined the pituitary bodies. Examples of the typical effects on the pituitary are shown in the following protocols : — • Experiment I. — Ovarian removal : Cat, non-pregnant. February 21st. Ovaries removed. October 23rd. Animal killed with chloroform. Interval between operation and death : 245 days. Histological examination of the pituitary body : Anterior lobe. There is a very large preponderance of eosinophil cells ; so much so that most fields examined show only eosinophils (plate 5). Pars intermedia. The cells appear fused. There are 1 Mayer, E., Arch.f. Gyn,, 1910, xc, 600. 2 Degener, L. M., and A. E. Livingston, Amer. Journ. Physiol. (Proc. Amer. Physiol. Soc ), 1913, xxxi, xxiv. [Facing page 192. PLATE 5. Section of the pars anterior of the non-pregnant cat 245 days alter oophorectomy, showing intense eosinophilia of the cells. X 500 (Direct colour photomicrograph). Facing page 193.] EH PLATE 6. Section of the pars intermedia of the non-pregnant cat 245 days after oophorectomy, showing eosinophil colloid. X 500 (Direct colour photomicrograph). EFFECTS ON PITUITARY OF OOPHORECTOMY 193 colloid-vesicles, and in one place a colloid-cyst. The colloidal material is eosinophil (plate 6). Pars nervosa. This structure has a teased-out appear- ance. There are no granular or ' hyaline ' bodies. Experiment II.— Ovarian removal : Cat, non-pregnant. April 24th. Ovaries removed. November 20th. Animal killed with chloroform. Interval between operation and death : 210 days. * m^ a Iv • *■ 9 i % Fig. 127. Section of the pars anterior of the non-pregnant cat 210 days after oophorectomy showing eosinophils, large chromophobe cells with clear nuclei, and a few basophils. {Photomicrograph.) X 500. Histological examination of the pituitary body : Anterior lobe. This is largely composed of eosinophil cells ; but there are many active chromophobe cells, and at the periphery some faint, and a few dark, basophil cells (fig. 127). Pars intermedia. There is considerable degree of fusing of the cells ; and there is much eosinophil secretion, especially in the reticulated portion (fig. 128). In the compact portion at the neck are to be seen coarsely granular cells, exactly resembling the nucleated 13 194 PHYSIOLOGY <* l % Fig. 128. Section of the reticulated part of the pars intermedia in the non-pregnant cat 210 days after oophorectomy, showing eosinophil secretion. | « %' t mU X500. Fig. 129. Section of the pars posterior of the non-pregnant cat, at the junction of the partes intermedia and nervosa, 210 days after oophorectomy, showing secretion and granular bodies. {Photomicrograph.) X 500. EFFECTS ON OVARIES OF PITUITARY REMOVAL 195 granular cells sometimes seen in the pars nervosa, and much secretion (fig. 129). Pars nervosa. There are no granular bodies. From an examination of a large number of specimens I am forced to the conclusion that although there is considerable increase in the activity of the anterior lobe and pars intermedia of the pituitary after oophorectomy, yet this is not so well marked as after removal of the thyroid. In some cases, such as in cat 5 of my series, which was killed after an interval of 208 days, there was no divergence from the normal ; consequently my observations are opposed to the hypothesis, which many authorities have sought to establish, that genital atrophy is the primary cause of acromegaly (hyperpituitarism). Fichera 1 be- lieves, as the result of his experiments, that removal of the ovaries causes a change in the anterior lobe analogous to that produced by pregnancy. My experiments give some evidence of this in the fact observed that the chromophobe cells present seem to be large and active. It is unsettled, however, whether removal of the ovaries produces a permanent change in the pituitary, although it is certain that the immediate effect of oophorectomy is to cause an increase in the secretory activity of the anterior lobe and of the pars intermedia, especially in regard to the eosinophil cells. The effects on the ovaries of partial removal of the pituitary As we have seen, the work of Paulesco 2 and of Crowe, Cushing and Homans 3 demonstrated beyond doubt that the removal of a large portion of the anterior lobe may produce genital atrophy. These observers state that in the ovaries the follicles cease to develop, and that subsequently the uterus and other parts of the genital tract undergo atrophy. Degeneration is also stated to be produced in the germinal cells of the testes after the removal of the major portion of the pars anterior in dogs. 1 Fichera, G., Polidinico, Rome, 1905, xii, 250, 299 and 319 ; also 1910, xvii, 333. 2 Paulesco, N. C, Lhypophyse du cerveau, Paris, 1908. 3 Crowe, S. J., H. Cushing and J Horaans, Bull. Johns Hopk. Hosp., 1910, xxi, 127. 196 PHYSIOLOGY In connexion with my own experimental operations on the pituitaries of bitches, I took the precaution of removing pieces of one ovary and the uterus before operating on the pituitary. In this way I had a specific control in each case with which to compare the organs subsequently to operation. I usually found 1 that profound changes in the ovaries fol- lowed extensive partial removal of the anterior lobe (figs. 130, a Fig. 130. Sections of the ovaries of the bitch before (a) and 210 days after (b) partial removal of the pars anterior. X 200. and b) and compression or separation of the stalk (figs. 131, A and b). The primordial ova undergo a hyaline degeneration : instead of showing chromatin fibres with translucent interstices, after operation the whole ovum becomes opaque and structureless. The epithelium of the Graafian follicles degenerates and dis- appears, leaving an empty space in the place previously occupied by the follicles. The stroma becomes dense and fibrous ; and I found a total disappearance of the interstitial cells (figs. 130b and 131b). In some of my experiments after partial resection of the anterior lobe the ovaries and uterus showed no retrograde 1 Bell, W. Blair, Quart. Journ. Exp. Physiol, 1917, xi, 77. EFFECTS ON OVARIES OF PITUITARY REMOVAL 197 Fig. 131a. Section of the ovary of the bitch before operation. {Photomicrograph.) x 120. 131b. Section of the ovary of the same bitch 128 days after separation of the stalk of the pituitary. {Photomicrograph.) X 120. 198 PHYSIOLOGY changes, although possibly they did not develop to the normal extent in the interval between operation and death. Removal of the posterior lobe alone or with a small portion of the anterior lobe does not affect the development of the ovaries in the slightest degree : they go on to maturity in a normal Fig. 132. Sections of the ovaries of the bitch before (a) and after (b) removal of the pars posterior of the pituitary. The lower part of B is occupied by cells of a corpus luteum. X60. manner (figs. 132, a and b) ; and in one of my cases the bitch came ' on heat ', and took the dog, but without becoming pregnant. Effects on the pituitary of removal of the suprarenals Since removal of both suprarenals is always fatal in a few days to the larger animals, such as the cat, rabbit and dog, it is impossible to obtain experimental evidence, except in regard to acute results, from this procedure. I have, however, removed one suprarenal from cats and rabbits in the hope of producing insufficiency. This I was unable to do to any obvious or marked extent except in two cases. In a few of my experiments I first removed one suprarenal, and Facing, page 199]. PLATE 7. Section of the pars anterior of the non-pregnant cat 36 hours after the removal of both suprarenals. The cells for the most part are chromophobe, but here and there eosinophil cells are to be seen. X 500 (Direct colour photomicrograph). EFFECTS ON PITUITARY OF SUPRARENAL REMOVAL 199 subsequently the second. This last operation was always fol- lowed by the death of the animal. In some of these cases I observed changes in the pituitary which were probably the result of suprarenal insufficiency 1 . The following are illustrative experiments : — Experiment I. — Suprarenal removal: Cat, non-pregnant. September 11th. Roth suprarenale removed. September 13th. Death occurred in spite of careful nursing and keeping the animal in a warm temperature. There were tremors and great muscular weakness. Interval between the operation and death : 36 hours. Histological examination of the pituitary: Anterior lobe. There is a large proportion of chromo- phobe cells, with a comparatively moderate number of eosinophil cells (plate 7). In many places the nuclei are small and darkly stained, and they stand out sharply. Pars intermedia. The cells are discrete ; that is to say. they are not fused. The nuclei stand out prominently ; they are small and darkly stained (fig. 133). A few granular bodies can be seen among the cells of the pars intermedia. Pars nervosa. The nervous portion is invaded by the cells of the pars intermedia ; and the appearance produced is that of nuclei, with the cell-protoplasm lost, stranded among the neuroglia -cells (fig. 134). Experiment II. — Suprarenal removal : Cat, non-pregnant. September 18rh. Left suprarenal removed. November 6th. All but the very small fragment of the right suprarenal removed. November 8th. Animal died. Interval between first operation and death : 51 days. Histological examination of the pituitary : Anterior lobe. — There is a large proportion of chromo- phobe cells, with fewer eosinophil cells than in the first experiment. The nuclei are small, round and darkly stained. and they appear to stand out from the surrounding cell protoplasm (fig. 135). Pars intermedia. — The cells arc not fused, and their nuclei stand out very prominently (fig. 136). Pars nervosa. — This portion is much invaded by the 1 Bell, W. Blair, Arris and Gale Lectures : Lancet, 1913, i, 937. 200 PHYSIOLOGY •\ \ • *■*_ * ^ • J iff • ' • v Fig. 133. Section of the pars [posterior of the cat 36 hours after removal of both suprarenale, showing invasion of the pars nervosa by the cells of the pars intermedia. {Photomicrograph.) X 140. * ~ ♦ * • $ e " % »v * • *>. s t «. • V-' , a • « w Fig. 134. Section of the pars nervosa of the pituitary of the cat 36 hours after removal of the suprarenals, showing invasion of the pars nervosa by cells from the pars inter- media, and the stranding of their nuclei. X 200. EFFECTS ON PITUITARY OF SUPRARENAL REMOVAL 201 Fig. 135. Section of the pars anterior of the cat after removal of the suprarenals, showing chromophobia of the cells, the nuclei of which show chromatosis. (Photomicrograph.) X 400. \ • ••** Fig. 136. Section of the pars posterior of the cat after removal of the suprarenals, showing well-defined cells in pars intermedia, and invasion by these cells of the pars nervosa, and the stranding of the nuclei. [Photomicrograph.) X 140. 202 PHYSIOLOGY cells of the pars intermedia (fig. 136), which present an exactly similar appearance to that seen in the former case (fig. 133). The changes, then, in the pituitary of the cat that appear constant with suprarenal insufficiency, acute or chronic, are, first, an increased chromophobia of the cells of the pars anterior ; second, a peculiar smallness and chromatosis of the nuclei, to some extent in the anterior lobe but most definitely in the pars intermedia, the cells of which are discrete ; and third, a rapid and extensive invasion of the pars nervosa by the cells of the pars intermedia. Many of these cells appear to lose their cell- protoplasm, and the nuclei in consequence are left stranded (figs. 133, 134 and 136). Effect of removal of the pituitary on the suprarenals Exact observations from this point of view have not been obtained, dishing 1 states that in experimental forms of hyper- pituitarism (presumably injection experiments, but details are not given) there is a condition of vacuolation of the zona fascic- ulata of the suprarenal cortex, as I have found after ingestions of an extract of the anterior lobe ; but this author also states that the same condition is observed after extirpation of the pituitary. In my own experiments on the pituitary I was unable to detect definite changes in any part of the suprarenals after operation. I have seen this lipoid (?), or secretory, change, mentioned by dishing, after removal of the ovaries, and during pregnancy ; so, as the extent of it varies in different individuals of the same species in normal circumstances, any specific cause assigned to such a condition must be received with caution. It has, too, been stated that a similar change occurs in the secretory and collecting tubules of the kidney after extirpation of ductless glands ; and I myself have observed this after some of my experiments, but as I subsequently found the same change in the kidneys of control animals, especially when they had been killed with, chloroform, I was compelled to acknowledge the absence of specific causation. These vacuolations require much more 1 Cushing, H., The Pituitary Body and its Disorders, 1912. EFFECTS ON SUPRARENALS OF PITUITARY REMOVAL 203 careful observation by means of differential stains, before we can discuss them with profit. Meanwhile, I have no suggestions to make as to the exact nature of the condition, which is probably less abnormal in animals than is usually believed. The pituitary and the other internal secretory organs There is a certain amount of material available concerning the interrelationships between the pituitary and the pancreas and thymus. Pancreas. — Cushing and his fellow-workers 1 first advanced the view that the carbohydrate-tolerance observed in hypopituitarism is due to disturbance of the internal secretion of the pancreas. Later, after more pathological experience, Cushing withdrew this opinion and attributed the tolerance to insufficiency of the posterior lobe 2 . It appears, however, that even the last view is not entirely correct ; consequently the results of the researches that are now being conducted by Cushing and his colleagues on this subject are awaited with interest. In my experiments on the pituitaries of dogs I always found the pancreas normal, but in an actively secreting state, subse- quently to the operation. Sweet and Allen 3 lay particular stress on a similar finding. I have already referred to the effect of injections of infund- ibulin on pancreatic secretion (p. 119). Pancreatectomy is said by Cushing 4 to produce changes in the posterior lobe of the pituitary. This observation is. I believe, unconfirmed. Thymus. — -Very little is known from an experimental point of view of the relationship between the thymus and the pituitary. In my experiments on the pituitary I found in most cases, regardless of the actual lesion, that the thymus was in an active state, as indicated by the embryonic and unwhorled 1 Goetsch, E., H. Cushing and C. Jacobson, Bull. Johns Hopk. Hosp., 1911, xxii, 165. 2 Cushing, H., The Pituitary Body and its Disorders, 19 1 2. a Sweet, J. E., and A. R. Allen, Ann. Surg., 1913, lvii, 485. 4 Cushing, H. s Amer. Joum. Med. Sci., 1910, xxxix, 473. 204 PHYSIOLOGY character of the epithelium in Hassall's corpuscles (fig. 137)- a normal condition in young animals. Fig. 137. Section of the thymus of the bitch, showing unwhorled epithelial cells. {Photomicrograph.) X 120. DISCUSSION OF THE RESULTS OF REMOVAL OF THE VARIOUS HORMONOPOIETIC ORGANS The interpretation of all these experimental facts is not easy, and involves a short reconsideration of the whole question of increased activity in the pituitary. As already stated, I believe that the three types of cells found in the anterior lobe represent different phases of secretory activity. If there be not much immediate demand for the secretion of the anterior lobe, in the higher mammals a basophil condition of some of the cells is found. From these cells basophil colloid is formed for storage purposes. After yielding up their secretion the basophil cells, as we have seen, appear as shrunken chromo- phobe cells. These in time become eosinophil, before ultimately again becoming basophil. Now, the greatest demands on the secretion of the anterior lobe occur normally in pregnancy, and experimentally after removal of the thyroids and suprarenals. In both circumstances HORMONOPOIETIC INTERRELATIONS 205 we find what may be called ' active chromophobe ' cells — chromo- phobe cells, that is, which deliver up their secretion without going through the further phases of eosinophilia and basophilia. Next in secretory activity is the phase of eosinophilia which is an intermediate condition, and, as a result, many eosinophil cells are usually present. After removal of the thyroid, especially when the condition of insufficiency is chronic, the preponderance of eosinophil cells is most pronounced. In such circumstances we may conclude that the demand for secretion is not very urgent, and there is time for fully formed, normal, secretion to be delivered. There can be little doubt that the secretion of the ' pregnancy cells ' and of the artificially produced ' active chromophobe ' cells is similar, and is an emergency substance. And since in these circumstances the secretion is abstracted from the cells as fast as it is formed, there is no collapse of the cell — they remain ' on duty ', as it were. If the demand be less urgent eosinophilia develops in the contents of the cells. This is normally the active condition of the cells which deliver the secretion of the anterior lobe ; while in times of plenty in the higher mammals the further phase of basophilia develops. These basophil cells eventually burst, basophil colloid is poured out and the collapsed cells represent the shrunken chromophobe cells, as already stated. These points have been reiterated because it is important to emphasize them, and to show their bearing on the present discussion. If my observations be correct they afford evidence concern- ing the ' secretory-phase hypothesis ' — if so it may be called — in which many believe, but which has not been previously described in similar detail. These observations offer, too, the only explanation of the fact that basophil cells do not occur prominently in the lower mam- malian orders in which no doubt the anterior lobe is normally more active than in higher orders. With regard to the number of nuclei — apparently bereft of cellular protoplasm — in the pars nervosa after the production of suprarenal insufficiency, it is probable that the protoplasm and its contained secretion have been rapidly utilized before the nuclei themselves have had time to disappear. This is borne out by the fact, previously recorded, that the granular masses 206 PHYSIOLOGY of secretion not infrequently seen in the pars nervosa in norm- al circumstances, at first possess nuclei which subsequently disappear. Thus far, therefore, monoglandular removals have helped us to solve some of the mysteries concerning the physiology of the pituitary body. Later, we shall consider this same question of the internal secretion in relation to the pathology of this organ. It would have been a satisfactory conclusion to this section, concerning the interrelationship between the pituitary and the rest of the hormonopoietic system, if it had been possible to give a definite and lucid exposition of the exact dependence each has on the secretion of the rest. Our information, how- ever, is too fragmentary and unsatisfactory for such a disquisi- tion, yet I cannot help feeling that the day is not far distant when we shall be in a position to describe this part of the subject with comparative comprehensiveness and certainty. Too little attention has been paid to those secretory organs which do not easily and certainly yield so-called ' physiologically active ' secretions — that is, an active extract which will produce an immediate physiological effect. No doubt we have been hampered by technical and experimental difficulties, such as are encountered in the removal of certain parts of organs — for example, the suprarenal cortex. Meanwhile there are two other lines of very profitable in- vestigation, one physiological and the other pathological. We require more information in regard to the activation of the so- called ' inactive ' organs : in other words, we must identify the hormones. It is probable that the secretions of these so-called ' inactive ' organs are active enough when combined with, or stimulated by, one or other, or by several, of the other internal secretions. In seeking to discover the reason of the uncertainty of action of the ovarian extract I found that this preparation is much more active when thyroid extract is administered at the same time. The second line of investigation is an easy one. It consists of careful histological examinations of the whole hormono- poietic system in all cases of disease of one or more members of the series. Many deaths occur yearly from these lesions, yet there exists no study of importance from this pathological point of view. THE EFFECTS OF INOCULATIONS WITH BACTERIA Although a certain amount of work has been done from the clinicopathological point of view in regard to the changes in the pituitary as a result of infections, extremely little experi- mental work has been carried out. Delille 1 refers to the striking hyperplastic changes to be observed in the pituitaries of rabbits after inoculations with typhoid bacilli. I have conducted a series of inoculation experiments in guinea-pigs with tubercle, colon bacilli, staphylococci and streptococci. In figures 63 (p. 86) and 138 are seen the normal appearances of the pars anterior of pregnant and non-pregnant guinea-pigs, respectively. In the pregnant guinea-pig there is marked lobul- ation— the so-called adenomatous disposition — of the chromo- phobe cells (fig. 63). In the non-pregnant animal (fig. 138) the cells present a more uniform appearance of eosinophilia. In figure 139 is shown the pars anterior of a non-pregnant guinea-pig which had received 13 injections of an emulsion of colon bacillus. It will be observed that there is hyperplasia with considerable increase in cell-contrast and definition. Many of the cells are chromophobe, and vacuoles containing secretion are plentiful ; the appearance, indeed, is not unlike that seen in the pars anterior after thyroidectomy. Staphylococcal infections produce, in most cases, a more advanced change. The blood-sinuses appear very full, and in parts of the pars anterior there are necrosis and disappearance of many of the cellular elements. For the most part the eosino- phil cells are few, and where necrosis is not complete faintly staining chromophobe cells are plentiful. A peculiar feature is the survival of deeply basophil cells — normally absent in the 1 Delille, A. (quoted by Gushing, H., The Pituitary Body and its Disorders, 1912). 208 PHYSIOLOGY « S Jjr,- , »~ * s *#* Fig. 138. Section of the pars anterior of the normal non-pregnant guinea-pig, micrograph. ) (Photo- X 400. - L t • • * •%r * * Fig. 139. Section of the pars anterior of the guinea-pig after 13 injections of an emulsion of colon bacillus, showing chromophobia with increased secretory activity. ( Photomicrograph. ) X400. THE EFFECTS OF INOCULATIONS WITH BACTERIA 209 guinea-pig — -which consequently appear in some cases to domin- ate the picture (fig. 140). In the series of animals dying from tuberculosis, or killed when deeply affected by this disease, three were pregnant and six were non-pregnant. It is important always to take into consideration the presence or otherwise of pregnancy in female animals, since the normal changes during gestation are con- siderable, as already indicated. In the non-pregnant animals the cells of the anterior lobe present a greater degree of chromophobia m ...- Fig. 140. Section of the pars anterior of the guinea-pig after injections of an emulsion of staphylococcus, showing necrosis with survival of basophil cells. {Photomicrograph.) X 400. than normal ; and in the pregnant animals the chromophobe cells are more numerous, more indistinct, and apparently larger than normal. The nuclei appear brightly and distinctly stained against a hazy background of cell-cytoplasm. But on the whole the tubercle bacillus affects the pars anterior less than is the case with the other organisms. In the streptococcal eases there is very well-marked chromo- phobia, and in the non-pregnant animals the large chromo- phobe cells resemble those seen in pregnancy. The appearance 14 210 PHYSIOLOGY of blurring, also, may be an indication of increased activity, if it be not a sign of commencing degeneration. The changes, then, that may occur in the pituitary as the result of experimental inoculation of bacteria vary from hyper- plasia of the eosinophil cells to chromophobia with considerable increase in activity. The later necrotic changes are due to direct infection of the gland and thrombosis of the vessels. In no case was any change observed in the pars nervosa, but in the pars intermedia there usually appeared to be considerable activity in the cells — that is, fusion of the cell-bodies ; this, of course, we should expect in view of the changes in the pars anterior. THE INTERPRETATION OF PATHOLOGICAL PROCESSES AFFECTING THE NORMAL PHYSIOLOGY The method of studying physiological processes through ' Nature's experiments ' is one of the greatest value, but un- fortunately is not used to any great extent by physiologists or clinicians, probably because as a rule neither class of investi- gator is sufficiently acquainted with the work and requirements of the other. I shall deal very briefly with the subject here, for the facts on which my arguments will be based are set out in more detail in the next part of this work. Infections Infections, whether local or general, cause hyperplasia in the pars anterior ; consequently it has been presumed that one of the normal functions of the pituitary is to neutralize toxins which may be circulating in the blood. Diseases associated with pregnancy In the so-called toxaemias of pregnancy we shall observe abnormal conditions of the pituitary. For the most part these indicate that this organ is not in the high state of activity that is usual during pregnancy. Possibly this leads to a condition of acidosis ; for one of the normal functions of the pituitary is the retention of alkaline bases in the tissues, a state of affairs which is directly opposed to acid intoxication. Diseases of the hormonopoietic system We observe in pathology, as in physiology, close relationships between the pituitary and the other organs of internal secretion. 212 PHYSIOLOGY Furnivall 1 found only one normal thyroid in twenty-four cases of pituitary lesions which he had collected from the litera- ture, and in which complete records were given, dishing 2 in fifteen cases found marked excess of colloid in all the thyroids. Of these fifteen cases the pituitary condition in all but a single case was one of insufficiency. No changes were found in the parathyroids. It does not appear, therefore, that the thyroid acts vicariously for the pituitary, as has been suggested by some. On the one hand, there is evidence, already mentioned, that whole-gland pituitary extract stimulates the activity of the thyroid. On the other hand, I have found that infundibulin has a beneficial effect on hyperthyroidism. Schonemann 3 , in an investigation of eighty -five cases of goitre, found ' marked alterations ' (no details are given) in the pituitary. I myself have observed changes in the pituitary in diseases of the thyroid which indicate that the pars anterior acts in a complementary fashion so far as the thyroid is concerned, and that the activity of the former is related to the relative insuffic- iency of the latter. Regarding the relation of the pituitary to the gonads, we have evidence that in acromegaly there may be stimulation of the male genital organs. This, however, is only observed in the early stages of the disease. I shall mention a case later in which hypertrophy of the clitoris occurred in a woman with this disease. In view of the physiological and pathological evidence at our disposal we may assume that lesions and removal of the pituitary have a far more pronounced effect upon the genital glands than the extirpation of these organs has upon the pituitary. The pathological evidence of a relationship between the pituitary and suprarenals is very slight, although it is impossible not to recognize in many cases of hyperpituitarism a plurigland- ular syndrome, for acromegaly may be accompanied by mani- festations resembling Addison's disease. 1 Furnivall, P., Trans. Path. Soc., 1898, xlix, 204. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 3 Schonemann, A., Virchow , s Arch. f. Pathol. Anat. u. Physiol., 1892, exxix, 310. INFLUENCE OF PATHOLOGICAL CONDITIONS 213 It is possible, therefore, that in hyperpituitarism (acromeg- aly), in which there is an excess of secretion, the suprarenals become inactive, and that in hypopituitarism (dystrophia adiposogenitalis) suprarenal activity increases. This, at any rate, is the interpretation dishing places on the results of his extirpation experiments. In my own I failed to observe definite changes in the suprarenals after operations on the pituitary; and I do not think the second conclusion is justified by the clinical evidence at our disposal in regard to hypo- pituitarism. We have very little pathological information that throws any light on the normal relationships of the pancreas, the pineal and the thymus to the pituitary — certainly nothing that calls for discussion here. § iii. COMPARATIVE PHYSIOLOGY Very few words are necessary to describe the comparative physiology of the pituitary. We have seen that in all vertebrates higher than the elasmo- branchs there is a definite pars nervosa ; and it has been found that extracts made from this structure, or from the whole gland containing this part, are active in all the respects already de- scribed. For our information on this subject we are chiefly indebted to the work of Herring 1 . This observer has, moreover, noted the extremely interesting fact that although the pituitary of the skate (elasmobranch) contains no pars nervosa, and that, therefore, an extract of the gland gives none of the well-known pressor effects associated with the action of infundibulin, yet the extract made from the epithelial portion has a definite augmenta- tive effect on the flow of milk from the mammae of a lactating animal. This same result was obtained with an extract made from the epithelial portion of the pituitary of the cod, but there was also a rise in blood-pressure, and this, as Herring justly says, may indicate the inclusion of some of the extract of the pars nervosa which is present in teleosts. Further investigations are required to confirm and extend these interesting observations, especially in regard to the acquisition of evidence which might further indicate that it is the epithelial portion which dominates the functions of the pituitary. The investigations of Halliburton, Candler and Sikes 2 , and of A. S. Griinbaum and Helen Grunbaum 3 , have shown that the extract of the pars posterior of the human pituitary has physio- logical actions similar to those produced by the same extract from other vertebrate animals. 1 Herring, P. T., Quart. Journ. Exper. Physiol., 1908, i, 261 ; idem., 1913, vii, 73. 2 Halliburton, W. D., J. P. Candler, and A. W. Sikes, Quart. Journ. Exper. Physiol., 1909, ii, 229. 3 Grunbaum, A. S., and Helen G. Grunbaum, Journ. Physiol. (Proc. Physiol. Soc. ), 1911, xlii, x.wiii. PART III DISORDERS ASSOCIATED WITH THE PITUITARY AND THEIR TREATMENT PART III DISORDERS ASSOCIATED WITH THE PITUITARY AND THEIR TREATMENT It was not till the year 1886 that pathological lesions of the pituitary body were recognized and associated with clinical manifestations. In that year Marie 1 described changes in this organ in the disease known as 'acromegaly' (anpog = extremity, and fiiyag, /ayuX- = large). In the following year, possibly inde- pendently, Minkowski 2 described in more detail the relationship between acromegaly and lesions of the pituitary. Since then many investigators have not only confirmed this pioneer work and elucidated the finer points in the histopathology of acromeg- aly, but have extended their observations to other morbid conditions arising from disordered states associated directly or indirectly with the pituitary body. The earlier investigators were hampered considerably in drawing their conclusions by lack of definite information con- cerning the anatomy and physiology of the pituitary. Even in the present day there is considerable doubt whether the pituitary body should be considered one organ or two organs ; and we shall see that many of the difficulties in regard to the interpretation of pathological phenomena have arisen from this uncertainty concerning the unity or duality of the pituitary. There is, too, in regard to the normal physiology, another serious obstacle that confronts those who are not fully satisfied with merely recording disjointed facts : I refer to the imper- fections in our knowledge concerning the undoubted correlations 1 Marie, P., Rev. de Med., 1886, vi, 297. 2 Minkowski, O., Berl. Klin. Woch., 1887, xxiv, 371. 216 DISORDERS ASSOCIATED WITH THE PITUITARY that exist between the pituitary and the other hormonopoietic organs. This lack of comprehension often prevents our knowing whether certain symptoms are due to primary pituitary disease or to associated changes in some other of the organs of internal secretion. This is a difficulty which is likely to trouble us for some time — until far more work has been done on the inter- relationships between the internal secretions. Meanwhile, no good can come of attempting to disguise the ill-defined, if not chaotic, state of our acquaintance with the subject. Further, a clear conception of the gaps in our knowledge is necessary before we can identify with certainty the established facts that stand out from the host of other obscurer details with which the subject is burdened. The recognition, then, of acromegaly as a primary disease of the pituitary body first turned the attention of clinicians to this organ ; but it was not until Tamburini 1 showed that there may be two stages — hyperpituitarism and hypopituitarism —asso- ciated with acromegaly, and Frohlich 2 described the condition of dystrojyhia adiposogcnitalis (hypopituitarism), that many hitherto little understood and apparently contradictory facts became intelligible. Much more recently Cushing 3 has described all conditions of perverted pituitary function as * dyspituitarisms ' ; and he subdivides these into five clinical or symptomatic groups 4 . From a scientific point of view, as w r ell as for the sake of lucidity, it appears to me better to consider pituitary lesions 1 Tamburini, A., Riv. Speriment. di Freniat., 1894, xx, 559. 2 Frohlich, A., Wien. Klin. Bundsch., 1901, xv, 883. 3 Cushing, H., The Pituitary Body and its Disorders, 1912. 4 The following are the groups described by Cushing : — " 1. Cases of dyspituitarism in which not only the signs indicating distortion " of neighbouring structures, but also the symptoms betraying the effects of altered " glandular activity are outspoken. " 2. Cases in which the neighbourhood manifestations are pronounced, but " the glandular symptoms are absent or inconspicuous. " 3. Cases hi which neighbourhood manifestations are absent or inconspicu- " ous, though glandular symptoms are pronounced and unmistakable. " 4. Cases in which obvious distant cerebral lesions are accompanied by symp- " tomatic indications of secondary pituitary involvement. " 5. Cases with a polyglandular syndrome in which the functional disturb- " ances on the part of the hypophysis are merely one, and not a predominant " feature, of a general involvement of the ductless glands." DISORDERS ASSOCIATED WITH THE PITUITARY 217 as primary, and as secondary to disease in the neighbourhood, to general disorders or to derangements of the other organs of internal secretion ; and, also, in each case according to whether there is a condition of excess of secretion or deficiency— so far, at any rate, as our knowledge will allow such an estimation. § i. PRIMARY LESIONS OF THE PITUITARY HYPERPITUITARISM 1 Many authors do not state whether they consider that in hyper- pituitarism only the epithelial elements are concerned ; most, however, infer it. In the recent work of Cushing 2 the relative importance of the anterior and posterior lobes is not made suffic- iently clear ; indeed, this surgeon in the work mentioned con- tradicts the results of his previously published experimental observations. A normal condition of hyperhypophysism 3 exists in pregnancy, as already described ; and there are, also, fluctuations in the functional activity of the pars anterior, as of other ductless glands, at various periods of life, in accordance with the state of the metabolism in regard to growth, reproduction and decay. It is still a debated point whether a pathological state of hyperhypophysism is due merely to an increase of secretion, or whether the secretion is also a perverted one. There is con- siderable evidence in favour of the latter view, and no one has succeeded in producing the symptoms of hyperhypophysism by the administration of hypophysial extracts to the human subject or to animals. The results of pathological hyperhypophysism (an expression which we will consider admits the possibility of a perverted function) depend on the period of life at which the lesion becomes manifest, and also on the extent of departure from the normal in regard to the secretion. When there is hyperplasia of the anterior lobe in early life the effect produced depends on the sex of the patient. If the subject be a boy sexual precocity may occur. In the cases on record the evidence is generally incomplete or conflicting as to 1 ' Hyperpituitarism ' implies abnormal activity of the whole organ. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 3 ' Hyperhypophysism ' implies abnormal activity of the partes anterior and intermedia. HYPERPITUITARISM 219 whether the pineal may not have been concerned 1,2 ; but the fact that in girls hyperplasia of the pars anterior leads to the manifestations of precocious masculinity — hypertrichosis, a deep voice and the rest — gives point to the view that the pituitary may sometimes be concerned in the way indicated in regard to masculine precocity. When the onset of hyperhypophysism occurs before the epiphyses have joined, a remarkable growth of the skeleton follows, and gigantism results. Subsequently, the typical signs and symptoms of acromegaly may appear. If the disease commence late in life when the epiphyses have joined, then, of course, gigantism does not supervene, but certain typical skeletal changes to be described directly are to be seen. The only specific disease known to be produced by hyper- pituitarism is acromegaly, for although gigantism may be asso- ciated with this condition, well-marked skeletal development cannot be considered pathological in the absence of acromegaly. It may, in fact, be due merely to adolescent hyperhypophysism, just as one sees in girls hyperthyroidism at puberty — a condition which produces a temporary effect that subsequently subsides. ACROMEGALY Incidence of the disease. — Acromegaly occurs more com- monly in women than in men, and most often makes its appear- ance between the 20th and 40th years. It is, in fact, a disease of the reproductive period, and more especially of that immedi- ately following puberty. In some cases there is a family history of hyperhypophysism, especially in regard to skeletal overgrowth. Symptoms, signs, and course of acromegaly. — It is very difficult to say what are the prodromal signs — apart from gigan- tism — if such exist. But among the earliest definite symptoms arc slight ocular disturbances, such as photophobia ; headache and facial neuralgia, also, are not uncommon, and there is usually, but not always, muscular weakness. At first, the patient may be 1 Cushing, H., The Pituitary Body and its Disorders, 1912. 2 Poynton, F. J., Proc. Boy. Soc. Med. {Neurol and Ophthalmol. Sects.), 1913, vi, xviii. r 220 DISORDERS ASSOCIATED WITH THE PITUITARY restless, and in men the sexual appetite is sometimes increased 1,2 . A little later, manifestations may occur as the result of the impli- cation of other organs of internal secretion. In men there may be impotence, and in women there is inevitably amenorrhcea and usually sterility. Not infrequently, however, there are periods of abatement in the disease, during which the sexual functions become reestablished. This interesting phenomenon shows us that actual atrophy of the genital organs does not occur — at any rate until late in the disease. Another very striking train of events in connexion with acromegaly in women is the tendency towards masculinity. The bones become enlarged, the voice deep, the skin coarse and the features heavy. In one case which came under my notice there was considerable hypertrophy of the clitoris, and this caused the patient much mental distress. The metabolism is directed towards calcium retention — an essentially masculine characteristic 3 . The amenorrhcea with which women suffer in acromegaly is probably due to this change to masculinity, and not primarily to hyperpituitarism. The alterations which take place in the skeleton have been studied by Keith 4 , and according to this observer the results produced are due to a hormone secreted by the pars anterior. " It renders," he says, " the osteoblasts hypersensitive to the various stresses which fall on the human skeleton during life. Thus the osteoblasts at the origins and insertions of muscles become increasingly sensitive to the traction of the muscle fibres ; the muscular impressions and processes of the skeleton become unduly raised, extended, and emphasized by the forma- tion of new bony matter ". Keith reminds us that John Hunter showed that deposition and absorption of bone go hand in hand ; and he himself considers that in acromegaly the coordination between growth and absorption is lost. The patient with acromegaly soon notices that the hands, feet and head are becoming enlarged : larger boots and gloves are required, and if the patient be a man, he will from time to time need larger sizes in hats. 1 Buday, K., and N. Iansci, Deutsch. Arch. f. Klin. Med,, 1898, lx, 385. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 3 Bell, W. Blair, The Sex Complex, 1916. * Keith, A., Lancet, 1911, i, 993. ACROMEGALY 221 d -5 © <5 © 5i fcO S c '5 o c3 02 '3 o .S © p © £a -*-• «4-l O © "3 p eg c3 d d O CO © CO eg o d o eS - g © zz +a fl ^ O CO © — — © bo — 222 DISORDERS ASSOCIATED WITH THE PITUITARY Enlargement of the vault of the skull can be recognized in a radiograph by the increase of bone on the superciliary ridges, and the greater size than normal of the frontal sinuses (fig. 141). Likewise the enlargement (fig. 142) and often deformation of the sella turcica become noticeable (figs. 143 and 144). In acromegaly there may be thickening of the clinoid processes and Fig. 142. Base of the skull in a case of acromegaly, showing the greatly enlarged sella turcica. {Photograph.) X\. dorsum sellse, as of the other bones ; but eventually there is pressure-atrophy with thinning of the bones and the disappear- ance of the posterior clinoid process (figs. 141, 143, 144). According to Johnston 1 there is a form of ' localized acro- megaly ' in which epilepsy is a common symptom ; and this 1 Johnston, G. C, Atner. Journ. Roentgenol., 1914, i (New Ser.), 172. ACROMEGALY Fig. 143. Radiograph of the skull of a woman suffering with acromegaly, showing enlargement and deformation of the sella turcica. {By Tliurstan Holland.) X }. Fig. 144. Radiograph of the skull of a woman suffering with acromegaly, showing the dis- appearance of the posterior clinoid processes. (By Thuratan Holland.) X ]. 224 DISORDERS ASSOCIATED WITH THE PITUITARY symptom, his radiographic studies lead him to think, is due to the close confinement of the pituitary by the overgrowing clinoid processes and dorsum sellae. The changes in the bones of the extremities can, also, easily be recognized in a radiograph : the phalanges become widened Fig. 145. Acromegaly in a woman. The features are thickened and heavy and the hands are splayed. (Photograph.) and the terminal bones are tufted at the extremities (fig. 146). These alterations cause the hands to become broad and splayed (fig. 145). Gradually the face becomes distorted : the malar bones increase in size and the lower jaw so enlarges that it may project beyond the upper (prognathism) (figs. 145 and 147), which is itself often enlarged. There is, however, no increase in the size ACROMEGALY 225 Fig. 147. Profile-view of a woman suffering with acromegaly, showing prognathism. (Photograph.) v Fig. 14S. Separation of the teeth in a woman suffering with acromegaly. (Photograph.) 15 226 DISORDERS ASSOCIATED WITH THE PITUITARY of the palate. The maxillary expansion involves the whole circumference of the jaws and causes the teeth to become widely separated (fig. 148) — a very constant sign of the disease. The skin becomes coarse, rough and thick owing to hyper- trophy of the papillae and thickening of the cutis and the sub- cutaneous tissues, and it may be yellowish or pigmented ; the hair and nails become brittle. The nose and ears enlarge and the lower lip becomes bulky and pendulous (fig. 145), as the result of the changes mentioned in the cutaneous and sub- cutaneous tissues. Likewise there is an increase in the size of the tongue ; and the mucous membrane of the nose and pharynx becomes thickened. The enlargement of the tongue may cause the patient to keep the mouth always open, and the thickening of the nasal mucosa gives rise to discomfort and difficulty of breathing, and even to deafness from involvement of the Eustachian tubes. The patient often suffers with polyuria, and glycosuria, the result of hyperglycaemia, is sometimes present. Unless the disease become arrested — as not infrequently happens— various other symptoms soon make their appearance : the patient complains of tinnitus auriuni, and invariably of the severity of the 'pituitary headache' which results from pressure in the pituitary fossa, of giddiness, unsteady gait and occa- sionally of epileptiform seizures ; and there is usually progressive lassitude and torpidity, although sometimes the psychical func- tions remain undisturbed until an advanced stage of the dis- ease. Vomiting due to intracranial pressure is rare, but may occur. Simultaneously with the symptoms just described, or later, the patient complains of serious disturbances of vision. On examination, various degrees of divergence from the normal, according to the extent of the intracranial injury to the optic tracts, are found. Bitenmoral hemianopia is usually present early in the disease (fig. 149), but is often undiscovered at first by the patient, owing to the fact that colour-vision disappears before the white field (fig. 150, a). Sometimes there is diplopia ; and even external strabismus from injury of the third nerve is not uncommon. Eventually the fields of vision may become extremely restricted (fig. 150, b), and finally blindness may super- vene from atrophy of the optic nerves. Extensive involvement, however, of the optic tracts and of the oculomotor nerve is, ACROMEGALY 227 according to Gushing 1 , uncommon in acromegaly. Sometimes there is exophthalmos. This train of events, short in the description, takes long in the development. Patients suffering with acromegaly live for many years in a condition of hyperhypophysism, but most of them drift finally into the condition of hypohypophysism which I shall describe presently, and this occasionally after a period of apparent quiescence in the disease. In very rare cases when acromegaly has been due to a functionating malignant tumour of the anterior lobe the disease runs a rapidly fatal course 2 . Fig. 149. Restricted white fields of vision in a case of acromegaly. {By T. H. Bickerlon.) As we have seen, during pregnancy the activity of the anterior lobe is normally increased, and, as a result, minor and temporary symptoms of acromegaly may occasionally occur, especially thickening of the subcutaneous tissues. Marek 3 has reported a case in which acromegaly, with glycosuria, prognathism and some of the other symptoms of the disease, commenced during pregnancy and disappeared during the puerperium. The metabolism in acromegaly. — Observations concerning the metabolic disturbances in acromegaly are so conflicting that it is probable that many of the abnormalities found depend not 1 Gushing, H., The Pituitary Body and its Disorders, 1912. - Fischer, B., Hypophysis, Akromegalit und Fettsucht, Wiesbaden, 1910. 3 Marek, R., Zenlralbl.f. Uynak., 1911, xxxv, 1612. 228 DISORDERS ASSOCIATED WITH THE PITUITARY White right Red White Red 90 90 White RIQHT. Red 90 SO Fig. 150. Fields of vision (colour and white) in a case of acromegaly, a, on December 18th, 1911, when the colour-fields were greatly restricted, and the white fields only slightly, b, on February 17th, 1913, when the white fields were much limited and the colour-fields less than previously. (Doyne.) ACROMEGALY 229 only on hypophysial disease, but also on a pluriglandular syndrome. Franchini 1 , and Franchini and Giglioli 2 investigated several cases of acromegaly and concluded that in the active stages of the disease there is an excessive excretion of nitrogen and phosphorus, and a considerable retention of calcium and magnesium. These observers state that the metabolism of chlorine, sodium, and potassium is not appreciably altered. Moraczewski 3 and others have found an abnormal retention of calcium and phosphorus. Table XI. N. H. Female, mt. 30 Years. Case op Acromegaly. Examination of Urin t e. <3 a a '■3 a CD M 60 O Date. •p '3 a p k X ^ 5 o o° s 5 o eg 0> o a. O i - £ a £ L4 & -1 - C o a o a § g cj o a a "3 S M m < — ""i f. H H < < grms. grms. o c.c. grms. grms. grms. % % 28.1.15 acid 1016 — — 0-78 1-69 0-064 8-1 034 0-17 0016 29.1.15 acid 1010 — — 0-49 113 0-039 7-3 0-38 0-188 013 30.1.15 acid 1015 — — 0-714 0071 0-10 0-4 0-288 00145 1.2.15 acid 1015 — — 0-77 0-059 7-7 0-3 0-318 0-0017 2.2.15 acid 1012 063 0-05 8-0 032 0-212 0-0095 3.2.15 4 513 neutral 1012 0-448 0-04 9 45 0161 0052 12.2.15 1311 acid 1013 0-462 1-75 0067 145 037 0-26 0-0004 13.2.15 1625 acid 1012 0-742 1-22 0061 8-3 0-3 015 0-032 15.2.15 1083 acid 1015 0-84 1-75 0-061 7 3 0-35 0-34 00227 Hi. 2. 15 acid 1013 0-644 111 005 7-8 0-41 0-22 0-0088 17.2.15 1311 acid 1012 0-826 1-75 05 61 0-4 0-24 0-0005 L8.2.15 1254 acid 1014 0-812 1-72 0047 5-8 0-3 0-33 001 19.2.15 1311 acid 1015 0-700 1-41 049 7-0 0-25 0-2! 0001 20.2.15 1311 acid 1011 0-559 1-19 0-35 0-23 0003 22.2.15 1454 acid 1020 0-729 1-55 0-07 !>-i; 0-5 0-18 00015 23.2.15 1340 acid 1015 0-491 1061 0-05 10-0 0-6 017 00015 24.2.15 1(553 acid 1010 043 10 0-04 8-6 0-26 0-21 0002 I have examined the urinary excretions of two cases of acro- megaly with the patients on a full mixed diet. Tables XI and XII show the results obtained. 1 Franchini, G., Riv. Speriment. di Freniat, 1907, xxxiii, 888 ; and Berl. Klin. Woch., 1908, xlv, 1636. 2 Franchini, G., and G. J. Giglioli, Nouvelle Icon, de la Salpetriere, 1908, xxi, 325. 3 Moraczewski, W. D. von, Zeit.f. Klin. Med., 1901, xliii, 336. 4 Decompression operation: February 3, 1915. Calcium index in blood, 1*05. February 16, 1915. Calcium index in blood, 0*54. 230 DISORDERS ASSOCIATED WITH THE PITUITARY It will be seen that there is no definite abnormality to be discovered, except in regard to the calcium metabolism. The excretion of this substance was very variable and below normal except on a few occasions, when large quantities were excreted. Table XII. G. J. Male, mt. 27 Years. Case of Acromegaly. Examination op Urine. a ea a a ! fc 3 g P O H 0) ft ■6 '3 5 o CO a 43 'o Date. >> a «s c £ CS o^ 33 "5 c3 s .2 "8 a S3 z ~ '■5 ., Bull. Johns Hopk. Hosp., 1905, xvi, 157. 6 Linsmayer, L., Wien. Klin. Woch., 1894, vii, 294. 7 Cushing, H., The Pituitary Body and its Disorders, 1912. ACROMEGALY 233 asserts that eosinophil adenoma is the hall-mark of acro- megaly. It appears, therefore, that the symptoms of the disease known as acromegaly are primarily dependent on an excessive secretion of the eosinophil or the active chromophobe cells of the anterior lobe (fig. 152). This is in keeping with the explanation already given of the secretory functions of the cells of the pars anterior. ^•1. «... °%° 8 se/ •?■»*•%**'. °'i% '*■ '.« r fc*-^ . iv^^v^iv •£ Fig. 152. Section of a portion of the pars anterior removed at operation (by W. Theltvall Thomas) from a case of acromegaly, showing an adenomatous arrangement of chromophobe cells. There is much blood scattered through the section — probably the result of surgical interference. X 150. Although in these circumstances there is always at first a condition of hyperplasia present in the pars anterior, it is pro- bable that the main features of acromegaly exist for some time after the anterior lobe has ceased to be excessively active. Further, it has rightly been emphasized by Cushing that hypo- pituitarism very frequently succeeds hyperpituitarism, and that it is not uncommon to find in this later stage a cystic or necrotic change present in the anterior lobe. 234 DISORDERS ASSOCIATED WITH THE PITUITARY Before leaving the discussion of the pathology of acromegaly and the question of the actual situation of the lesion in the pituitary body, it is necessary briefly to refer to the interesting fact that acromegaly may be caused by hyperplasia in an acces- sory anterior lobe ; that is to say, hyperplasia may occur in a congenital inclusion of the hypophysis in the track of the cranio- pharyngeal canal through the sphenoid bone. These inclusions of a portion of Rathke's pouch are probably not rare, but only a few cases are known in which acromegaly has arisen from such rests. Erdheim 1 has recorded such a case. He found an eosinophil hypophysial tumour, extending into the sphenoidal cells below the sella turcica, which had been associated with the symptoms of acromegaly. The pituitary body proper was quite normal. The following question now arises : How far are pathological lesions in the pituitary responsible for the clinical manifesta- tions associated with acromegaly ? Tandler and Grosz 2 considered that hyperplasia and event- ually hypoplasia in the pituitary were secondary to primary genital atrophy. This assumption was partly based on experi- mental evidence ; but it in no way accords with the clinical facts, for genital hypoplasia folloAvs, rather than precedes, the onset of acromegaly, and undergoes remissions when improve- ments occur in the course of the disease. In most cases there is no doubt that while in this disease the primary pathological lesion is in the epithelial portions of the pituitary and most of the clinical manifestations are the result thereof, yet in their entirety the clinical phenomena form a pluriglandular syndrome. This, indeed, is the only explanation that can be offered in some anomalous cases. Many recent observers have recognized changes in the other hormonopoietic organs in acromegaly ; but if we except tentative discussions by Biedl 3 and Cushing 4 , and the work of Claude and Gougerot 5 on somewhat similar lines, it does not appear to have been seriously put forward that primary disease of an organ of 1 Erdheim, J., Beitr. z. Pathol. Anat. u. z. Allg. Pathol, 1909, xlvi, 233. 2 Tandler, J., and S. Grosz, Wien. Klin. Woch., 1907, xx, 1596. 3 Biedl, A., Innere Selcretion, 2nd ed., 1913. 4 Cushing, H., The Pituitary Body and its Disorders, 1912. 5 Claude, H., and H. Gougerot, Joum. de Physiol, et de Pathol. Gen., 1908, x, 469 and 505. ACROMEGALY 235 internal secretion does not produce symptoms entirely dependent upon that lesion, but rather upon a pluriglandular involve- ment. It is, for example, not impossible that hyperthyroidism — apparently a pathological entity — is dependent partly on the withdrawal of the restraining influence of other internal secretions. The way for this point of view has been prepared by our consideration of the physiological interrelations between the pituitary and the other organs of internal secretion ; but in order to view the whole subject more completely I shall first consider the pathological condition known as 'hypopituitarism'. HYPOPITUITARISM Incidence and symptoms. — It is possible that hypopituitar- ism may exist as a congenital lesion, but such a state of affairs is difficult to determine, for it is not until the child is growing up that the signs of this lesion become recognizable. Hypopituitarism occurring before puberty gives rise to three distinct conditions : (a) infantilism somatic and sexual, with- out adiposity (Lorain type) ; (b) stunted growth with sexual infantilism and adiposity ; (c) overgrowth with some adiposity and genital inactivity. Levi 1 was probably the first to direct attention to infan- tilism (Lorain type) due to pituitary lesions. This type of case is attributed by Gushing 2 and others to insufficiency in the secretion of the pars anterior ; and in his case (iv) there was an enlargement of the sella turcica. I have seen a case in which a girl at the age of 18 years resembled a child of 10 years of age (fig. 153), and in whom there was a shallow sella turcica (fig. 154). Rennic 3 , also, has recorded an interesting case of this type of infantilism in a boy suffering with an endothelioma of the pituitary. It seems probable that in those cases in which the sella turcica is small the condition has existed ab initio ; while in those in which the sella is distorted and large there has been some postnatal and preadolcscent destruction of the pars anterior without injury to the pars posterior. It is probable, also, that when there is a preadolcscent lesion of the pituitary producing adiposity, stunted growth and sexual infantilism, the whole organ is affected. Since the condition of dystrophia adiposogenitalis was first described by Frohlich 4 in the case of a boy, 14 years of age, a 1 Levi, E.. Nouv. Icon, de la Salpetriere, 1908, xxi, 297 and 421. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 3 Rennie, G. E., Brit. Med. Joum., 1912, i, 1355. 4 Frohlich, A., Wien. Klin. Bundsch., 1901, xv, 883. HYPOPITUITARISM BEFORE PUBERTY 237 Pio. 153. Photograph of a girl, aged 18 years, showing general infantilism due to under- development of the pituitary. The patient measured 4 ft. 3 ins. in height and weighed 4 stones 3 lbs. 238 DISORDERS ASSOCIATED WITH THE PITUITARY number of cases of this state of affairs is on record 1,2 — so many that it is impossible to give all the references. One of the most interesting cases is that of Madelung 3 in which a girl 9 years of age was shot with a rifle-bullet which lodged in the sella turcica. The child developed the typical symptoms of this syndrome, but these were not recognized as such when the case was reported. Most of the cases, however, have been due to neoplasms or cystic formations in the pars anterior. Fig. 154. Radiograph of the sella turcica in the case of ateliosis illustrated in figure 146. (By Thurston Holland.) X}. The syndrome, dystrophia adiposogcnitalis, is easily recog- nized (fig. 155). I shall discuss it in detail presently ; but one point must be mentioned here. In boys the skeleton tends to develop on feminine lines, for the bones are light and the ex- tremities tapering. The third group of preadolescent cases of hypopituitarism, in which there is some skeletal overgrowth with adiposity and genital inactivity, has been described by Neurath 4 and dishing 1 . Cushing interprets the phenomena seen as being dependent on 1 Cushing, H., The Pituitary Body and its Disorders, 1912. 2 Special discussion, Proc. Roy. Soc. Med. (Neiirol. and Ophthalmol. Sects.), 1913, vi, i. 3 Madelung, 0., Virhandl. d. Deutsch. Gesellsch.f. Chir., 1904, xxxiii, 164. 4 Neurath, R., Wien. Klin. Woch., 1911, xxiv, 43. HYPOPITUITARISM BEFORE PUBERTY 239 excessive secretion from, the pars anterior with diminished pars posterior secretion. But this certainly does not explain the genital infantilism in the case of males. Neurath, however, considers it possible that the whole train of symptoms is due to primary lesions in the gonads producing a condition of re- sembling eunuchism. But neither of these explanations quite accounts for the features of the following case. Fig. 155. Three views of a boy, aged 16 years, suffering with dystrophia adiposogenitalis. He measured 4 ft, 6 ins. in height and weighed 7 st. 9 lbs. There was a carbo- hydrate-tolerance of over 300 grammes of sugar. (Photograph.) (F. E. Batten.) This patient came under observation at the age of 18-| years, being referred to me by her father who is a doctor. Her only complaint was that she had not menstruated. On examination the uterus was found to be infantile — rudimentary, I thought at the time. A radiograph of the sella turcica showed this fossa to be re- markably small (fig. 15G). When first seen the patient was a bright, handsome, finely developed girl measuring 5 feet 8| 240 DISORDERS ASSOCIATED WITH THE PITUITARY inches in height, and weighing 11 stones 2 pounds. The carbo- hydrate-tolerance was over 350 grammes of dextrose — that is to say, no sugar appeared in the urine after this amount had been consumed, and it was impossible for the patient to take more. Two years later her father wrote to say that she weighed 15 stones 4 pounds in spite of the administration of whole-gland pituitary extract. After that time the administration of pituit- ary extract was discontinued. Fig. 156. Radiograph of the human sella turcica in a case of underdevelopment of the pituitary associated with an infantile uterus. (By Thurston Holland.) Recently, at the age of 23 years, the patient has commenced menstruating regularly. It is this last fact which almost places the case in a category of its own. After puberty there may be, as in hyperpituitarism, many stages and phases of hypopituitarism ; but, as is so frequently the case in newly described conditions, only the most pronounced HYPOPITUITARISM AFTER PUBERTY 241 types are generally recognized, while the less severe lesions with slight clinical manifestations escape adequate recognition. The milder forms of hypopituitarism are undoubtedly much commoner than is generally supposed. The patients are usually of the female sex between 25 and 35 years of age. The most prominent symptoms are increasing obesity, lassitude and amenorrhcea. Advice is usually sought for the menstrual sup- pression. At first the amenorrhcea alternates with irregular and scanty menstruation, and finally this function ceases. Most text-books of gynaecology describe obesity as a primary cause of amenorrhoea and sterility. That it may be is probable 1 ; but it appears likely that in many cases the obesity is really due to pituitary insufficiency. I have seen atrophy of the uterus from this cause in a woman of 36 years of age. Up to 30 years of age her menses had been regular. In the adult, as in the child, the more serious states of hypopituitarism — produced by cysts, neoplasms or traumatic lesions — form the definite syndrome dystrophia adiposogenitalis. In this condition the subject becomes obese ; and the male assumes a feminine configuration (feminine type) (fig. 157). In the female men- struation ceases ; in the male there is impotence ; and the genital organs of both sexes eventually atrophy. The blood- pressure is low and the temperature sub- normal. There is, also, so great an increase in the carbohydrate-tolerance with hypo- glycaemia, that the ingestion of more than 500 grammes of dextrose may be required to produce glycosuria. The sugar-tolerance may be reduced and the blood-pressure raised by the injection of an extract of the posterior lobe, while the temperature maybe Parsons.) elevated by anterior lobe extract ('thermic reaction' of Gushing). In the more severe and progressive types of the disease the 1 Marshall, P. H. A., Sci. Progress, 1908, ii, 369. 16 Case of dystrophia adip- osogenitalis in a man, showing a tendency to feminine contour (typus f< mi n't mi). {Photograph.) [Grainger Stewart and 242 DISORDERS ASSOCIATED WITH THE PITUITARY 20m.m white & Colours Shaded' scotoma R eo * Fig. 158. Fields of vision in a case of dystrophia adiposogenitalis, showing bitemporal hemianopia, and disappearance of the colour-fields before the white. (Bishop Harman.) Fig. 159. Left fields of vision in the case of dystrophia adiposogenitalis shown in figure 157, showing gradual progression towards blindness: A, on May 10, 1911; b, on Feb. 12, 1913. (Grainger Stewart and Parsons.) HYPOPITUITARISM AFTER PUBERTY 243 increasing size of the tumour raises the intracranial tension, causing severe headaches, and by injury to the optic tract gives rise to hemianopia — colour-vision disappearing before the white field (fig. 158) — sometimes diplopia, and eventually almost complete blindness (fig. 159). In these circumstances the sella turcica is usually greatly enlarged, and often the posterior clinoid processes are completely eroded (fig. 160). The deformation of the sella is usually greater in dystrophia adiposogenitalis than in acromegaly. Vomiting is very rare in these cases. Fig. 160. Radiograph of the sella turcica in a case of dystrophia adiposogenitalis, showing disappearance of the posterior clinoid processes. The fields of vision of this case are shown in figure 158. (Bishop Harman.) Psychical disturbances may be present as the result of pres- sure on the frontal lobes ; and a specific hypophysial psychosis, due, it is supposed, to perverted pituitary secretion, has been described. The subjects may, however, show all degrees of cerebral disturbance from a torpidity or irritability to advanced forms of epilepsy and insanity. The relationship of epileptiform seizures to lesions producing hypopituitarism has been studied by dishing 1 . There appears to be no doubt that, with a pituitary lesion 1 Cashing, H., The Pituitary Body and its Disorders, 1912. 244 DISORDERS ASSOCIATED WITH THE PITUITARY extending upwards into the interpeduncular region, pressure on, or irritation of, the uncinate gyrus may be produced. In these circumstances attacks of loss of memory, or even ' fits ' preceded by gustatory or olfactory phenomena, occur. These manifestations, with general epileptiform seizures, appear occa- sionally to follow pituitary insufficiency apart from pressure on the gyrus, and are probably due to increased cortical irritability. The skin of patients with hypopituitarism differs from that of patients suffering with acromegaly : in the former condition the integument is soft and smooth, the hair tends to fall out, and, unless the condition be a sequel to acromegaly, the extremi- ties are usually delicate and tapering. The pathology of hypopituitarism. — As we have seen in certain preadolescent types, the lesion of the pituitary may be congenital ; but of this we have no certain knowledge. Until quite recently it had been accepted by nearly all who have inquired into the subject that hypopituitarism is, strictly speaking, hypohypophysism — that is to say, insufficiency of the partes anterior and intermedia. In order to discuss this question we shall be obliged to reconsider the relative positions occupied by the anterior and posterior lobes, including the pars intermedia. The experimental work of Paulesco 1 , of dishing 2 and his colleagues, and of Biedl 3 appeared to place beyond all doubt the fact, as emphasized by them in their respective publications, that in dogs dystrophia adiposogenitalis is always produced by partial extirpation of the anterior lobe, and that removal of the posterior lobe causes no symptoms. Yet we find that Cushing who has done the most experimental work on this subject, and was apparently certain of his results and conclusions, in his clinical exposition 4 states that the condition of hypopituitarism is due to posterior lobe insufficiency. This view has also been advanced by Fischer 5 , apparently on pathological grounds. The reason why Cushing changed his views appears to have been partly because of post-mortem findings, and partly because 1 Paulesco, N. C, Lliypophyse du cerveau, Paris, 1908. 2 Crowe, S. J., H. Cushing, and J. Homans, Bull. Johns Hoph. Hosp., 1910, xxi, 127. 3 Biedl, A., Inncre Sekretion, 2nd ed., 1913. 4 Cushing, H., The Pituitary Body and its Disorders, 1912. 5 Fischer, B., Hypophysis, Akromegalie und Fcttsucht, Wiesbaden, 1910. HYPOPITUITARISM AFTER PUBERTY 245 injections of the extract of the posterior lobe lessen some of the symptoms associated with hypopituitarism, such as the carbohy- drate-tolerance and the low blood-pressure. On the other hand, he himself pointed out that the subnormal temperature found with hypopituitarism is raised by extract of the anterior lobe ('thermic reaction '), and not by infundibulin. Apart from the effects produced by the extract of the posterior lobe in hypopituitarism, dishing adduces other clinical evidence which, he considers, confirms his latest conclusions. He states that an internal hydrocephalus may produce insufficiency of the secretion ot the posterior lobe, and at the same time " may apparently either stimulate or inhibit the anterior lobe " 1 . But the fact that the pars nervosa of the pituitary in man is not hollow, as it is in some of the lower animals, and cannot, therefore, be distended by intraventricular tension appears to have been overlooked by Gushing. Any pressure that may be produced by hydrocephalus in Man must affect equally both lobes. This observer, therefore, introduces a fresh syndrome : namely, a condition of adiposity with sexual precocity or excitation. Further, this syndrome may be associated, he says, with skeletal undergrowth or overgrowth. Cases are cited, it must be admitted, from his exceptional experience to illustrate these phenomena ; but whether a correct interpretation has been placed on them is open to argument. With regard to Cushing's experiments and those of Biedl, I have demonstrated that it is possible to remove large or small quantities of the anterior lobe and so to bring about in- sufficiency in this structure, as is shown by the genital atrophy which subsequently occurs, without in any single case producing the syndrome dystrophia adiposogenitalis by this procedure. Further, it has been proved that removal of the whole or a portion of the posterior lobe causes neither genital atrophy nor carbohydrate-tolerance. The only way in which I was able to produce dystrophia adiposogenitalis was by separating or clamping the stalk. These results, read in conjunction with the foregoing views of Cushing, serve to illustrate the uncertainty of our knowledge or at any rate the conflicting nature of the experi- mental evidence at our disposal for interpretation into the terms 1 Cushing, H., Tin Pituitary Body and Us Disorders, 1912. 246 DISORDERS ASSOCIATED WITH THE PITUITARY of clinical phenomena. Fischer 1 , without any experimental data of his own to support him and arguing from a pathological standpoint, asserts that dystrophia adiposogenitalis is due to lesions of the posterior lobe. My experimental results show that interference with the stalk is the only lesion which gives rise to this condition. Erdheim 2 has shown that not infrequently in dystrophia adiposogenitalis aggregations of squamous or columnar epi- thelium are found in the neighbourhood of the cleft. These are either embryonic rests or metaplasias, and from them growths and cysts may arise. Seven cases have been described by Erdheim, and similar tumours have been recorded by others. Cushing 3 , in an interesting discussion of the subject, mentions a case of a tumour arising in the upper part of the cleft, and he illustrates the histological appearances which resemble those of thyroid tissue. It is doubtful, however, whether large aggre- gations of colloid-containing acini in the pars intermedia of the human subject can be considered neoplastic. I have seen this condition well marked in pregnancy, and in other conditions. Possibly this state of affairs is pathological in so far as the amount of colloid and the extent of the acinous formation of the cells are concerned, but it does not usually constitute neoplasia. When there is a definite tumour in the neighbourhood it may cause compression of the pituitary and interfere with its function to such an extent as to produce dystrophia adijwso- genitalis. There are many cases of this character on record. On the other hand, it is, of course, obvious that extreme hyperplasia and other causes of enlargement of the anterior lobe will produce pressure on the posterior. Yet all the evidence in our possession seems to point to the fact that insufficiency of the pars posterior is not primarily the cause of dystrophia adiposogenitalis, especially as the whole of this part of the pituitary can be removed without causing symptoms. It seems to me more probable that in these circumstances the syndrome may be caused by the pressure produced by enlargement of the pars anterior on the cells themselves, and on the blood-sinuses. 1 Fischer, B., Hypophysis, Akromecjalie und Fettsucht, Wiesbaden, 1910. 2 Erdheim, J., Sitz. d. k. Akad. d. Wissensch. Math-naturw. Kl, Wien, 190-1, cxiii, 537. 3 Cushing, H., The Pituitary Body and its Disorders, 1912. HYPOPITUITARISM 247 The typical histological appearance of the pars anterior from a case of dystrophia adiposogenitalis is shown in figure 161. The cells are shrunken and widely separated, just as they are in the pituitary of the dog in which this syndrome has been produced by separation or compression of the infundibular stalk (fig. Ill, p. 164). * -**•.-•• ill /• *•*- ♦ '. Fig. 161. Section of the pars anterior from a case of dystrophia adiposogenitalis in a young man, showing intense atrophy of the cells. (From a section kindly lent by E. E. Glynn.) X 150. It appears, then, that the state of adiposity with genital atrophy is due to interference with secretory function or the blood-supply of the pituitary as a whole, and that some of the symptoms can be mitigated, as we have seen, by injections of infundibulin and some by the extract of the anterior lobe. Thus again we have evidence that the pituitary is one organ and not two. PLURIGLANDULAR AFFECTIONS IN PRIMARY LESIONS OF THE PITUITARY Of the physiological relationships between the pituitary and the other hormonopoietic organs we have had some proof in the extirpation experiments already recounted ; and of the alterations which may occur in distant organs of internal secretion with pathological lesions of the pituitary we have had an indica- tion in respect of the gonads, in which retrograde changes may form a characteristic symptom of the diseases in question. It will be well, however, shortly to consider the question in more detail, for undoubtedly some of the symptoms of hyperpituit- arism and hypopituitarism are dependent not on the lesions in the pituitary but rather on those in other hormonopoietic organs. Gonads. — We have seen that the metabolism of hyper- pituitarism is largely concerned in the retention of the lime and magnesium salts. This is a masculine characteristic ; con- sequently it is not surprising to find other evidence of emphasized male characterization in this state. /Attention has been called to the fact 1, 2 that in the early stages of acromegaly in men there is often increased sexuality. No doubt this is directly dependent on the hypophysial lesion. In women, on the other hand, hyperhypophysism causes the immediate cessa- tion of menstruation, and in a short time the assumption of male secondary characteristics. There can be little doubt, then, that there is a close con- nexion between the gonads and the pituitary ; and the difference in the two sexes is interesting, and may in part be related to the effect pituitary lesions are believed to have on the suprarenals. 1 Gushing, H., The Pituitary Body and its Disorders, 1912. 2 Buday, K., and N. Iansci, Deutsch. Arch.f. Klin. Med., 1898, lx, 385. PLURIGLANDULAR COMPLICATIONS 249 Tandler and Grosz 1 , as we have seen, came to the conclusion that hyperhypophysism follows hypoplasia in the gonads — no doubt from the fact that ablation of the ovaries leads to eosino- philia and hyperplasia of the pars anterior. I have already discussed this question and have pointed out the unlikelihood of this suggestion representing the true state of the case. Cushing 2 discusses the relative importance of the interstitial cells of the gonads and the reproductive cells, and appears to attach undue importance to the interstitial cells in the production of the secondary sex-characteristics. I have adduced evidence elsewhere 3 which proves conclusively that these cells have very little influence, if any, in this respect. However, in regard to the subject under discussion, the matter is only of importance in connexion with the integrity of the uterus which is dependent on the interstitial cells, and bears no relation to sex-character- ization, which may be directly influenced by the pituitary as well as by other members of the hormonopoietic system. In the later phases of acromegaly, when there may be hypo- pituitarism, there is in both sexes genital hypoplasia and a tendency towards a neutral type in regard to the secondary sex- characteristics. Suprarenals. — It is well known that the suprarenal cortex has an important influence on sex-characterization 3, 4 » 5 , and the medulla a pressor action on the blood-pressure. In many cases of pituitary disease there seems to be asso- ciated asthenia, with a low blood-pressure and pigmentation. In these circumstances the suprarenals have been found to be very small. A typical case of this character is shown in figure 1G2. The patient was deeply pigmented — even having patches on the sclcrotics — and the other symptoms of Addison's disease were pronounced ; at the same time there was well-marked acromegaly. Cushing 2 records eases in which ' hypcrsupra- renalism ' existed in association with hypopituitarism. In a case, from which I have had the opportunity of 1 Tandler, J., and 8. Gro^z, Wien. Klin. Woch., 1907, xx, 1596. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. 3 Bell, W. Blair, The Sex Complex, 1916. 4 Bulloch, W., and J. H. Sequeira, Trans. Path. Soc., 1905, lvi, 189. 5 Glynn, E. E. s Quart. Jowrn. Med., 1:112, v. L57. 250 DISORDERS ASSOCIATED WITH THE PITUITARY examining sections, and in which a young woman developed masculine characteristics with amenorrhcea, there was a chromo- phobe adenoma in the pars anterior of the pituitary (fig. 163) and a hyperplastic tumour in the suprarenal cortex (fig. 164). Both these lesions would produce masculinity in a woman, and increased masculinity in a man. In the case recorded there were no symptoms other than those mentioned. Fig. 162. A case of combined Addison's disease and acromegaly in a man. Thymus. — Experimental evidence has shown that de- structive lesions of the pituitary are associated with a normal or hyperplastic thymus ; but, on the other hand, we must re- member that after oophorectomy or removal of the testes there is eosinophil hyperplasia in the pars anterior together with enlargement of the thymus. This apparently paradoxical state of affairs indicates that probably the thymus is unaffected by affections of the pituitary, and that if it be enlarged in these circumstances this is due to the genital hypoplasia which co- exists with most pituitary lesions. Thyroid. — The results of experimental thyroidectomy and partial removal of the pituitary lead us to conclude that the PLURIGLANDULAR COMPLICATIONS 251 thyroid and pars anterior are closely related, and that as an immediate result of the extirpation of one of these organs there is a change in the other ; this, however, is much more decided in the pituitary than in the thyroid. It has already been mentioned (p. 232) that Furnivall has found the thyroid affected in a large number of primary pituitary lesions. -., ., °j$? - v -,S? "*<*<* ;« >-.':. • - .. ..:. • -V-. : -:- •;.••:-.::••. ■'.•-.'* ^ ** *&\<*,^%T* • .;.•:■■■■:■:• ■: • •. ■.. •.- .... ; ... ■•,.;■ / v.-.v>; -: : -- ; 'V.'- * *..•:.• ;'•*.•. : *. • ■■:;■■:.•. i.'^^-v ""' ;■- ^-' . Fig. 163. Section of the pars anterior of the pituitary of a young woman who had developed masculine characteristics, showing a chromophobe tumour in the lower part. (From a section kindly lent by J. Anderson.) X 60. Pineal.— We have no definite information of any con- nexion between pituitary lesions and affections of the pineal. It is, however, believed from experimental and pathological evidence that the pineal is related to the development of sex- characteristics, and that a decreased function in this organ before puberty leads to sexual precocity in boys. It is doubtful whether the pineal has any genital functions after puberty, or is related to the alterations in the sexual functions and characteristics associated with pituitary lesions. 252 DISORDERS ASSOCIATED WITH THE PITUITARY Si •'. : P.'\ -■: : ': : --^\ : - : X : /. ; :' : '.:^--.'. :: K; ..- : -' "•■■>■'■'• ".■•■' » ^/l| '"■■ ' : '^:-:S. : ^^Vv:: v ^; A'. v : - " v • • • ■- - ' '■■'.•.•.••■•.."-'.'• •:' . V-. ' . '■ . -" • • ■■: ■ ■'' ^- ' '. Fig. 164. Section of the suprarenal of a young woman who developed masculine characteristics, showing encapsuled hyperplasia in the lower part of the picture. {From a section kindly lent by J. Anderson.) X 60. PRIMARY LESIONS IN THE PITUITARY PRO- DUCING SYMPTOMS NEITHER OF EXCESSIVE NOR OF DIMINISHED SECRETION It not infrequently happens that extensive lesions occur in the pituitary body which are associated with but few symptoms. In these circumstances the patients may complain only of dis- turbances of vision, but sometimes they suffer also with head- aches. As a rule, therefore, they consult an oculist in the first instance. In one case of this character, which came under my notice, the patient, an unmarried lady 42 years of age, was completely blind in the left eye and had a very restricted field of vision in the right eye. At no time had there been either vomiting or headache. The menopause had occurred somewhat prema- turely a few years previously. The patient had never exhibited symptoms either of acromegaly or of dystrophia adiposogenit- alis. There was a moderately raised carbohydrate -tolerance (200 grammes of lsevulose), but this is not unusual after the menopause. There was no thermic reaction. The systolic blood-pressure was raised and was equal to about 140 mm. of mercury. A radiograph showed that the sella turcica was con- siderably enlarged backwards (fig. 165). It is probable that in this ease portions, at least, of every part of the pituitary were functionating, and that there was some cystic lesion present in the anterior lobe. The patient, however, refused operation. There is a large number of these cases now on record ; and they appear to be readily recognized by oculists as a typical class of case about which not infrequently they are con- sulted 1 . This seems, therefore, the most suitable place in which to 1 Discussion, Proc. Roy. Soc. Med. {Neurol, and Ophthalmol. Sects.), 1913, vi, i. 254 DISORDERS ASSOCIATED WITH THE PITUITARY discuss the causation of the ocular symptoms with which patients suffering from pituitary lesions are so often afflicted. The matter is by no means an easy one ; at the same time it is one of considerable moment, since a correct interpretation of the ocular anomalies may enable us definitely to decide in which direction the tumour is extending, and from which side the disease must be attacked when the temporal route is employed. So far as I know, this point has rarely been adequately con- sidered in all its bearings, the general assumption being that the Fig. 165. Radiograph of the skull of a woman complaining of loss of sight, showing considerable enlargement of the sella turcica. {By Thursian Holland.) ocular symptoms, scotoma and hemianopia, are due to primary optic atrophy from the direct pressure on the chiasma pro- duced by the enlarging pituitary. Such an explanation, how- ever, is not entirely satisfactory, for a patient may become totally blind in one eye without the other being appreciably affected. A short consideration of the anatomy of the optic tracts and of the oculomotor nerves is necessary to make clear the difficulties that may arise in connexion with this question. It is generally accepted that the fibres connected with the LESIONS OF THE OPTIC TRACT 255 retinae, on which sight depends, have a peculiar course ; that is to say, those on the nasal sides of the retinae decussate in the optic chiasma, as illustrated in figure 166, while those on the temporal sides have a more direct course, and are enclosed below and at the sides by the decussating fibres from the opposite eye. The nasal fibres of the maculopapillary bundle, which is con- cerned with acute vision at the macula, decussate, while those from the temporal side of the macula do not do so. Now, the pressure of the enlarging pituitary body is exerted chiefly backwards, and only slightly forwards. This is shown in most radiographs by the erosion and destruction of the posterior clinoid processes and the posterior wall of the sella turcica (figs. 141, 143, 144, 160 and 165), due, no doubt, to the lesser resistance behind ; consequently in these circumstances the pressure must be exerted away from the optic chiasma, and not entirely on it. But the enlargement and resulting pressure is not only backwards, but laterally as well. If, however, the chiasma be involved the pressure of the growing tumour will affect the fibres from the nasal fields of the retinae, and the anterior and posterior commissures of Stilling and Gudden respectively, which, however, are believed to be unconnected with vision. Pressure on the optic chiasma forwards will, then, usually produce the well-known ocular symptom of bitemporal hemianopia, since the rays of light from the temporal fields impinge, after passing through the lenses, on the nasal sides of the retinae (fig. 166) ; and also in some cases central scotoma or scotomata may be caused by injury to the nasal fibres of the highly differentiated and easily damaged maculopapillary bundles, which pass through the chiasma. It is doubtful if the direct (temporal) fibres can be much affected by pressure in this region. On the other hand, as already indicated, it is certainly more usual for the optic tracts to be involved by extension backwards and laterally of the pituitary enlargement. Fisher 1 has shown that the field of vision is not only first limited on the temporal side, but also from above downwards ; further, this writer 2 agrees with dishing 3 that the colour-vision 1 Fisher, J. H., Tran*. OpMh. Sue Unit. Kingdom, 1911, xxxi, 51. 2 Fisher, J. H., Proc. Roy. Soc. Med. (Netirol. and Oj)hthalmol. Sects.), 1913, vi,liii. 3 Cushing, H., The Pituitary Body and its Disorders, 1912. 256 R. OPTIC NERVE PITUITARY BOD? R. PEDUNCLE R. OPTIC TRACT SIXTH NERVE INTERNAL GENICULATE BODY SUPERIOR COLLICULUS OPTIC RADIATIONS THIRD NERVE FOURTH NERVE SUDDEN'S COMMISSURE PULVINAR EXTERNAL GENICULATE BODY NUCLEUS OF THIRD NERVE -NUCLEUS OF FOURTH NERVE NUCLEUS OF SIXTH NERVE R. OCCIPITAL AREA X— ,_ Fig 166. Diagram illustrating the optic nerves and tracts and the fields of vision. The possible directions of extension of enlargements of the pituitary are shown by LESIONS OF THE OPTIC TRACT 257 disappears before the form-vision. Fisher 1 states that in his opinion the ocular symptoms can be only explained on the assumption that there is a dragging or stretching of the fibres in the optic tract of the side opposite to that on which direct pressure is being exerted. He says : " My cogitations are leading me to the conclusion that the visual phenomena in many of the cases are explained by traction effects on the visual pathways as the tumour extends upwards behind the chiasma and between the optic tracts in the interpeduncular space. A tumour fairly symmetrical in outline would stretch the decussating fibres in the chiasma, while in no way dragging on the direct fibres, and give us a bitemporal hemianopia ; it is conceivable that the highly specialized function of the macular fibres might be more readily injured than that of the other fibres in the chiasma ; on a traction hypothesis the expanding scotoma cases are to be understood, and hemiachromatopia can be recognized as a symptom which it would be very difficult to accept on a direct pressure hypothesis. If the tumour mass, having already caused a bitemporal hemianopia, increased now more to the right than to the left side, it would probably drag on the left optic nerve as a whole, or accentuate the angle between the left optic nerve and the left optic tract ; in either way the fibres from the temporal half of the left retina would now suffer by dragging, and the eye would be rendered blind ; the tumour expanding to the right would diminish the acuteness of the angle or curve formed by the right optic nerve and the right tract, and the uncrossing fibres from the right retina might long preserve their function. A pituitary tumour growing in the interpeduncular space asymmetrically and from the first lying more to the right than to the left of the median line might, I think, be expected to injure by traction first the decussating fibres from the left optic nerve and then its non-decussating fibres before any fibres of the right optic nerve became unduly stretched ; as the crossing fibres from the right retina became involved, loss of temporal field on this side would be expected to occur, either centrifugally or centripetally. The possibility that a displaced optic nerve may receive injurious pressure from the bony optic foramen on that side towards which it is displaced 1 Fisher, J. H., Proc. Roy. Soc. Med. {Neurol, ami Ophthalmol. Sects.). 1913, vi, liii. 17 258 DISORDERS ASSOCIATED WITH THE PITUITARY can also be conceived. In the rarer cases of homonymous hemianopia direct pressure on the optic tract concerned is, no doubt, the true explanation ; in the tract the uncrossed fibres seem to be afforded the more sheltered situation." Further, I do not think it has been sufficiently emphasized how frequently there is some degree — often very considerable — of oculomotor paresis on one side. The close relationship of the third nerve to the pituitary (fig. 166) accounts for the great frequency with which it is involved in the pressure pro- duced by an enlarging pituitary tumour. I think, too, that in the paresis of this nerve, which produces the symptoms of ex- ternal squint with diplopia and possibly nystagmus, we have the most important evidence as to the direction in which the tumour is extending ; that is to say, the lateral pressure is greatest on the side on which there is evidence of paresis of the third nerve. Sometimes the fourth and sixth nerves are affected. It is necessary, also, to bear in mind the possibility of in- direct pressure from a large tumour, either of the pituitary or in the neighbourhood, on the lower visual centres (fig. 166). Such a phenomenon might lead to very confusing ocular symptoms. § ii. SECONDARY LESIONS OF THE PITUITARY NEIGHBOURING PATHOLOGICAL CONDITIONS Hydrocephalus. — -Although Marienesco and Goldstein 1 in 1909, and later Goldstein 2 described cases of dystrophia adiposo- genitalis associated with hydrocephalus and supposed mening- itis, to Gushing 3 belongs the credit of definitely calling attention to the connexion between hydrocephalus and pituitary lesions. The last-named surgeon quotes several illustrative cases. In one of these there was a cerebellar cyst giving rise to moderate ventricular hydrocephalus, and the symptoms pointed to hyper- hypophysism — that is, acromegaly. In other cases of hydro- cephalus from various causes — congenital and new growths — there was hypopituitarism. We have seen (p. 245) that dishing believes that hydro- cephalus produces pressure on the posterior lobe, particularly through the infundibulum. But, as I have already stated, the infundibulum in man is not hollow ; consequently the pressure should be evenly distributed on the pituitary as a whole, or on the blood-supply ; and this is borne out by Cushing's own cases. In the first (case xxxviii) there was hyperhypophysism, due no doubt to irritation of the anterior lobe, for the ventricular pressure was only moderate. In the other cases the pressure was greater and the anterior lobe — according to the illustrations given — suffered equally with the posterior lobe ; indeed, the whole appearance is that of a pituitary in which there had been interference with the blood-supply. Neurath 4 , also, has reported cases apparently of hyperplasia 1 Marienesco, G., and K. Goldstein, Nouv. Icon, tie la Xalpetritre, 1909, xxii, 628. 2 Goldstein, K., Arch. f. Psychiat., 1910, xlvii, 126. 3 Gushing, H., The Pituitary Body and its disorders, 1912. 4 Neurath, R., Wien. Klin. Woch., 1911, xxiv, 43. 260 DISORDERS ASSOCIATED WITH THE PITUITARY in the anterior lobe with skeletal overgrowth in association with hydrocephalus. Cushing raises another point which is open to criticism. He states that in these circumstances there is stasis in regard to the secretion of infundibulin ; that the intraventricular tension is such that the secretion cannot be poured into the cerebrospinal fluid in normal quantities. As the whole question of the destina- tion and method of conveyance of infundibulin to the body-fluids, and indeed, of the vital importance of this hormone is by no means settled, we are not in a position to discuss this matter further. Attention may be called, however, to what has been said from a physiological point of view on page 102 and following. Fig. 167. A cholesteatoma in the neighbourhood of the pituitary which exerted pressure on that organ and so caused dystrophia adiposogenitalis. (Fro?n a specimen kindly lent by E. E. Glynn.) + h Neighbouring tumours.— A growth such as a glioma or an endothelioma, or possibly a gumma, in the neighbourhood of NEIGHBOURING PATHOLOGICAL CONDITIONS 26J the pituitary may give rise to some of the symptoms of pituitary tumours, especially headaches and ocular disturbances. With these we are not at the moment concerned. But neighbouring tumours may produce pressure on the pituitary and lesions therein. If the pressure be moderate there may be glycosuria and other symptoms of hyperpituitarism ; when the pressure is Fig. 168. Erosion of the right posterior clinoid process caused by the tumour shown in figure 167. {From a specimen kindly lent by E. E. Glynn.) XI. considerable hypopituitarism will be caused. If the growth be more or less centrally placed (fig. 167) diagnosis may be somewhat difficult, although a radiograph should show little or no enlarge- ment of the sella turcica, and this would help us to exclude a primary pituitary lesion. Nevertheless, even in these circum- stances the posterior clinoid processes may be eroded (fig. 168) — a lesion which may lead to the supposition that the pituitary fossa is enlarged in a backward direction, as is usually the case with a primary pituitary tumour. DISEASES OF THE OTHER HORMONOPOIETIC ORGANS Lesions of the thyroid. — From the close relationship between the pituitary and thyroid, to which attention has been directed, we would expect to find that the pituitary is affected in diseases of the thyroid, which arc very common in women ; and such is the case. I have had the opportunity of examining the organs from a case of a cretinism, and as the appearances of the pituitary are somewhat remarkable it may be worth while to describe them in some detail. In this case — a female subject, 33 years of age — the pituitary was found on macroscopical examination to be about the maximum average size in an adult, measuring 1*5 cm. in the antero -posterior diameter and 0-7 cm. in the superior-inferior diameter. Unfortunately the transverse diameter was not recorded, but it appeared to correspond with the other measurements. On histological examination the first point noted was that the organ is enclosed in a dense fibrous tissue capsule, from which it cannot readily be separated. The pars anterior is for the most part composed of chromophobe cells ; there are extremely few eosinophil cells, and only occasional collections of lightly staining basophil cells around the periphery. Large masses of secretion, which appear to be formed by a syncytial confluence of chromophobe cells, are scattered throughout the pars anterior (fig. 169). A considerable number of colloid-acini are to be seen in the pars intermedia, and there is much neutrophil granular secretion underlying the pars intermedia and extend- ing in a branching fashion into the pars nervosa (fig. 170), the neuroglia-fibres of which have a ' teased-out ' appearance. These characteristics of the intrinsic structure of the pituitary indicate considerable activity, which is probably compensatory in character. DISEASES OF OTHER HORMONOPOIETIC ORGANS 263 * «•• e <» • •» *v » e • ' .<•>; '*•"•**•*» * o I „° ' -. • ft * .'(.»'«» 4 • I I • •/ ' » . j ' *?&^ Fig. 175. Section of the pituitary in a case of eclampsia, showing colloid in the pars intermedia and cleft, and invasion of the pars nervosa by the cells of the pars intermedia. (Photomicrograph.) X30. 18 274 DISORDERS ASSOCIATED WITH THE PITUITARY Fig. 176. Section of the pars posterior in a case of eclampsia, showing masses of pars intermedia cells invading the pars nervosa. (Photomicrograph.) X60. £ 6 • GO I ■ *N» ' c B / tf &** c 9 oo^ V-., jt'.-.- SJ<2fcS <« Fig. 177. Section of the pars anterior in a case of cortical necrosis of the kidneys, showing vacuolation of the basophils. X 200. TOXEMIAS OF PREGNANCY 275 of vacuolation of the cells, which was most obvious in the baso- phils, owing to the colour-contrast (fig. 177). 5&I2 A *w** . ri-: ■ i ' W-JL Fig. 178. Section of the pars intermedia in a case of cortical necrosis of the kidneys, showing a large amount of colloid. X 40. There seemed to be a rather excessive quantity of colloid in the pars intermedia (fig. 178), although this substance is generally plentiful in this situation during pregnancy. § iii. GENERAL CONSIDERATION OF THE PATHOLOGY OF THE PITUITARY In all that has gone before it has been very evident that our knowledge of pathological lesions of the pituitary is still imperfect and uncertain. And it is unlikely that we shall reach a more scientific standpoint until pathologists realize that no post-mortem examination is complete until all the hormono- poietic organs have been exhaustively examined. We know, also, still too little of the age-changes and sex-differences in the normal pituitary. Further, we have not yet conclusively and unanim- ously decided exactly what the situation and nature of the lesion is in many cases which we associate with hyperpituitarism and hypopituitarism ; and we are still confused by the supposed morphological and physiological separation of the different parts of the pituitary. Personally, I believe it to be one organ, and that it has many functions, just as all the other hormonopoietic organs have ; indeed, I believe that until we recognize the physio- logical unity of the pituitary body, we cannot reconcile w r hat we now look upon as the conflicting facts of morphology, physiology and pathology in regard to this structure. If the anterior and posterior lobes were separate and distinct organs, we would expect to find more evidence of their independent importance in comparative anatomy. We some- times find, however, the reverse state of affairs — striking examples being, from one point of view, the absence of a pars nervosa in some elasmobranchs, and, from the other, the channelling of the pars nervosa by the cells of the pars intermedia in the mono- treme (ornithorhynchus) (figs. 35 and 36, p. 57). So, too, with respect to the physiology of the pituitary, the whole sum of the evidence obtainable — which I need not reiterate — points in the same direction. Then, when we come to difficult pathological questions we find GENERAL PATHOLOGY OF THE PITUITARY 277 the obsession concerning the duality of the different lobes of the pituitary still overshadowing us. Thus Cushing states that hydrocephalus may produce hypo- pituitarism from secretory stasis in the pars nervosa. But before this explanation can be accepted we must understand how it is that other tumours in the neighbourhood of the base of the brain not acting in the same way may produce a similar train of symptoms. Further, we have seen that neither removal of the anterior lobe nor of the posterior can produce this state : inter- ference with the whole blood-supply in the stalk is necessary. Again, it has been pointed out — for the most part by Cushing 1 himself — that the lowered body-temperature in dystrophia adiposo- genital! s can only be raised by an extract of the anterior lobe ; while the low blood-pressure can only be raised, and the carbo- hydrate-tolerance reduced, by an extract of the posterior lobe. This observer, therefore, in one sentence sweeps aside his own conclusions and the conclusions of others based on the assignment of syndromes to one or other part of the pituitary, instead of to the whole organ. To press the point a little further : It is common knowledge that in the development of the pituitary body the epithelial structures are all derived from the ectoderm ; consequently the anterior lobe and the pars intermedia have the same origin. From our histological observations we know that the pars inter- media is closely related physiologically to the pars anterior — so much so that the cells of both secrete a similar substance. Further, it is often difficult to say where the pars intermedia begins and the pars anterior ends, for at the point of junction the cells appear to change almost imperceptibly from one type to the other. It has always been my opinion that the active principle of the posterior lobe is secreted by the cells of the pars intermedia. We have evidence, too, in an experiment of Vincent 2 , that an extract of the central portion of the pars nervosa is much more active in its pressor effects than is the extract made from the periphery and the cells of the pars intermedia, which is com- paratively inert. We have had evidence, also, that the secretion of the pars intermedia passes into the pars nervosa. Whether the secretion passes on entirely into the third ventricle, as 1 Cushing, H., The Pituitary Body and its Disorders, 1012. 2 Vincent, Swale, The Internal Secretions, 1!»12. 278 DISORDERS ASSOCIATED WITH THE PITUITARY described by Herring 1 and Cushing 2 , which, however, I regard as doubtful, or whether the larger portion passes into the blood- vessels of the pars nervosa which are seen in such profusion in the ox (fig. 40, p. 62), as seems most likely, is of little import- ance in regard to the question we have in hand. But it is of considerable importance that the secretion of the pars intermedia does pass into the posterior lobe ; and that the pars intermedia does secrete a substance similar to that secreted by the anterior lobe. It seems highly probable, therefore, from the evidence at our disposal, that the secretion of the pars intermedia is changed into a pressor substance as it passes through the posterior lobe ; and that the colloidal substance found among the cells of the pars intermedia and the secretion found in the cleft is ot the same character as that secreted by the anterior lobe. If this be so, we arrive at the principle I have so often enunciated- — a principle which is of the greatest importance in the interpreta- tion of diseases of the pituitary body — I mean that the pituitary body is one organ. Much that is supposed to be obscure becomes clear : for instance, insufficiency of the hormone from the pars nervosa can in many cases be accounted for by insufficiency of the cells of the pars anterior and the pars intermedia, which I believe to be fundamentally the same physiologically as they are anatomically. In these circumstances there would be an in- sufficient supply of secretion to the pars nervosa, in the substance of which the secretion of the pars intermedia undergoes altera- tion and acquires pressor qualities. No pressure, therefore, on the pars nervosa need be presumed to account for posterior lobe insufficiency — a state of affairs which can be relieved by the injection of infundibulin. So, too, from the other point of view, it is easy to understand the reason why in acromegaly, in which disease there is admittedly hyperplasia in the anterior lobe, we so frequently see polyuria and glycosuria. In accordance with the view just expressed an excess of secretion may pass into the pars nervosa and thence, after being converted into infundibulin, into the blood. The acromegaly-syndrome may be summarized from this point of view. Some of the symptoms — the gigantism and bony 1 Herring, P. T., Quart. Journ. Exper. Physiol, 1908, i, 121. 2 Cushing, H., The Pituitary Body and its Disorders, 1912. GENERAL PATHOLOGY OF THE PITUITARY 279 changes with the acral enlargements, the coarse skin, the genital stimulation are all due to the direct influence of the hyperplasia in the partes anterior and intermedia. The polyuria and the glycosuria are caused by the increase in the amount of secretion of the pars intermedia, which is passed into the pars nervosa and subsequently absorbed. With regard to the other condition — dystrophia adiposo- genitalis — which is seen with destructive lesions that impair the blood-supply and produce hypopituitarism, the entire secretion is greatly reduced. The failure of secretion refers not only to that which is passed directly into the blood, but also that which is passed into the pars nervosa. We have seen, indeed, that at least one of the symptoms — the subnormal temperature — is relieved by the extract of the anterior lobe, and others — namely, the excessive carbohydrate-tolerance, and the low blood-pressure — by infundibulin. This explanation of the interrelationships between the various portions of the pituitary body is, therefore, no idle hypothesis. It is based on morphological grounds, on all the best of the histological work that has been done, and on all the clinical data that are at our disposal. Practically, it makes clear many of the apparently contradictory features of hyperpituitarism and hypopituitarism. It explains, too, why with cystic changes in the anterior lobe, even with great enlargement and sella deforma- tion, the pressure symptoms may only be those of any tumour in the interpeduncular space- — so long as normal cells exist in sufficient quantity to produce the necessary secretion. In these cases, too, the pars nervosa is usually crushed, yet — provided there are normal cells of the pars anterior, as I have just said — no intrinsic symptoms of pituitary origin arc evident. This point of view — founded on, and compatible with, all the evidence at our disposal — should, if correct, in the future do much to render intelligible the pathology of the pituitary body. § iv. TREATMENT OF PITUITARY LESIONS The treatment of pituitary disease is partly medical and partly surgical. It may be stated that medicinal methods are only indicated to relieve certain metabolic and distant phenomena, and that they are of little value when there are local symptoms, such as headache and visual disturbances — these require relief by surgical procedures. MEDICAL TREATMENT OF PHENOMENA DUE TO PITUITARY LESIONS Hypopituitarism. — Medicinal treatment at the present time largely resolves itself into the supplementation of the deficient secretion. No doubt in a majority of cases the best results are obtained with whole-gland extracts. Supplementary medica- tion will be discussed more fully in connexion with the thera- peutical uses of pituitary extracts. It is extremely difficult permanently to reduce the sugar- tolerance by medicinal means, but the psychical and sexual disabilities are often removed : mental torpor disappears ; men- struation and potency return. As the preparation must be administered over a consider- able length of time oral administration is generally practised. Very large doses may be necessary : dishing 1 states that he has administered 100 grains of whole-gland extract three times a day. Glandular administrations are frequently of value after operations for the relief of local pressure-symptoms in lesions producing hypopituitarism. I have observed an objectionable effect that is often produced 1 Cushing, H., The Pituitary Body and its Disorders, 1912. MEDICAL TREATMENT OF PITUITARY LESIONS 281 by glandular extracts — especially extracts of the pars anterior — namely, intense headache. This, however, has been most noticeable in those minor cases of hypopituitarism, in which amenorrhcea was the only obvious symptom. Cushing found in one case after the failure of oral adminis- trations that daily hypodermic injections of whole-gland extract, in a dose representing 2 grains of the dried extract, produced an amazing effect in regard to the mental and physical vigour of the patient. In the same patient a graft from the pituitary of a child dying in child-birth was subsequently implanted in the subcortical tissues of the temporal lobe with permanent benefit, in spite of the discontinuance of hypodermic medication. Hyperpituitarism. -The medicinal treatment of this con- dition is not satisfactory, except in the presence of a plurigland- ular syndrome which beckons unmistakably to the extracts of the organs whose secretion is diminished. Thyroid extract has, however, often been given with advantage, especially in cases of arrested acromegaly. Kelladey 1 records a case of acromegaly in a woman, in whom intravenous injections of ovarian extract induced the return of menstruation with subsequent conception. 1 Kelladey, L., Zentralbl. /. Gynak., 1913, xxxvii, 1030. SURGICAL TREATMENT OF PITUITARY LESIONS SURGICAL ANATOMY We have seen that the modern experimental procedures designed for the removal of the whole or of part of the pituitary are not difficult to carry out by the intracranial (bitemporal) route in the case of dogs owing to the fact that in this animal, which is also of a fair size, the organ rests in a very shallow fossa ; but that in an animal, such as the cat, in which the pituitary fossa is deep, the intracranial method is impracticable. Further, we have seen that the buccal route is invariably unsatisfactory because the operator cannot control by sight his manipulations in regard to the pituitary, and in any case he cannot do more than blindly destroy the whole structure or remove a portion of the pars anterior, and because there is, also, an almost inevitable risk of sepsis from the buccal cavity, with fatal mening- itis. Thus it has come about that no experimental results obtained by operative procedures have been found worthy of acceptance, except when they have been practised on one species of animal (dog), and by the route of election (bitemporal) in that animal. It will readily be realized, then, that in man, in whom the pituitary is situated in a deep fossa, which is closely guarded on every side by nerves, arteries and large venous channels, suitable access has been found difficult to obtain. As a result, many different directions have been chosen by surgeons for attacking pituitary lesions in the human subject (fig. 179). These various routes will be discussed presently, but before we consider them in detail it will be worth while to study a few details of the surgical anatomy of the parts. First, when the temporal route is chosen it should be re- membered that the temporal lobe is situated in a deep concave SURGICAL ANATOMY 283 fossa, and that the brain must be raised before the edge of the sella turcica can be reached ; and further, that when the sella is reached the pituitary disease cannot be attacked owing to the depth of the fossa unless the lesion extend upwards. Second, with regard to the frontal intracranial route, it will be evident that when the frontal lobes are to be raised the success of the operation will depend greatly on the production of a low intracranial pressure, and that by this route it is Fig. 179. Incisions (shown by dotted lines) for the various procedures that have been adopted, a, Horsley-Paul temporal method ; b, Frazier orbitofrontal method ; c, Eiselsberg first superior nasal method ; d, Eiselsberg second superior nasal method ; e, Schloffer-Eiselsberg superior nasal method ; /, Kanavel inferior nasal method ; g, Halstead-Cushing sublabial method ; h, Chiari-Kahler orbitonasal method. impossible satisfactorily to deal with a pituitary lesion that does not extend upwards. Third, with respect to the nasal routes, we shall see that some are much better than others owing to the differences in regard to the possibility of minimizing the risk of sepsis and the degree of mutilation inflicted. But the operative procedures by this route are not always easy because of the variations that may occur in the anatomy of the parts. 284 DISORDERS ASSOCIATED WITH THE PITUITARY With this difficulty in mind, Gibson 1 has made a careful investigation of the principal measurements in relation to the pituitary fossa in 107 skulls, apparently without distinction as to sex. He also paid particular attention to the character of the sphenoidal sinuses and to the floor of the sella turcica. Cope 2 , too, has recently studied these questions, also without regard to sex. Although no doubt surgeons with large experience in operations on the pituitary by the nasal route— of whom there are at present only a few- — are able to accommodate themselves to the varying circumstances, Gibson's and Cope's figures and observations are of considerable value to the less experienced operator. At the same time, the fact has not been adequately emphasized by these writers that pituitary lesions by pressure and extension downwards may alter considerably the character of the floor of the sella turcica, and the relation of it to the sphenoidal cells. Gibson gives the following average measurements (fractions omitted), which, with very few exceptions in regard to the larger measurements, were found not to vary to the extent of one centimetre : — Nasion to sella turcica 3 62 mm. Nasion to posterior surface of sella turcica . . . 75 mm. Anterior nasal spine to sella turcica 4 78 mm. Anterior nasal spine to clivus 88 mm. Length of the pituitary fossa ...... 12 mm. Depth of the pituitary fossa 6 mm. Depth of the sphenoidal sinus on the line from the anterior nasal spine to the sella turcica . . .18 mm. These and other measurements are shown in figure 180; but fractions have been omitted. With regard to the variations in the sphenoidal sinuses, which are illustrated in figure 14 (p. 23), Gibson gives the following particulars. Complete or practical absence of sinuses (fig. 14, b) occurs in 1 Gibson, W. S., Surg. Gynecol. Obstet., 1912, xv, 199. 2 Cope, V. Z., Brit Journ. Surg., 1916, iv, 107. 3 Cope (he. cit.) found the average of this measurement to be 604 mm. 4 Cope (loc. cit.) found the average of this measurement to be 76-19 mm. SURGICAL ANATOMY 285 3 per cent. ; small sphenoidal sinuses in 9 per cent. ; no projection of sinuses beneath the sella turcica (fig. 14, d) in 22 per cent, of all cases examined. The fact that in these variations the floor of the sella does not bulge into the sphenoidal sinuses might cause difficulty in the determination of its position. He also found that in 2 per cent, of the cases there was a transverse sphenoidal septum (fig. 14, e), which might be mistaken for the roof of the sinuses. When the sphenoidal sinuses project beneath the sella tur- cica, and have thin posterior walls (fig. 14, c), these may be pierced by the operator, and the pons injured. Fig 180. Sectional measurements of the skull in relation to the sella turcica and sphenoidal sinuses. The figures are accurate, but the skull is reduced approxim- ately by one-half. Besides these vagaries the cribriform plate may dip down unduly, and, by obscuring the direct line of attack, cause the operator to divert his course below the sella turcica ; or a deflected septum may cause him to miss the correct median approach. 286 DISORDERS ASSOCIATED WITH THE PITUITARY INDICATIONS FOR OPERATION The following symptoms demanding interference must be shown to he dependent on enlargement of the pituitary, or on lesions situ- ated in the neighbourhood of, and affecting, the pituitary. (a) Symptoms due to increased general intracranial pressure, such as headache. (b) Symptoms due to local pressure, such as blindness, oculo- motor palsy and ' pituitary headache '. (c) Symptoms due to disturbances of the pituitary secretion producing acromegaly or dystrophia adiposogenital . SELECTION OF THE ROUTE OF APPROACH The method adopted for approaching the pituitary should depend, to a great extent, on the special reason for operation. Thus, general intracranial pressure must be relieved by an intra- cranial method, whereas the relief of ' pituitary headache ' and the evacuation of pituitary cysts are better effected by the nasal route ; consequently an accurate diagnosis of the condition present is the first step in the selection of a route by which the lesion may be reached and the symptoms relieved. The direction of extension of the lesion may, too, be a matter of importance. To a certain extent, also, the surgeon should be influenced in his choice of direction by the anatomical conformation of the sphenoid and sphenoidal sinuses. A good radiograph conveys the necessary information in regard to this matter. In spite of these associations which should guide the surgeon in the selection of a method of approach, it appears that most operators have a route of election for every case. Schloffer 1 , Proust 2 , Cushing 3 , and more recently Cope 4 , have discussed the subject, but it is evident that no final decision has yet been reached as to the indications for the different routes. 1 Schloffer, H., Beitr. z. Klin. Chir., 1906, 1, 767. 2 Proust, R., Journ. de Chir., 1908, i, 665. 3 Cushing, PL, The Pituitary Body and its Disorders, 1912 ; Weir Mitchell Lecture : Journ. Amer. Med. Assoc, 1914, lxiii, 1515. 4 Cope, V. Z., Brit. Journ. Surg., 1916, iv, 107. SURGICAL TREATMENT 287 PREPARATION OF THE PATIENT In all operations on the pituitary hexamethylenamine (fora- mine) should be administered for some days before and after operation to render the cerebrospinal fluid antiseptic (see p. 129). Lumbar puncture as a preliminary operative procedure is extremely useful for reducing the intracranial pressure if more than decompression is to be attempted. Moreover, the over- Fig. 181. Base of the skull, showing the directions followed in the intracranial methods of approach to the sella turcica. (Photograph.) hanging-brain position (fig. 184, p. 295) suggested by Karplus and Kreidl 1 , may be used to facilitate the surgical manipulations. The other general preparations need no special description. INTRACRANIAL METHODS Two directions have been chosen for reaching the pituitary intracranially in the human subject — the temporal and the fronto- orbital (fig. 181). 1 Karplus, J. P., and A. Kreidl, Wien. Klin. Woch., 1910, xxiii, 309. 288 DISORDERS ASSOCIATED WITH THE PITUITARY Temporal and bitemporal routes The actual procedures in regard to this operation on the human subject need not be recapitulated, for they correspond almost exactly with those which have been adopted in experi- mental operations on animals, and have already been fully described and illustrated (p. 129 and following). This method of approach, as emphasized by Gushing 1 , is unquestionably the best for the relief of general intracranial pressure ; indeed, this surgeon advises that a temporal decom- pression operation should always be performed when the intra- cranial pressure is great, even though it be thought advisable subsequently to attack the actual lesion by another route, for in those cases in which headache is very severe, and is associated with a choked optic disc, superimposed on optic atrophy, a pituitary tumour is generally present and is extending upwards. It must be remembered that the so-called ' pituitary headache ' differs from the headache associated with general intracranial pressure in that it is caused by local pressure in the pituitary fossa. As a method of approach for operations on the pituitary in the human subject the temporal (fig. 179, a) has not secured much favour. It was originally suggested by Horsley 2 as the result of his experimental experiences, and Paul 3 was the first to employ the procedure in the human subject. Paul's operation — the first undertaken for pituitary disease — was attempted for the relief of severe headache in a case of acromegaly under the care of Caton in the Liverpool Royal Infirmary on February 2nd, 1893. The operation was not carried further than simple decom- pression, by the removal of a portion of the temporal bone. The headaches were relieved, and the patient lived for three months subsequently. Henceforth, the possibilities of surgical pro- cedures came to be fully recognized, and Horsley himself per- formed operations on the human subject by the same route. The details of his results were never published, but so far as is known they were not satisfactory. Cushing 1 , too, has performed a few operations on the 1 Cushing, H., The Pituitary Body and its Disorders, 1912. 2 Horsley, V., Lancet, 1886, i, 5. 3 Paul, F. T., and R. Caton, Brit. Med. Journ., 1893, ii, 1421. SURGICAL TREATMENT 289 pituitary by the temporal route — apart from simple decom- pression measures — and he has come to the conclusion that this method should not be the one of election for dealing with pituitary growths in general. He states that in the entire series of his cases, as published in his book, " in only one patient . . . did" post-mortem study indicate that a lateral subtemporal operation would have offered the only chance of surgical relief " 1 . This case was one in which there was an infundibular cyst situated above an otherwise normal pituitary. The only symptom was bitemporal hemianopia. The patient died from meningitis on the thirteenth day after an attempted transphenoidal operation. Orbitofrontal route This method of approach, originally put forward by Krause 2 and McArthur 3 , and perfected by Frazier 4 , has lately received considerable support, and was utilized by Cope 5 in the three operations performed by him. Erdmann 6 and Elsberg 7 , also, have employed this method with slight modifications. The technique of Frazier's operation is as follows. The patient is anaesthetized with ether — first by the open, and afterwards, when anaesthesia is complete, by the intratracheal method. He is then placed with the shoulders on a pillow over the top of which the head is allowed to fall back (over- hanging-brain position), and the frontal sinuses are transillumin- ated to show their size. Next, an incision is made extending along the supraorbital ridge from the external angular process to the nasion ; from this point the incision is carried vertically up wards beyond the hair-line almost to the summit of the fronto- parietal suture, and then outwards at right angles over the frontal bone till a point is reached vertically above the external angular process where the skin-incision was commenced (figs. 179, b and 182). The skin, subcutaneous and pericranial tissues are now 1 Gushing, H., The Pituitary Body and its Disorders, 1912. 2 Krause, F., Deutsch. Klin., 1905, viii, 1004. 3 McArthur, L. L., Journ. Amer. Med. Assoc, 1912, lviii, 2009. 4 Frazier, C. H., Ann. Surg., 1913, lvii, 145 ; Surg. Gynaecol, and Obstet., 1913, xvii, 724. 5 Cope, V. Z., Brit. Journ. Surg., 1916, iv, 107. 6 Erdmann, J. F., Ann. Surg., 1914, hx, 452. 7 Elsberg, C. A., Ann. Surg., 1914, lix, 454. 19 290 DISORDERS ASSOCIATED WITH THE PITUITARY retracted far enough to permit the formation of an osteoplastic flap which is turned outwards after the bone has been cut through by means of a trephine and wire-saw. The periosteum of the roof of the orbit is separated, and the supraorbital ridge is divided by means of converging incisions, in order that a wedge-shaped piece of bone may be removed (fig. 182), which will fall into position on replacement without the need of fixation. With Fig. 182. Fraziers orbitofrontal method of approach to the pituitary. (After Frazier.) this piece of the ridge the anterior portion of the roof of the orbit is resected. The posterior part of the orbital roof as far back as the optic foramen is now removed with a rongeur. This exposure permits the operator to displace the orbital contents downwards and outwards, and to raise the frontal lobe without opening the dura mater. If, however, the intracranial tension be great and a preliminary lumbar puncture have not been performed, a small opening may be made in the dura to SURGICAL TREATMENT 291 allow the cerebrospinal fluid to escape. The frontal lobe is then raised with a retractor — preferably spoon-shaped (fig. 87, p. 135) — until the optic nerve is seen leaving the cranial cavity ; at this point the dura is incised and the retractor slipped through the opening thus made in order that the pituitary region may be fully exposed. At the conclusion of the operation the supraorbital fragment is replaced and the osteoplastic flap sutured in position. It is claimed that by this route suprasellar lesions can easily be attacked, and the general intracranial pressure relieved. The orbitofrontal competes, therefore, with the temporal method. EXTRACRANIAL METHODS Nasal (transphenoidal) routes Schloffer 1 first suggested reaching the pituitary by way of a nasal route. The interest aroused by this method of procedure is shown by the enthusiasm with which it has been adopted and modified (fig. 183). The technique of these operations may be described under two headings. Superior nasal methods. -This route, which was origin- ally advocated by Schloffer 1 , if we except the experimental nasofrontal operation of Giordano 2 , has been employed chiefly by von Eiselsberg 3 . The operation was at first performed by this operator in the following manner. The posterior nares were packed to prevent the inhalation of blood. One incision through the skin was made across the brows bilaterally, and another, which joined the first incision at the root of the nose on the left side, was carried down the side of the nose and along the nasolabial furrow beneath the left nostril to the mid-line (fig. 179, c). The nasal bones were cut through with a chisel. The septum -- cartilaginous and bony — was then divided in such a way as to leave a large portion of the cartilage, ethmoidal plate and vomer to be turned over with the nose to the right side. This 1 Schloffer, H., Beitr. z. Klin. Chir., 1906, 1, 767. 2 Giordano, D., Comp. di Chir. Operat. Hal, 1897, ii, 100. 3 Eiselsberg, F. von, Trans. Amer. Svrg. Assoc, 1910, xxviii, 55 ; Ann. Surg., 1910, lii, 1 ; Arch.f. Klin. Chir., 1912, c. 8. 292 DISORDERS ASSOCIATED WITH THE PITUITARY precaution retained subsequently a good ' bridge ' for the nose. Next, the anterior wall of the frontal sinuses was raised through the transverse incision. The turbinate bones and ethmoidal cells were excised, and the operator then came down upon the anterior wall of the sphenoidal sinus. This and the anterior wall of the floor of the sella turcica were removed and the pituitary exposed. Later, Eiselsberg 1 performed much the same operation after making a slightly different incision (fig. 179, d) and, later still, by turning back the nose alone without interfering with Fig. 183. Vertical section through the skull, showing the direction of the chief routes by which the pituitary has been attacked from the front. A, Orbitofrontal route ; B and C, superior nasal routes ; D, inferior nasal route ; E, buccal route. the frontal sinuses. This last procedure has, however, been attributed to Schloffer (fig. 179, e). These methods are unnecessarily mutilating and have been discarded in favour of the submucous inferior nasal procedures. Inferior nasal methods. — Kanavel 2 was the first to show that it is possible to reach the pituitary fossa through the inferior nasal route. By this method the nose was turned upwards by means of a U-shaped incision which divided the nasolabial 1 Eiselsberg. F. von, Arch. /. Klin. Chir., 1912, c, 8. 2 Kanavel, A. B., Journ. Amer. Med. Assoc, 1909, liii, 1704. SURGICAL TREATMENT 293 junction (fig. 179, /). The cartilaginous septum was divided along the inferior border, and was partly raised and partly cut away from its attachment to the ethmoidal plate. Next, the middle turbinates were removed and the septum was deflected to one side. The anterior walls of the sphenoidal sinuses were then excised and the floor of the sella turcica was cut through. Mixter and Quackenboss 1 , who employed this route subseq- uently in the case of a pituitary tumour in a child, made the important modification of submucous resection of the septum — a procedure that lessened considerably the risk of sepsis. Hirsch 2 , basing his procedures on Hajek's 3 radical operation on the sphenoidal sinuses, modified the method by performing the operation through one nostril. The procedures were com- pleted in several sittings. In the earlier steps the nasal septum, the middle turbinates and the ethmoidal cells, were excised, and the sphenoidal sinuses laid open ; subsequently, the anterior wall of the floor of the sella turcica was removed, and the pituitary attacked. These procedures were all carried out under local anaesthesia. Later Hirsch 4 recommended the same operation with submucous resection of the septum. Halstead 5 , also, modified the original method of Kanavel by gaining access to the nasal cavity by means of a sublabial incision (fig. 179, g). The upper lip and nose were raised and the operation was performed through the aperture into the nares so created. These modifications led to the perfected technique — now practised by Gushing 6 and others — which appears to be the best of all the nasal methods, combining as it does the principal ad- vantages of several of the intranasal route procedures. Since this method is likely to be used extensively, the following par- ticulars of the technique are worth recording. After undergoing preliminary treatment for a few days with f ormamine the patient is anaesthetized with ether by the * open ' 1 Mixter, S. J., and A. Quackenboss, Ann. Surg., 1910, Hi, 15 ; Trans. Amer. Surg. Soc, 1910, xxviii, 94. 2 Hirsch, O., Wien. Med. Woch., 1909, lix, G3G. 3 Hajek, M., Arch. f. Laryngol. und Rhinol, 1904, xvi, 105. 4 Hirsch O., Journ. Amer. Med, Assoc, 1910, lv, 772. 5 Halstead, A. E., Trans. Amer. Surg. Assoc, 1910, xxviii, 73. 6 Cushing, H., Weir Mitchell Lecture: Journ. Amer. Med, Assoc, 1914, lxiii, 1515. 294 DISORDERS ASSOCIATED WITH THE PITUITARY method. As soon as anaesthesia is complete this mode of administration is changed for the intratracheal method. The patient is placed in the overhanging-brain position. The operator stands leaning over the top of the head. First, the upper lip is pulled towards the surgeon and an incision an inch in length is made through the frsenum, as suggested by Halstead. The lip and nose are retracted as the incision is carried down to the anterior nasal spine of the superior maxilla (fig. 184). Blunt dissection is employed to raise the soft tissues from the bony floors of the nasal cavities, and from the lower lateral aspects of the septum, great care being taken lest the mucosa be button-holed. Retractors with blades 6 cm. in length and 1*8 cm. in width are now inserted on either side to keep back the mucous membrane set free from the septum and inner aspects of the floors of the nasal cavities (fig. 185). Next, a strip of cartilage, the lower edge of the plate of the eth- moid, and a large portion of the vomer are cut away. A special dilator is then pushed into the cavity thus made while the lateral retractors are still maintained in position. By this means the turbinates are temporarily flattened and room is obtained for the subsequent steps of the operation. The lateral retractors are now removed and a suitable bivalve nasal speculum is inserted (fig. 186). With this in place, and by the use of a head-lamp, the sphenoidal attachment of the septum can be identified, and the sphenoidal sinuses opened by means of a nasal ronguer (fig. 186). So far the principal danger has been lest the orientation should not have been properly determined, and the ethmoidal cells have been opened instead of the sphenoidal. This can be avoided by recognition of the posterior margin of the vomer, and by careful examination of the radiograph taken before operation, which should show the size and the relationships of the ethmoidal and sphenoidal sinuses. During the whole course of the opera- tion it is absolutely imperative that the field be kept free of blood. When the anterior and lower walls of the sphenoidal sinuses and their mucous linings have been removed, the roof is easily identified. Usually it is thin, and it may so bulge forwards from the pressure in the sella turcica above as practically to occlude the sphenoidal sinuses. The thin lamina of bone SURGICAL TREATMENT 295 Fig. 184. Partly sectional view of the first stage of the submucous inferior nasal method of approach to the pituitary (P). {After Gushing.) 296 DISORDERS ASSOCIATED WITH THE PITUITARY forming the roof of the sinuses and floor of the sella turcica is cut through, and the dura mater lining the fossa is incised with a hooked knife similar to that employed in experimental operations (fig. 88, p. 130). In this last stage some care is necessary lest a Fig. 185. Second stage of the submucous inferior nasal method of approach to the pituitary. (After Gushing.) transverse sphenoidal septum be mistaken for the floor of the sella turcica. A good radiograph of the region should, however, reveal such an anomaly. The pituitary is now exposed, and the operator can deal with SURGICAL TREATMENT 297 it as may be considered necessary. In some cases, in which relief from ' pituitary headache ' is the object of the operation, nothing further is done — a sella decompression has been accom- plished. In other cases a cyst may be evacuated or a portion of a hyperplastic gland removed for the relief of symptoms occurring in acromegaly. Fig. 186. Third and fourth stages of the submucous inferior nasal method of approach to the pituitary. (After Gushing.) At the conclusion of these procedures, after the operator has ascertained that there is no oozing of blood, the speculum is withdrawn and the parts are allowed to fall together. Two or three stitches are then used to close the initial sublabial incision. It is advisable lightly to pack the nares for a few hours in order to keep the septal mucosa in position and to prevent the accumul- ation of blood in potential spaces. With regard to these operations by the nasal route it may be 298 DISORDERS ASSOCIATED WITH THE PITUITARY said that only those procedures which are performed by the submucous methods can be conducted with any pretence of asepsis. Practically all the cases that are lost die from meningitis. Cushing's latest mortality figures are, however, so excellent that there can be little doubt that in suitable cases this is the safest and most convenient operation. Orbital and orbitonasal routes In 1910 I attempted experimentally to reach the pituitary through the orbit 1 , after excision or displacement of the eye, and removal of the posterosuperior bony wall of the orbit. Owing to the limited space in small animals it was not found to be a suitable experimental procedure. Kahler 2 has employed in the human subject a paranasal operation in which a curvilinear incision is made around the inner aspect of the orbit (fig. 179, h), and the eye retracted out- wards. To some extent there is encroachment upon the nasal cavity, and this renders sepsis likely, although there is less danger than in the operation of a similar nature practised by Chiari 3 who removes the inner wall of the orbit and clears away the neighbouring ethmoidal cells. Buccopharangeal route Early investigators employed the buccal method of approach in their animal experiments ; but, partly owing to the frequent occurrence of sepsis and partly because of the limited view, these investigations have been held to be of little value. It is, therefore, somewhat surprising to find that this method has been advocated for reaching the human pituitary in operative procedures. Konig 4 has described an operation of this nature. The soft palate is split, and a portion of the hard palate removed (fig. 183 e). In this way the base of the sphenoid is reached and the sella turcica opened. The almost inevitable sepsis that must follow such a pro- cedure renders its general adoption extremely unlikely, especially 1 Bell, W. Blair, Hunterian Dissertation, Roy. Coll. Surg., Eng., 1912. 2 Kahler (quoted by von Szily, Klin. Monats. /. Augenheil, 1914, lii, 202). 3 Chiari, O., Wien. Klin. Woch., 1912, xxv, 5. 4 Konig, F., Bed. Klin. Woch., 1900, xxxvii, 1040. SURGICAL TREATMENT 299 in view of the fact that there are much safer and more suitable methods of approach. RESULTS OF OPERATIONS Cope 1 has collected the results of the principal operators with a view to determining which procedure has the least mortality. Naturally, there is an element of uncertainty that obtains in any such series, both in regard to the seriousness of the cases attacked and to the skill and experience of the operator. One fact stands out clearly, however, and that is that up to the present time the benefit derived from operation has rarely been permanent. Nevertheless, there is ample evidence to encourage surgeons to operate more frequently for pituitary disease. From the following table, adapted from Cope's paper, it will be obvious that the palatal operation should never be attempted, while the orbitonasal procedure in a limited number of cases was free from mortality. But, on the other hand, we have in- sufficient information to tell us by which measure the greatest ultimate good can be accomplished so far as relief of symptoms is concerned. Table XII Method. Operators. Number of operations. Deaths. Mortality per cent. Superior nasal von Eiselsberg 10 4 25 Inferior nasal ,, ,, Submucous Hirsch Gushing 10 6 °}' 32 > 9 Temporal .... /Horsley 1 Gushing "»« l)> 11 i Frazier 4 1 °) Orbitofrontal I Gushing j Sargent »\m !« 77 vCope 3 J oJ Orbitonasal .... /Kahler 'Ghiari \\ • U}» Preysing 6 4 66 It is obvious that in the future the benefits that will accrue from surgical interference will be directly proportional to the correct application of the most suitable method to the particular 1 Cope, V Z., Brit. Journ. Surg., 1916, iv, 107. 300 DISORDERS ASSOCIATED WITH THE PITUITARY condition present, as determined by all the scientific methods of investigation at our disposal. At present, sufficient attention does not appear always to be directed to this all-important question of the nature, situation and exact direction and extent of the lesion which gives rise to the symptom or symptoms for which relief is sought. Enough has been said in connexion with the various operations to indicate the type of case for which the better methods arc suitable. PART IV THE THERAPEUTICAL USES OF PITUITARY EXTRACTS PART IV THE THERAPEUTICAL USES OF PITUITARY EXTRACTS § i. GENERAL CONSIDERATIONS The extracts made from the pituitary have as many names as there are trade-firms manufacturing these products. I shall endeavour as far as possible to avoid the use of such terms for obvious reasons. These extracts have been prepared from the whole gland, from the pars anterior alone, and from the pars posterior ; con- sequently they may be described as extract of the whole gland, of the pars anterior, and of the pars posterior. If the most suitable and convenient nomenclature for these extracts could be generally adopted they would probably be described as pitui- tarin, hypophysin, and infundibulin respectively ; but as already stated these and other terms have been so incorrectly and indiscriminately used by competing firms as to make this impossible 1 . The term ' infundibulin ', however, which was 1 In their propaganda for placing these products before the medical profession some firms have issued pamphlets which purport to give a resume of the original work on which the various claims put forward in respect of the extracts are based. These accounts are often intentionally inaccurate, in that the literature quoted refers only to work done itnth the preparations made by the firms concerned. In this way credit has been wrongly given to, and assumed by, continental clinicians for what was discovered and described in this country at least a year before the first continental paper appeared ; and, unfortunately, some medical writers appear to obtain their historical information from these pamphlets, rather than from the scientific literature on the subject. That section of the medical profession, too, which relies on trade-announcements for guidance in therapeutical matters should be warned against accepting the extravagant and often dangerous claims that have been made. It is only fair to add that there are, on the other hand, firms that publish accurate and reliable information. 302 THERAPEUTICAL USES OF PITUITARY EXTRACTS originally introduced 1 for the extract of the pars posterior, will be used here. METHODS OF MANUFACTURE I am indebted for the following particulars concerning the preparation of pituitary extracts for the market to Dr. H. E. Annett of the Runcorn Research Laboratories. Carefully selected, healthy glands are taken, and, after all the extraneous tissues have been removed, they are treated for the preparation of liquid extracts or of dried, powdered products. Dried-gland preparations are obtained in the following way, according to the product required. The pars anterior or the pars posterior — which are easily separated — or the whole pituitary gland is finely minced in a sterilized mincing apparatus, and, after the ' wet weight ' has been noted, is dried in vacuo at a low temperature, and afterwards ground to a fine powder. The ' dry weight ' is then obtained, and the relation of this to the ' wet weight ' is recorded. Liquid extracts. — The whole gland, or a portion of the gland, such as the pars posterior from which infundibulin is prepared, is extracted with saline solution. The albuminous matter is removed ; the liquid is sterilized by filtration through unglazed porcelain, and then is distributed by bacteriological methods. The final preparation is again tested in regard to its absolute freedom from microorganisms. The usual strength of the liquid extract in the case of infundibulin is 0-2 gramme in 1 c.c. of solution. In the case of liquid extracts of the pars anterior the strength is generally 0-5 gramme in 1 c.c. of solution. Infundibulin and the extract of the pars anterior are not destroyed by boiling ; consequently absolute sterility can always be ensured. In the case of infundibulin physiological tests are invariably carried out in regard to the effect on the blood- pressure and uterine muscle of each batch that is prepared. Should these tests be satisfactory the preparation is ready to be placed on the market. 1 Bell, W. Blair, Brit. Med. Journ., 1909, ii, 1609. METHODS OF ADMINISTRATION 303 METHODS OF ADMINISTRATION However valuable a drug may be when administered by the method of election, it may be comparatively, or completely, inert when introduced into the body in another way ; con- sequently it is always of importance to know the method of administration that will give the maximum effect for the purpose required. These differences are dependent to some extent on the chemical composition — often unknown — of the substance em- ployed. Thus, suprarenal medullary extract is destroyed by the gastric juices, but the active principle of the thyroid gland is absorbed — so far as we know, unaltered — from the alimentary tract. On the other hand, both these extracts can be success- fully injected into the subcutaneous tissues. The method of administration, however, will depend — other conditions being equal — on the result required ; if an immediate and maximum effect be desired the substance must be introduced directly into the blood-stream, or other tissues of the body, that it may be rapidly absorbed. Heaney 1 states that in his observa- tions on the normal human subject, subcutaneous injections of infundibulm produced only a very slight rise in the blood-pressure and very little slowing of the pulse-rate. With intramuscular injections a definite rise in blood-pressure and some slowing of the pulse was observed. With intravenous injections great alterations were observed : in one case the blood-pressure rose within one and one-half minutes from 142 mm. to 200 mm. Hg, and the pulse-rate fell from 76 beats in a minute to 54. I have observed 2 that relatively greater effects follow intra- muscular injections in atonic conditions of the unstriped muscle- fibres than in normal circumstances. If the substance be not destroyed by the digestive juices and a slow metabolic result be required, then oral administra- tion is indicated. In the case of the pituitary extracts administration is effected intravenously or intramuscularly 3 when a rapidresult is necessary. 1 Heaney, N. S., Surg. Gyncecol. and Obstet., 11113. xvii. 103. 2 Bell, W. Blair, Brit. Med. Journ., 1909, ii, 1609. 3 If injected hypodermic-ally superficial sloughs may result from the intense local vasoconstriction ; consequently infundibulin must be injected intramuscularly. 304 THERAPEUTICAL USES OF PITUITARY EXTRACTS and orally when slow metabolic influences are required. It has already been stated that infundibulin is not destroyed by pepsin, but many believe that little, if any, of this substance is absorbed from the bowel. I have, however, seen very pronounced eleva- tion of the blood-pressure follow prolonged oral administration. As with thyroid extracts, we would expect the active principles of the pars anterior to be absorbable from the alimentary tract since this structure is morphologically derived therefrom ; but we have but little certain knowledge on this point, apart from the somewhat indefinite results which may follow. Extracts of the pituitary are made, as we have seen, in the form of dried and liquid preparations. The dried extracts are usually given by the mouth, and the liquid intravenously or intramuscularly. There is, however, no reason against the oral administration of the liquid extracts ; indeed, in the form of an elixir pituitary extracts are often prescribed. Dosage. Dried extracts of the anterior lobe, of the posterior lobe, and of the whole gland may be administered by the mouth in large quantities — as much as one hundred grains have been given three times a day. The dose should be regulated by the requirements of the case and the effects produced. Infundibulin, when injected intramuscularly, must be given with caution : the quantity administered may vary from 0-25 to 1-0 c.c. In primary and secondary uterine inertia the amount of the first injection should never exceed 0*5 c.c., for a larger quantity may have too violent an action in a susceptible woman. GENERAL INDICATIONS FOR ADMINISTRATION The most notable effects and benefits of pituitary medication are obtained in those cases in which a rapid result is desirable. In such circumstances the extract used is that made from the pars posterior, and its action is exerted upon all the unstriped muscle-tissues of the body. These effects have been described and illustrated in the physiological section of this work, so they need not be rediscussed here. Following physiological investigations 1 infundibulin was first 1 Bell, W. Blair, and P. Hick, Brit, Med. Journ,, 1909, i, 777. (Received for publication Sept. 1908.) INDICATIONS AND CONTRAINDICATIONS 305 employed, in the treatment of shock, uterine atony and intestina paresis in 1908 x . Since that time innumerable papers on this subject have appeared, and a few further indications for the use of infundibulin when an immediate effect is required have been suggested. As we shall see, the therapeutical uses of the extract made from the pars anterior are not so well defined. The indications for the administration of pituitary extracts may be divided into the following categories, according to the requirements of the case, although sometimes more than one action is indicated, especially when antagonistic and metabolic effects are required. A. For pressor effects on : (1) the circulatory system ; (2) the uterus ; (3) the alimentary tract ; (4) the urinary system ; (5) the spleen. B. For supplementary effects. C. For antagonistic and metabolic effects. GENERAL CONTRAINDICATIONS Infundibulin should not be administered, except possiblv with great caution and in small doses, in the following circumstances. When there have been signs of respiratory failure during an operation an injection of infundibulin may bring about a fatal issue. Owing to the action of this extract on the blood-pressure it is entirely contraindicated in cases of heart-disease which is not compensated ; even when there is compensation none but the smallest doses are admissible. Likewise, this preparation is contra- indicated in any condition associated with high arterial tension. Infundibulin should not be used after operations involving intestinal repairs, or anastomoses, lest the suture lines be torn asunder by violent peristalsis. Infundibulin is absolutely contraindicated for the stimula- tion of labour when there is disproportion between the foetal head and the maternal pelvic measurements. So, too, all forms of foetal impaction or obstructed labour, and many forms of abnormal presentations form definite contraindications to its use. 1 Bell, W. Blair, Brif. Med. Joum., 1909, ii. 1609. 20 § ii. EFFECTS PRODUCED BY PITUITARY EXTRACTS PRESSOR EFFECTS OF INFUNDIBULIN CIRCULATORY SYSTEM It is worthy of note that after the injection of a full dose of infundibulin the patient becomes blanched owing to the contrac- tion of the superficial arterioles. This phenomenon may alarm unnecessarily an inexperienced nurse. Shock Infundibulin may be used either as a prophylactic measure for the prevention of shock, or as a remedial agent when shock is present. This is not the place to discuss the various theories concerning the causation of shock 1 . All surgeons know that the main factors are trauma and loss of blood, alone or together, and toxaemia ; and it is generally agreed that a low blood-pressure is present. The evidence on these points is quite unassailable ; and one has only to watch the effect on the blood-pressure of an anaesthetic, combined with loss of blood and trauma due to operative pro- cedures, to be convinced that the maintenance of a satisfactory blood-pressure and fluid-compensation are of the greatest import- ance in the treatment of shock. And it will be evident that if there have been a considerable loss of blood no attempt should be made to raise the blood-pressure until a corresponding, or greater, amount of fluid has been passed into the blood-stream by transfusion. It cannot, therefore, be too strongly emphasized 1 Since this section was written a memorandum of the Medical Research Com- mittee has been published (Brit. Med. Journ., 1917, i, 381). The views expressed therein in regard to treatment coincide very closely with those described here. SHOCK AND COLLAPSE 307 that although infundibulin is most valuable in the prophylaxis of shock, and in maintaining the blood-pressure after the trans- fusion of saline solution, this preparation must not be regarded as a specific remedy for the treatment of shock which follows loss of blood, unless that loss be made good before the patient is moribund. It is probable that at the present time no case should die of shock after operation. Continuous subcutaneous saline infusions during protracted operations, and an injection of 1 c.c. of a 20 per cent, extract of the pars posterior before the patient leaves the table, will usually enable her to be returned to bed in good con- dition — provided, of course, that the ordinary precautions in the matter of warmth, and of rapidity and gentleness in operating have been taken into account. No doubt the administration of infundibulin alone after an extensive operation is of considerable value, provided no great quantity of blood has been lost, nor too great evaporation have occurred from the peritoneum 1 . In the shock, also, that super- venes on an accident in which a limb, for instance, is badly crushed or injured without the loss of blood, infundibulin is most valuable to restore the vasomotor tone. One of the great advantages of infundibulin is the length of time its action is maintained. I have observed the blood-pressure to be beneficially affected for as long as eight hours after a single administration. This has important bearings, not only in regard to the advantage that accrues to the patient from this persistent action, but also in that it is both useless and inadvisable to repeat the administration of this substance within too short a period, for if this be done a fall rather than a rise in blood-pressure is produced. My own rule has been not to repeat a dose for at least two hours, at the end of which time a further pressor effect may be obtained. Collapse In collapse, due to sudden failure of the heart's action, rather than a general vasomotor paresis, I have come to regard infundib- ulin as useful only when employed in very small doses (0'25 c.c ) and given intravenously in saline. Elliott 2 and others consider 1 I have for man}- years employed a rubber sheet instead of a gauze pack in order to avoid irritation of the peritoneum and evaporation therefrom. 2 Elliott, T. R., Practitioner, 1915 (Special number), 123. 308 THERAPEUTICAL USES OF PITUITARY EXTRACTS that suprarenin is more valuable as a cardiac restorative in these circumstances. At the same time the fatal combination of chloroform and suprarenin must not be forgotten. Sepsis In sepsis of a serious character, such as may occur with appendicitis or puerperal infection, infundibulin is of the very greatest value. I have used it for the treatment of these conditions for some years, and am convinced that many lives have been saved by the administration of 0*5 c.c. of this preparation intramuscularly twice daily, so long as acute symptoms are present. Infund- ibulin has also been used with benefit in typhoid fever. Sepsis produces a profound depression of the blood -pressure, and loss of tone of the involuntary musculature generally. This is probably the result of lesions in the suprarenal medulla, which I have found in experimentally produced infections in guinea- pigs. The administration, therefore, of infundibulin counter- balances any temporary failure in the suprarenal secretion. It has already been mentioned that there is naturally increased activity in the pituitary — unless necrosis occur- — as the result of infections. Serum-sickness In this condition, in which a state of shock may be produced, the intramuscular injection of infundibulin is of great advantage. In addition to the elevation of the general blood-pressure, the administration of infundibular extract is of considerable value in preventing the development of the urticarial weals which may form so distressing a feature of serum-sickness. This beneficial result is probably due to the constriction of the arterioles and the prevention of dilatation. That there is little or no exuda- tion at the site of the lesion, but rather a condition of temporary vasodilatation, is shown by the rapidity with which a weal dis- appears from one spot and appears elsewhere. It is possible that infundibulin would be useful in the treat- ment of angioneurotic oedema — a similar condition — but I am not aware of any observations on the subject. MENOPAUSE. ASTHMA. ASTHENIA 309 Menopausal flushings These are due to sudden variations in the blood-pressure — probably the result of an irregular action of the thyroid. I have found that if the blood-pressure be maintained at a slightly higher level than normal by the administration of infundibulin this discomforting phenomenon can be entirely suppressed or made endurable. It is, however, advisable to combine the administration of infundibulin — given orally — with calcium lactate, and eventually to withdraw the extract partly or entirely in favour of the calcium salt, which is a less drastic vasomotor tonic. Spasmodic asthma Infundibulin is sometimes of great value in relieving the distress of an acute attack of asthma. There can be no doubt that when relief is obtained the result is due to the production of vasoconstriction of the pulmonary arterioles. Apparently, however, this beneficial action is somewhat uncertain in the case of infundibulin. The principle of treat- ment on which this action is based was first demonstrated in the case of ergot 1 , and later by the use of suprarenin 2 . Asthenia In chronic asthenic conditions associated with a low blood- pressure the tonic effect of the extract of the posterior lobe is most beneficial. In these circumstances it is advisable to give either the extract of the whole gland in five-grain doses three times a day, or an extract of the pars posterior in doses of two grains twice a day. A considerable amount of work has been done on this aspect of the subject by Renon and Delillc 3 , by Musser 4 and others. 1 Bell, W. Blair, Edin. Med, Journ., 189!), xlviii, 339. 2 Meulangracht, E., Ugeskr. f. Loeger, Copenhagen, 1913, Ixxv, 1847. 3 Renon, L., and A. Delille, Bull. gen. d. Ther., 1907, cliii, 178. 4 Musser, J. H., Amer. Journ. Med. Scl, 1913, cxlvi, 208. 310 THERAPEUTICAL USES OF PITUITARY EXTRACTS UTERUS Since the discovery of the pressor action of the extract of the pituitary, and of the pars posterior in particular, it is probable that the extract has been used in physiological laboratories for the comparative testing of the pressor substances. Thus we find that Dale 1 illustrated the action of an extract of the pars posterior on the uterus in a paper relating to the action of ergot ; but he did not suggest the possibility of its clinical application. In 1908 we 2 studied experimentally the action of infundibulin on the uterus, and applied our results to clinical practice 3 . Obstetrical uses Among the vast number of papers concerning the obstetrical uses of infundibulin that subsequently appeared it will be suffic- ient to call attention to those of Foges and Hof staffer 4 , Frankl-Hochwart and Frohlich 5 , Hofbauer 6 , Schmid 7 : Jaeger 8 , Watson 9 , and Madill and Allan 10 . The remarkable position that infundibulin has come to occupy in obstetrical practice has been the subject of frequent comment. Watson 9 , writing in 1913 of the value of pituitary extract in obstetrics, introduces his subject with the following words : "It seldom happens that a new drug or remedy comes into universal use in such a short space of time as has been the case with pituitary extract in obstetrical practice. Since it was first used ... in 1909 it has been employed in practically every obstetrical clinic throughout this continent, and in Britain and Europe." This very popularity has led to extravagant claims being made in regard to the virtues of this extract. More than one writer has stated that forceps are no longer required in difficult 1 Dale, H. H., Journ. Physiol, 1906, xxxiv, 163. 2 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, i, 777. 3 Bell, W. Blair, Brit. Med. Journ., 1909, ii, 1609. 4 Foges, A., and R. Hofstatter, Zentralbl. /. Gynak., 1910, xxxiv, 1500. 5 Frankl-Hochwart, L. v., and A. Frohlich, Arch. /. exper. Pathol, u. Pharmakol., 1910, lxiii, 347. 6 Hofbauer, J., Zentralbl. f. Oynak., 1911, xxxv, 137. 7 Schmid, H. H., Gynah Rundschau, 1911, v, (Reprint). 8 Jaeger, F., Munch. Med, Woch., 1912, lix, 297. 9 Watson, B. P., Canad. Med. Assoc. Journ., 1913, iii, 739. 10 Madill, D. G., and R. M. Allan, Surg. Gynaecol, ami Obstet., 1914, xix, 241. OBSTETRICAL USES 311 labour. Such statements are not only ridiculous, but positively dangerous. Properly used, infundibulin is analeptic ; improperly employed it may be catastrophic. The indications for the use of infundibulin in pregnancy, parturition and the puerperium, are now well defined. The dosage of infundibulin in parturition is a matter of great importance. The quantity injected in the first instance should never exceed 0*5 c.c. An even smaller quantity may advan- tageously be used in these circumstances. Induction of labour. — Although abortion has never been produced by the administration of infundibulin, there is no doubt that labour may occasionally be induced towards the end of the period of gestation by repeated intramuscular injections. Stern 1 , Fries 2 , Hofbauer 3 , Goebel 4 , Krakauer 5 , Stolper 6 , Hager 7 , Herzberg 8 , Watson 9 and others, have reported suc- cessful results, and I have myself on several occasions induced premature labour by the use of the extract alone. On the other hand, failure to induce labour has been very common 3, 10, 1X . Impressed with these facts, and noting the remarkable action of this extract in cases of primary uterine inertia, I came to the conclusion that infundibulin not only augments contractions in the expulsively contracting, or potentially contracting, uterus, but also sensitizes the non-contracting musculature which there- after responds readily to mechanical stimuli, and as a result con- tracts expulsively in a physiological manner after dilatation of the cervix or mechanical irritation with bougies 12 . Labour may, then, be induced in the following manner, within a few weeks of the full term, or in postmaturity of the foetus. The patient is confined to the house, not necessarily to bed, 1 Stern, R., Berl. Klin, Woch., 1911, xlviii, 1459. 2 Fries, H., Munch. Klin. Woch., 1911, lxviii, 2438. 3 Hofbauer, J., Munch. Med. Woch., 1912, lix, 1210. 4 Goebel (no initial in original), Munch. Med. Woch,, 1912, lix, 1669. 5 Krakauer (no initial in original), Bed. Klin. Woch., 1912, xlix, 2317. 6 Stolper, L., Zenlralbl. f. Gynah, 1913, xxxvii, 162. 7 Hager, W., Zenlralbl./. Gynak., 1913, xxxvii, 304. 8 Herzberg, S., Deut. Med. Woch., 1913, xxxix, 207. 9 Watson, B. P., Canad. Med. Assoc. Journ., 1913, iii, 739. 10 Hirsch, E., Munch. Med. Woch., 1912, lix, 984. 11 Xagy, T., Zenlralbl. f. Gynah, 1912, xxxvi, 300 and 826. 12 Bell, VV. Blair, Proc. Roy. Soc. Med. (Obslet, and Gyncecol. Sect.), 1915, viii, 71. 312 THERAPEUTICAL USES OF PITUITARY EXTRACTS and 1 c.c. of infundibulin (20 per cent.) is injected intra- muscularly at night and in the morning for three days. It is advisable that the patient should lie down for an hour after each injection. At the end of this period two or more bougies are inserted into the uterus in the ordinary way, immediately after the last injection has been given. If labour does not commence within twelve hours another intramuscular injection of infundibulin is administered. In a somewhat limited experience I have not known the induction of labour to be delayed for so long as twenty-four hours after the insertion of the bougies ; yet it is well known how un- certain is the action of bougies alone. A larger experience may, of course, somewhat modify my present opinion of the celerity of this method of induction. I have said that preliminary treatment with infundibulin should be carried out for three days before the bougies are in- serted, but it should be remembered that labour may be induced before this time, and so render the insertion of bougies un- necessary. On the other hand, it may be essential that the administration of infundibulin be continued for a longer pre- paratory period than three days. The obstetrician can decide the necessity, or otherwise, of the continuance of the administra- tion of infundibulin by observing the state of the uterus. The effect of infundibulin on the uterus before parturition is very striking : the eventual sensitization of the musculature is such that the slightest stimulus, such as gentle manual kneading, causes the uterus to spring to attention — that is, to contract firmly. This state must be produced before the bougies are inserted. It has been suggested 1 that the effect of infundibulin on the pregnant uterus may be used to distinguish labour pains from other pains occurring in the normal course of pregnancy. But it is doubtful if such a test would be reliable in view of the action of infundibulin on the intestine. Primary uterine inertia. — The precise cause of the uterine contractions in labour is still unknown, although all the evidence at our disposal points to the presence of some pressor substance in the blood which sensitizes the uterus to such an extent that 1 Benthin, W., Zeitschr. f. Geb. u. Gynah, 1912, lxx, 60. OBSTETRICAL USES 313 the foetus and placenta play the part of foreign bodies stimulating the musculature to expulsive contractions. And it is, no doubt, some deficiency in the sensitizing and pressor substance or sub- stances that is responsible for the condition known as primary uterine inertia. It is important that primary uterine inertia should be recog- nized before labour. This is not difficult, owing to the flabby state of the uterus which is indifferent to stimulation, to the low general blood-pressure, and to the subnormal calcium index in the blood 1 . Such a state should be treated by the oral adminis- tration of calcium salts and the dried extract of the posterior lobe (gr. v ter in die) or of the whole gland (gr. xx ter in die). It is an interesting fact, which will come under our notice again later, that infundibulin not only directly sensitizes the uterus, but also influences beneficially the retention of calcium salts in the blood and tissues of the body. I have seen women with bad obstetrical histories in regard to primary uterine in- ertia, go through easy and rapid labours after treatment in the manner described. When labour has commenced and the uterine contractions are feeble and ineffective, if there be no contraindications, such as disproportion between the maternal and foetal measurements, malpositions or obstructed labour, infundibular extract (0*5 c.c.) should be injected intramuscularly. As a rule, the contractions are increased in force and frequency within a few minutes, and the character of the contractions is entirely physiological and rhythmical (fig. 187). Further injections may be administered if necessary after intervals of a few hours. Madill and Allan 2 , in their series of cases at the Rotunda Hospital in Dublin, administered infundibulin for primary uterine inertia to four primigravidae and nine multiparas. The first injection was given to the former when the os uteri was one half to three quarters dilated and after the patient had been in labour for an average time of twenty hours. The sub- sequent duration of labour was on an average only two hours. In the cases of multiparae, who had been in labour for an average time of thirteen hours, the first injection was given when the 1 Bell, W. Blair, Proc. Roy. Soc. Med. (Obstel. and Gynozcol. Sect.), 1915, viii, 71. 2 Madill, D. O.. and R. M. Allan, Surg. Gyncecol. and Obsttt., 1914, xix, 241. 314 THERAPEUTICAL USES OF PITUITARY EXTRACTS os was one quarter dilated. The subsequent average period of labour in these cases was only forty minutes. These authors, like Strassmann 1 and most other observers, Fig. 187. Kymograph -tracing showing the increase in regular physiological uterine contractions during labour after an intramuscular injection of - 6 c.c, of infundibulin in primary inertia. (Malinowshy.) found that the placenta is expelled in about fifteen minutes — a shorter period than is usual in normal labour. Secondary uterine inertia. — It is probable that, other con- ditions being suitable, the use of infundibulin in secondary uterine inertia — a very common condition — far exceeds all other applica- tions of the effect of this preparation on the uterus. Fig. 188. Kymograph-tracing showing the resumption of regular physiological uterine contractions after an intramuscular injection of 1'2 c.c. of infundibulin in secondary inertia. (Malinowshy.) In these circumstances the head is usually in the pelvis, and the labour ' pains ' have either ceased or have diminished in frequency and force. Following the intramuscular injection of 0-5 c.c. of infundibular extract there is, almost immediately, re- establishment of rhythmical and forcible uterine contractions (fig. 188). This is illustrated by Madill and Allan 2 , who have published a series of charts in their paper to show the duration 1 Strassmann, P., Zentralbl. f. Gynah, 1912, xxxvi, 438. 2 Madill, D. G., and R. M. Allan, Surg. Gynaecol, and Obstet., 1914, xix. 241. OBSTETRICAL USES 315 and force of the ' pains ' (fig. 189). In these charts the effect of infnndibulin on the fcetal heart is recorded. Similar charts had previously been published by Jaeger 1 . The children born after the use of infundibular extract are sometimes cyanosed and have a slow heart-action 1 > 2 > 3 > 4 > 5 . It is possible that the condition of the fcetal heart is caused by the infundibulin circulating in the maternal blood, and that the cyanosis is due to the rapidity of recurrence and to the force of the uterine contractions. Anaesthetics have but little effect in diminishing the con- tractions produced by infundibulin 5 ; nor do opium derivatives interfere with its action — Schmid 6 , indeed, advises that pant- opon be used in conjunction with infundibulin as a routine pro- cedure. I have found that omnopon, or scopolamin and morphin (' twilight-sleep '), may very advantageously be combined with infundibulin, in order to shorten the period of labour. Placenta prasvia. — In this condition infundibulin appears to have been widely used, and many observers 5 > 6 > 7 - 8 > 9 > 10 > u » who have employed it — usually in conjunction with rupture of the membranes, hydrostatic bags, vaginal packing, or with turning — are convinced of its value in safely effecting delivery, provided the other conditions are favourable for its administration. It will be obvious that the best effect of infundibular extract will be obtained when the placenta prasvia is not central ; never- theless, good results have been obtained even when the placenta has been more or less centrally situated over the os uteri. Accidental haemorrhage. — In the absence of definite contra- indications, and after rupture of the membranes, an intramuscular 1 Jaeger, P., Munch. Med. Woch., 1912, lix, 297. 2 Hofbauer, J., Zentralbl. f. Gynak., 1911, xxxv, 137. 3 Fischer, O., Zentralbl. f. Gynak., 1912, xxxvi, 15. 4 Lieven, ¥., Zentralbl. f. Gynak., 1913, xxxvii, 337. 5 Madill, 1). G., and R. M. Allan, Surg. Gyncecol. and Obstet., 1914, xix, 241. 6 Sclmiid, H. H., Gynak. Rundschau, 1911, v, (Reprint). 7 Bell, W. Blair, Brit. Med. Joum., 1909, ii, 1609. 8 Hofbauer, J., Munch. Med. Woch., 1912, lix, 1210. 9 Watson, B. P., Canad. Med. Assoc. Joum., 1913, iii, 739. 10 Studeny, A., Wien. Klin. Woch., 1911, xxiv, 1766. 11 Gall, M. E., Zentralbl. f. Gynak., 1913, xxxvii, 77. 316 THERAPEUTICAL USES OF PITUITARY EXTRACTS -£--- r - - -H h-Jf -it - -i -C4T I - " i it " i °S | [-] 1^ [| -I! '- iff :: i : iS : rj::::::-:^-- ii"i ! = * ::::::-j— • ^^ r * l T T~H 1 ] - i"J ~ ■ H — | 1 ^T [ *♦ _,_ n ] 1 — f-j — |- - - '„ 1 -\_ 1 1 _£_::_-_:: ±__.±^ pw -f " x^55 t A 'rtn T -C _::::::: :::::::::::::: -yri"Z-lil--l — =li=EiiEli===================E5|= — -: :::: P- Hffl 1 1 1 1 1 1 1 1 1 IjfH 1 ^3 O as O S - a a ^ r-- Ci CD Cg -J -p P3 .2 rt -P C CD O OX ci fi^£ fi — fl § fi o, .= C5 CD ^^ S fi cS o -p fi CD (M fi ■43 EH X 2 cS -HO ■§ J^ -S § 12 a fl O > O CD CD P4 2 « _fi _ac a o fi ce^ ft fl 5 fi -rt •5 otl -fi cS -fi CD O CD fe ccj s ^« « CD S-g fi CD ~ ifi 1J H (U « 8 fi +3 o O O CO _J .s°§ 1 s O eg -fi « o c3 J.fl flg 2 -fi o .fi O (M OBSTETRICAL USES 317 injection of infundibulin may form a valuable adjunct to other treatment, even if it be not entirely effectual in itself. Postpartum haemorrhage. — Infundibulin, owing to its rapid action on the uterus after intramuscular injection, is very valuable in postpartum haemorrhage lj 2 > 3 . At the same time, since the contractions produced by this preparation in the uterus are rhythmical in character, its action is probably not always so lastingly effective as the preparations of ergot which produce tetanic spasm of the uterine musculature. But it has been found that the action of ergot is increased by simultaneous or previous sensitization of the uterus with infundibulin ; consequently it is advisable to use the two drugs in combination for the treat- ment of haemorrhage occurring post part urn . Caesarean section. — Infundibulin has been extensively used with most beneficial results 1 ' 2,3 ' 4 ' 5 . The injection may be made in the maternal muscles during the operation, or directly into the uterine muscle after the uterus has been emptied. In my experience the former method is the better, for if the extract be injected directly into the uterus, that organ may become so tightly contracted that it is difficult to suture the wound in the muscle- wall. Acute subinvolution. — It has been found that when there is no such cause for subinvolution as fibromyomata uteri or other gross pathological lesion, the condition can be effectually treated by the daily administration of infundibulin. It is, however, in these cases advisable also to prescribe calcium salts during the treatment with pituitary extract and after this extract has been discontinued. Abortion. — Infundibulin is ineffectual in causing the expulsion of the ovum and placenta in the first half of the period of gesta- tion. Indeed, the uterus is generally found to contract down on and grasp the embryo and placenta, and the cervix to be 1 Bell, W. Blair, Brit. Med. Journ,, 1909, ii, 1609. 2 Foges, A., and R. Hofstatter, Zentralbl. /. Oynak., 1910, xxxiv, 1500. 3 Schmid, H. H., Gynalc. Rundschau, 1911, v, (Reprint). 4 Hofbauer, J., Zentralbl. f. Oynak., 1911, xxxv, 137. 5 Herzberg, S., Deut. Med. Woch., 1913, xxxix, 207. 318 THERAPEUTICAL USES OF PITUITARY EXTRACTS tightly closed 1, 2 . If, however, the uterus have been emptied, the administration of infundibulin is very valuable, when injected intramuscularly daily for a few days to induce proper involution. Bad effects stated to have followed the use of infundib- ulin in obstetrical practice A few cases have been recorded in which the administration of infundibulin is said to have produced rigidity of the cervix during labour 3 - 4 - 5 . This must be a most unusual circumstance, and the accounts of these cases are somewhat unsatisfactory. Hour-glass contraction 6 of the uterus after the birth of the child, and postpartum haemorrhage 7 following injections of in- fundibulin have been recorded. There can be no doubt that both these occurrences would be likely if the placenta were Fig. 190. Kymograph-tracing showing tetanic uterine contractions of short duration, followed by powerful rhythmical contractions after an intramuscular injection of infundibulin in secondary uterine inertia. {Malinoivsky.) unduly retained. To avoid such accidents, when infundibulin has been given during labour, it is advisable to express the placenta at the end of twenty minutes after the birth of the child, if it have not already been expelled. Rupture of the uterus, which is quite avoidable and is a serious reflexion on the accoucheur, has followed the administration of infundibulin when there has been obstruction to delivery. A certain number of these disasters is on record, and several have been privately communicated to me. I myself have never seen such a mishap. 1 Hamm, A., Munch. Med. Woch., 1912, lix, 77. 2 Watson, B. P., Canad. Med, Assoc. Journ,, 1913, iii, 739. 3 Mackenrodt (no initial in original), Zentralbl. f. Gynak., 1911, xxxv. 679. 4 Heil, K., Zentralbl. f. Gynak., 1912, xxxvd, 1398. 5 Rieck (no initial in original), Munch. Med. Woch., 1912, lix, 816. 6 Glass, R. L., Brit. Med. Journ., 1914, ii, 72. 7 Levinson, W. E., Brit. Med. Journ., 1914, ii s 1046. CONTRAINDICATIONS TO OBSTETRICAL USES 319 Malinowsky 1 states that he has seen tetanic spasms (fig. 190) in the uterus lasting for one quarter of an hour when infundibulin has been injected before the dilatation of a rigid cervix ; but he states that the spasms disappeared as labour advanced. I have already referred to the slight bad effects that have occasionally been observed in regard to the child. Contraindications to the use of infundibulin in obstetrical practice If the mother be the subject of disease of the heart or kidneys, especially with arteriosclerosis, this preparation is dangerous and may be fatal. Madill and Allan 2 record a case of heart-disease in which in- fundibulin was administered for uterine inertia. As a result of this treatment the patient collapsed, and was with difficulty resuscitated with stimulants. Hauch and Meyer 3 , and Brammer 4 , also, advise against the use of infundibulin if the mother suffer with cardiac or renal disease ; and the former also call special attention to the fact that this extract should not be used in the presence of eclamptic manifestations with a high blood-pressure. It is only right, however, to state that certain writers 5, 6 state that kidney-disease is not a contraindication to the use of infundibulin. As a matter of fact, the state of the blood-pressure should afford a clue as to the safety or otherwise of the ad- ministration of the extract in these circumstances. Owing to the high blood-tension usually found in eclampsia I have never felt justified in using infundibulin to induce or terminate labour in these circumstances. Krakauer 7 and others have, however, employed the extract for these purposes. With regard to the local conditions — fcetal and maternal- there are many important contraindications to the use of infundib- ulin. 1 Malinowsky, M., Zentralbl. f. Gynak., 1912, xxxvi, 1425. 2 Madill, D. G., and R. M. Allan, Surg. Gynaecol, and Obstet., 1914, xix, 241. 3 Hauch, E., and L. Meyer, Hopitalstidende, Copenhagen, 1912, lv, 389. 4 Brammer, M., Hopitalstidende, Copenhagen, 1912, lv, 389. 5 Stern, R., Zentralbl. f. Gynak., 1911, xxxv, 1113. 6 Gussew, W., Zentralbl. J. Gynak., 1912, xxxvi, 1755. 7 Krakauer (no initial in original), licrl. Klin. Woch., 1912, xlix, 2317. 320 THERAPEUTICAL USES OF PITUITARY EXTRACTS In malpositions of the foetus, such as the oblique and the persistent mentoposterior positions, which render it impossible for the child to be born unless there be an alteration of the attitude, the uterus may be ruptured by the violent contractions induced by this oxytocic. So, too, when there is undue disproportion between the fcetal head and the maternal passages — a state that exists to some extent in all normal primigravidce — or there is obstructed labour from any cause whatsoever, infundibulin should not be given to augment the force of the uterine contractions lest rupture of the uterus occur; and in elderly primigravidae where the rigid parts may be lacerated the drug must be used with caution. Although infundibulin has been employed successfully in minor degrees of obstruction and in some malpositions, such temerity on the part of the accoucheur does not detract from the fact that its use in such circumstances is highly dangerous. From these remarks it will be evident that in experienced hands, when the indications and contraindications are duly con- sidered, no bad effects either to the mother or child are likely to follow. Gynaecological uses In menorrhagia due to increased or irregular activity in the thyroid and ovaries — such as is seen at puberty and the meno- pause — intramuscular injections of infundibulin are invaluable. Likewise, in those cases in which there is menorrhagia with intrauterine clotting of the menstrual blood as the result of decreased muscular tone in the uterus and involuntary muscular system generally, infundibulin may bring about a rapid im- provement. In these cases it is advisable to administer the infundibular extract during menstruation only and to prescribe calcium salts 1 during the menstrual intervals. Apart from excessive menstruation infundibulin will, tempor- arily, at any rate, control bleeding — due to almost any cause — from the corpus uteri 2 owing to its action on the muscle-fibres. 1 Mist, calcii lactatis recentis (C & A) : ^i om. nocte. 2 Bab, H., Munch. Med, Woch,, 1911, lviii, 1554. ALIMENTARY TRACT. URINARY SYSTEM 321 ALIMENTARY TRACT Infundibulin may be used to prevent and to relieve acute paralytic distension of the stomach and intestine which is sometimes seen after abdominal operations. We first called attention to this in 1909 12 . Since that time many observers have recorded their experiences 3 > 4 > 5 ; and the preparation is now very generally used in preference to eserine and the other drugs previously employed to stimulate peristalsis. The contraindications already mentioned, namely, cardiac disease, renal disease associated with a high blood-pressure, and intestinal suture, prohibit the use of infundibulin in the circum- stances under consideration ; and this is more especially the case since to secure pronounced peristalsis large doses are necessary — that is to say, 1 to 2 c.c. of the extract. In intestinal paresis, or distension, following abdominal operations, I have found, however, that 1 c.c. of infundibulin is always enough if a tur- pentine enema be given ten minutes after an intramuscular injection of the extract. It is probable, too, that the best results are obtained with acute gastric distension if the stomach be washed out ten minutes after an intramuscular injection of infundibulin. In chronic constipation the continued oral administration of an extract of the whole gland or of infundibulin has given good results in many cases in which the constipation has been due to loss of tone in the intestinal musculature 6 . URINARY SYSTEM Kidneys. — As we have seen, Magnus and Schafer 7 claim that the extract of the pars nervosa has a definite diuretic effect, and there is no doubt that this preparation has been extensively used for producing diuresis. Hofstatter 8 states that postoperative anuria is invariably relieved by injections of infundibulin. 1 Bell, W. Blair, and P. Hick, Brit. Med. Journ., 1909, i, 777. 2 Bell, W. Blair, Brit. Med. Journ., 1909, ii, 1609. 3 Bidwell, L., Clin. Journ. Lond., 1911, xxxviii, 351. 4 Houssay, B. A., and J. Beruti, Presse Medicale, 1913, xxi, 613. 5 Moyniban, B., Abdominal Operations, 1914, i, 63. 6 Musser, J. H., Amer. Journ. Med. Sci., 1913, cxlvi, 208. 7 Magnus, R., and E. A. Schafer, Journ. Physiol., 1901, xxvi, Ix. 8 Hofstatter, R., Wien. Klin. Woch. : 1911, xxiv, 1702. 21 322 THERAPEUTICAL USES OF PITUITARY EXTRACTS In my own experience I have not often noted clinically any very definite diuresis in patients who have had injections of infundibulin regularly twice a day for some days. Nevertheless, in the prevention and treatment of shock, in which state the secretion of the kidneys is diminished, infundibulin may act indirectly ; and this applies especially to postoperative anuria. Bladder. — Frankl-Hochwart and Frohlich 1 have shown that injections of infundibulin stimulate the musculature of the bladder, which subsequently reacts more energetically to stimul- ation of the hypogastric nerves. As a result of their experi- ments these investigators have recommended the clinical use of the extract in paresis of the bladder. In my experience the action of even large doses of infund- ibulin on the bladder is somewhat uncertain ; and in postoperat- ive paresis I have never seen the bladder emptied unless the injection were given when the bladder was fully distended, and even in these circumstances the extract often fails to produce the desired effect. I have, therefore, adopted the following procedure, which sometimes succeeds. An intramuscular injection of infundibulin is given when the bladder is distended. If no result is produced, a catheter is passed and a few ounces are allowed to flow through it ; the catheter is then withdrawn, and after this the patient may continue to pass urine normally. MAMMARY GLANDS Infundibulin, when intravenously injected, produces a rapid flow of milk from the incised lactating breast, as already demons- trated; and there has been much discussion as to whether this is an expulsive or a true galactogogue effect. The observations of Heaney 2 and others on the human sub- ject leave no room for doubt that any increased supply of milk obtained is temporary, and is usually followed by a decrease ; consequently it is certain that infundibulin is of little use 1 Frankl-Hochwart, L. von, and A. Frohlicb, Arch. f. Exper. Pathol, u. Phar- mahol, 1910, lxiii, 347. 2 Heaney, N. S., Surg. Gyn. and Obstet., 1913, x-sii, 103. MAMMARY GLANDS. SPLEEN 323 therapeutically as a galactogogue when the secretion of milk is deficient. The employment of infundibulin in threatened mammary abscess has been suggested, but it is difficult to understand how an abscess could be aborted by this means. SPLEEN I am not aware of any cases recorded in the literature in which infundibulin has been used to produce contractions in the mus- cular tissue of the spleen. My colleague R. J. M. Buchanan; however, has treated successfully a serious case of splenomegaly by the oral adminis- tration of an extract of the whole gland. SUBSTITUTIONAL AND SUPPLEMENTARY EFFECTS OF PITUITARY EXTRACTS It is probable that true substitutional effects are never observed in the human subject ; that is to say, total destruction or removal of the gland is not compatible with life, even though substitu- tion-therapy be practised. We are, therefore, only concerned clinically with the supplementary effects of pituitary extracts. We have seen that insufficiency of the pituitary may produce a very obvious train of symptoms giving rise to the syndrome dystrophia adiposogenitalis ; yet there is little doubt that minor degrees of insufficiency of a temporary or permanent character are by no means uncommon, just as are the minor and less easily recognized insufficiencies of the thyroid. It will be remembered, also, that dishing 1 has found that the subnormal temperature associated with the high degrees of pituitary insufficiency can be elevated by injections of an extract of the pars anterior, while the low blood-pressure is raised and the sugar-tolerance lessened by the administration of infundib- ulin ; consequently in such cases an extract of the whole gland is indicated. The results of this method of treatment are not very good. Cushing 1 after a large experience found that the hypodermic administration of an extract of the whole gland occasionally gave good temporary results. In one case, the patient became active mentally and physically, so the pituitary of a newly born infant, which died during birth, was grafted in the subcortical tissues of the temporal lobe of the patient with complete operative and therapeutical success. Nevertheless, it is difficult to estimate how far this excellent result was due to the effect of the grafted gland, for an hypophysial cyst had been evacuated a few weeks previously, although without any apparent benefit. 1 Cushing, H., The. Pituitary Body and its Disorders, 1912. SUBSTITUTION AND SUPPLEMENTARY EFFECTS 325 In a case which came under my own notice in the year 1910, a man almost completely blind, and suffering from adiposity and genital atrophy with impotence, was treated with hypodermic injections of an extract of the pars anterior for a long time. Eventually he recovered his potency and impregnated his wife who gave birth subsequently to a full-term child. From the evidence at our disposal it appears that supplement- ary medication should be combined with surgical treatment of the pituitary lesion; and, if permanent benefit is to accrue, that implantation may offer the most convenient method of meeting the deficiency of pituitary secretion. In the minor degrees of insufficiency the results obtained have been fairly good. Hofst after 1 claims to have had pro- nounced success in the alleviation of amenorrhcea associated with adiposity ; but in some cases thyroid extract was also given. Hoist atter's method of treatment was by hypodermic medication, and it was found that coincidental oral administration was of advantage. In only about a third of the cases could men- struation be preserved by frequent administration of the ex- tract. Fromme 2 has obtained similar results. Williams 3 , also, has reported an interesting case of amenorrhcea which was successfully treated with pituitary extract. If, in this case, the drug was discontinued amenorrhcea was again in evidence. In my own experience, chiefly of oral administration, the results have not been striking, although in a few patients scanty and infrequent menstruation has been induced. Most of the patients have complained bitterly of the severity of the headaches with which they suffered while taking the extract of the pars anterior. It seems certain that, unless the arrest of menstruation is subject to treatment at an early period, genital atrophy may supervene, and render all prospect of beneficial treatment hopeless. In no case have I observed any decrease in the adiposity of the subject after prolonged oral treatment with an extract of the whole gland, or with infundibulin, nor have I seen a permanent change in the carbohydrate-tolerance in these eireumstanccs. It 1 Hofstatter, R., Zenfralbl. f. Gynak., 1912, xxxvi, 1536. 2 Fromme, F., Zenfralbl. f. Gynak., 1912, xxxvi, 1366. :i Williams, L., Proc. Roy. Soc. Med. (Discussion), 1914, vii, 37. 326 THERAPEUTICAL USES OF PITUITARY EXTRACTS appears probable, therefore, that oral administration is of little value in supplementing diminished pituitary secretion. Before we leave the consideration of the supplementary effects of pituitary extracts mention must be made of the fact that since physiologically the pars anterior is supplementary to the thyroid and ovaries — if we can so interpret the hyperplasia that occurs in this part of the pituitary as the result of the removal of these glands — the administration of the extract of the pars anterior has been suggested in primary hypoplasia of the ovaries and possibly of the thyroid. But such treatment is not indicated, for we know that in hypoplasia of the thyroid an extract of this organ itself effects a cure ; and that in ovarian hypoplasia the administration of ovarian extract, which of itself is more or less inert, together with thyroid extract, may be beneficial 1 . Francesco 2 , Barker and Hodge 3 , and others consider that diabetes insipidus is due to insufficiency of the pars posterior of the pituitary, and find that injections of infundibulin arrest all the symptoms of this disease, including polyuria 4 . This somewhat paradoxical effect still awaits explanation. 1 Bell, W. Blair, The Sex Complex, 1916 ; The Disorders of Function : The Neu System of Gynaecology, 1917. 2 Francesco, P., Caz. d. Osp. e. d. Clin. Milan, 1913, xxxiv, 1127. 3 Barker, L. F., and M. Hodge, Bull. Johns Hopk. Hosp., 1917, xxxiii, 355. 4 Compare with pp. 109 and 177. ANTAGONISTIC AND METABOLIC EFFECTS OF PITUITARY EXTRACTS In the correlation of effects produced by the hormonopoietic organs we find that antagonistic and metabolic as well as supple- mentary actions are concerned ; so it is possible to utilize extracts of the pituitary to combat hyperplasia in some and hypoplasia in other organs, and to counteract abnormal metabolic states that have been produced by these conditions. Nevertheless, our knowledge on these matters is still most elementary, and the extracts of the pituitary are used almost empirically for the purposes indicated. It is, of course, impossible to separate and to distinguish the direct action of an organ of internal secretion upon the meta- bolism from the effects of its action on another member of the hormonopoietic system and the resulting total effect on the metabolism. The fact remains, however, that, should the antagonism of the remedial agent succeed, the effect is seen not only in the metabolism but in the lessened activity of the organ of internal secretion whose excessive activity has been restrained. Hyperthyroidism. — The extract of the posterior lobe may be used in the treatment of hyperthyroidism. We know that thyroid secretion lowers the blood-pressure and leads to the rapid excretion of lime salts. Infundibulin counteracts both these effects, and, like suprarenin, causes a rise in the blood-pressure and the storage of lime salts. At the same time, it often effects a diminution in the size of the thyroid gland and retrogression in the symptoms of hyperthyroidism, even to an improvement in, or the disappearance of, exophthalmos. Osteomalacia. — This disease has usually been attributed to hyperplasia of the ovaries which are normally concerned in 328 THERAPEUTICAL USES OF PITUITARY EXTRACTS the excretion of calcium from the maternal economy, and I have found hyperplasia of the ovarian interstitial cells in this disease 1 . Erdheim 2 , however, has observed with osteomalacia hyperplasia of the parathyroids ; but this is probably secondary, and is an antagonistic response to the ovarian hyperplasia. Bossi 3 believes that the osteomalacia is due to insufficiency of the suprarenal medullary secretion. Whatever the truth may be concerning the causal factors in this disease, there is no doubt that the actual metabolic dis- turbance is an excessive excretion of calcium salts. Formerly, the ovaries were removed in the treatment of this condition with satisfactory results in many cases. Then Bossi suggested the injection of suprarenal extract, also with satisfactory results. A few years ago Kate Knowles, who was then in Kashmir, at my suggestion used infundibulin in the treatment of these cases with very good results, both in regard to the relief of pain, and the arrest of the disease. Other conditions of imperfect calcium retention in the tissues. — As we have seen, much of the efficacy of continued medication of pituitary extracts is due to the effect of infund- ibulin, and possibly of the extract of the pars anterior, on the calcium metabolism. This power of causing calcium retention in the tissues has been utilized by Klotz 4 in the treatment of rickets with some success. Some years ago I was consulted in the remarkable case of a lady who suffered so severely from muscular and ligamentary weakness that she was quite unable to walk and even to hold a pen with which to write. This condition had followed an arti- ficially produced menopause. Prolonged treatment with infundibulin and calcium lactate led to a comulete cure of the serious disabilities 5 . 1 Bell, W. Blair, The Sex Complex, 1916. 2 Erdheim, J., Sitz d. k. Alcad. d. Wissench. Math.-naturw. Kl., Wien, 1907, cvvi, 3 Alt, 311. 3 Bossi, L. M., Zentralbl.f. Qynah, 1907, xxxi, 69. * Klotz, R., Munch. Med. Woch., 1912, lix, 1145. 6 Simpson, A. Hope, Liverp. Med. Chirurg. Joum., 1914, xxxiv, 357. ANTAGONISTIC AND METABOLIC EFFECTS 329 From the foregoing remarks concerning the therapeutical uses of pituitary extracts it will have been gleaned that much is entirely empirical if not purely speculative ; and that even in the present day our knowledge is only laid on sure foundations in regard to " the therapeutical value of the infundibular extract in shock, uterine atony, and intestinal paresis " — the title of the first clinical paper on the subject. INDEX Abortion, effects of infundibulin in, 317. Accidental haemorrhage, effects of infundibulin in, 315. Acidophil cells in pars anterior, see Cells, eosinophil. Acromegaly, 219- accessory pars anterior, hyperplasia in, causing, 234. adenocarcinoma of pars anterior in, 232. adenoma of pars anterior in, 231. amenorrhoea in, 220. an atavism, 230. bones, enlargement of, in, 220. breathing, difficulty of, in, 225. calcium retention in, 220. chromophobe cells in pars anterior in, 232. clinoid processes, pressure atrophy of, in, 222. „ ,, thickening of, in, 222. clitoris, hypertrophy of, in, 220. colour-vision in, 226. deafness in, 226. diplopia in, 226. dorsum settee, thickening of, in, 222. eosinophil cells in pars anterior in, 231. epileptiform seizures in, 222, 226. excretion, urinary, in, 229, 230. „ calcium, in, 229. „ chlorine, in, 229. „ magnesium, in, 229. „ nitrogen, in, 229. „ phosphorus, in, 229 „ potassium, in, 229. „ sodium, in, 229 exophthalmos in, 227. extract, ovarian, in treatment of, 281. „ thyroid, in treatment of, 282. extremities in, 215. 224. face, distortion of, in, 224. features, alterations of, in, 226. feet, enlargement of, in, 220. gait in, 226 genital organs, atrophy of, in, 220. giddiness in, 226. glycosuria in, 226, 232. hair, alterations of, in, 226. hands, enlargement of, in, 220. „ splaying of, in, 224. head, enlargement of, in, 220. headaches in, 226. hormonopoietic organs, implication of, in, 220. hyperglycemia in, 226 332 THE PITUITARY Acromegaly, incidence of, 219. „ infections as etiological factor in, 270. ,, localized, 222. ,, masculinity in women in, 220. ,, metabolism in, 227. ,, nails, alterations of, in, 226. ,, nerve, oculomotor, involvement of, in, 226. ,, nose, mucous membrane of, in, 226. „ optic tracts, involvement of, in, 226. „ osteoblasts, hypersensitive, in, 220. „ pars anterior, histology of, in, 231. ,, ,, ,, hypertrophy of, in, 230. ,, „ ,, type of cell in, in, 233. ,, pathology of, 232. ,, phalanges, tufting of terminal, in, 224. ., pharynx, mucous membrane of, in, 226. „ as pluriglandular syndrome, 234. ,, polyuria in, 226. ,, as precursor of hypopituitarism, 233. „ prognathism in, 224. ,, psychology in, 226. ,, sella turcica, deformation of, in, 222. ,, „ „ enlargement of, in, 222. ,, sex-characteristics, secondary male, production of, in, 220. „ sexuality, increased, in, 220, 248. „ sinuses, frontal, enlargement of, in, 222 ,, skin, coarseness of, in, 220, 226. „ ,, pigmentation of, in, 226. „ sterility in, 220. „ superciliary ridge*, enlargement of, in, 222. ,, symptoms, lesions in pituitary as cause of, in, 234. „ ,, signs and course of, 219. „ teeth, separation of, in, 226. ,, tinnitus aurium. in, 226. „ tongue, enlargement of, in, 226. „ torpidity in, 226. ,, vision in, 226. ,, voice, deepening of, in, 220. „ vomiting in, 226. Adenocarcinoma of pars anterior in acromegaly, 232. Adenoma of pars anterior in acromegaly, 231. Adiposity, see Fat. Age, variations in microscopical appearances of pituitary according to, 38. >» .-, in weight of pituitary according to, 17. Alligator mississippiensis, 51. Amenorrhcea in acromegaly, 220. ,, effects of pituitary extracts in, 324. ,, in hypopituitarism, 241. Ammocoetes, 40. Amphibia, 48. Caudata, 49. ,, Salamandra maculosa, 49. Ecaudata, 48. ,, Bufo vulgaris, 48. ,, Rana esculenta, 48. „ Rana sylvatica, 48. Anaesthesia, method of producing, in removal of pituitary, 129, 293. Anatomy, comparative, of pituitary, 40. INDEX 333 Anatomy of pituitary, 14. „ „ niacroscopical, 14. ,, ,, microscopical, 28. ,, „ „ variations according to age in, 38. „ ,, surgical, 282. Anguilla vulgaris, 46. Anomalies, anatomical, 284. „ ,, of cribriform plate, 285. „ „ „ sphenoidal sinuses, 284, 285. Anterior lobe, see Pars anterior. Asthenia, effects of infundibulin in, 309. Aves, 52. Baboon, 76. Bacteria, effects on pituitary of inoculations with, 207. Basophil cells in pars anterior, see Cells, basophil. Bladder, effect of infundibulin on, 1 10, 322. Blindness in hypopituitarism, 243. Blood-channels in pars anterior of ovis aries, 63. ,, ,, ,, ,, ,, raia batis, 44. ,, ,, ,, ,, ,, salamandra maculosa, 49. ,, „ „ ,, ,, torpedo marmorata, 44. Blood -pressure, effects of infundibulin on, 108. „ in hypopituitarism, 241. Blood-sinuses in pars anterior, 28. Bones, enlargement of, in acromegaly, 220. Bos taunts, 60. Breathing, difficulty of, hi acromegaly, 226. Bufo vulgaris, 48. Bullet- wound as cause of hypopituitarism, 238, Cachexia hypophyseopriva, 140, 166. Calcium excretion in acromegaly, 229. ,, metabolism, effect of infundibulin on, 328. ,, retention in acromegaly, 220. Canis familiaris, 66. Cannula, uterine, 111. Carbohydrate-tolerance in experimentally produced dystrophia adiposogenitalis, 166. „ ,, ,, hypopituitarism, 241. Cardiac rhythm, effect of stimulation of pituitary on, 171. ,, ,, ,, ,, infundibulin on, 106. Carnivora, 66. Cs&sarean section, effect of infundibulin in, 317. Cat, 66. Gaudata, 49. Cavia familiaris, 65. Cells, acidophil, in pars anterior, 29. (See also Cells, eosinophil.) „ basophil, hi pars anterior, 29, 83, 92. „ „ „ „ ,, in exophthalmic goitre, 264. „ ,, .... ,, after inoculation with staplvylococci, 207. „ chief, in pars anterior, 85. ,, chromophil, hi para anterior, 29, 83. (See also Cells, eosinophil and basophil.) „ chromophobe, in pars anterior, 29, 83, 92. „ ,, ,, ,, ,, in acromegaly, 232. „ „ ,, „ „ », cretinism, 261. „ „ „ „ „ after inoculations with bacteria, 207. „ „ ,, „ ,, in parenchymatous goitre, 264. „ „ „ „ ,. after removal of ovaries, 193. 334 THE PITUITARY Cells, chromophobe in pars anterior after removal of suprarenals, 199. ,, „ „ „ ,-. „ „ „ thyroid, 183, 205. ,, ,, in pars intermedia, 33, 95. ,, eosinophil, in pars anterior, 29, 83, 92. ,, „ „ „ „ in acromegaly, 231. „ ,, ,, „ ,, „ eclampsia, 272. ,, ,, ,, „ „ after removal of ovaries, 193. „ ,, „ „ ,, ,, „ „ suprarenals, 199. „ „ „ „ „ „ thyroid, 183, 205. „ ,, ,, „ intermedia of hedgehog, 73. ,, hgematoxylinophil, in pars anterior, 29. (See also Cells, basophil.) „ neutrophil, in pars anterior, 29. (See also Cells, chromophobe.) „ „ „ „ intermedia, 33. (See also Cells, chromophobe.) „ pregnancy, in pars anterior, 85. ,, „ „ ,, ,, in eclampsia, 272. ,, ,, „ „ „ after removal of thyroid, 183, 205. ,, principal, in pars anterior, 85. ,, syncytial, in pars anterior, in cretinism, 262. „ „ „ „ „ lemur, 74. „ „ „ „ „ „ pregnancy, 85. ,, „ „ „ „ after thyroidectomy, 185. „ wandering, of pars intermedia in pars nervosa, 35, 97. „ ,, „ „ „ „ of cat, 69. „ „ ,, ,, „ „ ornithorhynchus, 58. „ ,, „ „ „ „ after thyroidectomy, 182. Cerebrospinal fluid, infundibulin in, 102. Chemistry of the pituitary, 101. Chief cells in pars anterior, see Cells, chief. Chlorine excretion in acromegaly, 229. Chromophil cells in pars anterior, see Cells, chromophil. Chromophobe cells in pars anterior, see Cells, chromophobe. Circulatory system.;, effects of infundibulin on, 105, 306. Clinoid processes, pressure atrophy of, in acromegaly, 222. ,, ,, thickening of, in acromegaly, 222. Clitoris, hvpertrophy of, in acromegaly, 220. Cod, 45. Collapse, effects of infundibulin in, 307. Colloid bodies, see Cells, wandering. „ formation in pars anterior, 92. Colon bacillus inoculations, effects of, on pituitary, 207. Colour-vision in acromegaly, 226. „ ,, hypopituitarism, 243. Commissure of Gudden, 255. „ Stilling, 255. Comparative anatomy, 40. physiology, 214. Contraindications to administration of pituitary extracts, 305. „ ,, „ ,, „ infundibulin in obstetric practice, 319. Cortical necrosis of kidneys causing changes in pituitary, 272. Craniopharyngeal canal, 22, 234. Cretinism causing secondary changes in pituitary, 262. Cribriform plate, anatomical anomalies of, 285. Cyclostomata, 40. ,, Pelromyzontes, 40. ,, Ammocoztes, 40. „ Pelromyzon Jluvialilis, 41 Cynocephalus babuin, 76. INDEX 335 Deafness in acromegaly, 226. Destruction of pituitary, 126. Development of pituitary; 3. Diabetes insipidus caused by secondary lesions of pituitary, 269. ,, „ extracts of pituitary in treatment of, 326. Didelphys virginiana, 58. Dimensions of pituitary, 14. Diplopia, in acromegaly, 226. „ cause of, 258. „ in hypopituitarism, 243. Distal epithelial portion, definition of, 2. (See also Pars anterior .) Diuresis, see Polyuria. Dog, 66. Dog-fish, 45. Dormouse, 65. Dystrophia adiposogenitalis, see Hypopituitarism. Ecaudata, 48. Eclampsia, causing changes in pituitary, 272. Eel, 46. Elasmobranchii, 45. „ pars posterior, absence of, in, 43. Emboli, bacterial, causing secondary lesions of pituitary, 271. Embryonic rests as cause of hypopituitarism, 246. Endothelioma as cause of hypopituitarism, 236. Eosinophil cells hi pars anterior, see Cells, eosinophil. Epileptiform seizures in acromegaly, 222, 226. „ ,, „ hypopituitarism, 243. Ennaceus europceus, 71. Excretion, calcium, in acromegaly, 229. „ chlorine, in acromegaly, 229. „ magnesium, in acromegaly, 229 „ nitrogen, in acromegaly, 229. „ phosphorus, in acromegaly, 229. ,, potassium, in acromegaly, 229. „ sodium, hi acromegaly, 229. ,, urinary, in acromegaly, 229, 230. Exophthalmic goitre, see lly\» rthyroidism. Exophthalmos in acromegaly, 227. Extirpation of pituitary, 145. „ „ „ with implantation of grafts, 170. „ „ „ results of, 164. Extracranial methods of operation, 291. Extract, duodenal, effect on pituitary of, 110, 177. „ ovarian, in hyperpituitarism, 281. ,, pituitary. (See also Infundibuhn.) „ „ in amenorrhcea, 324. ,, „ antagonistic and metabolic effects of, 327. ., ,, contraindications to use of , 305. dry, 302. „ ,, in dystrophia adiposogenitalis, 324. „ „ effects produced by, 105, 306. „ „ in hypoplasia of ovaries, 326. „ „ „ „ „ thyroid, 326. „ ,, indications for administration of, 304. „ „ liquid, 302. ,, „ manufacture of, 303. „ „ methods of administration of, 303. 336 THE PITUITARY Extracts, pituitary, strengths of, 302. „ ,, substitution and supplementary effects of, 324. „ ,, supplementation with, 180. ,, thyroid, in hyperpituitarism, 282. Extremities, in acromegaly, 215, 224. ,, tapering, in hypopituitarism, 244. Face, distortion of, in acromegaly, 224. Fat, deposition of, after compression of the stalk, 158. ,, ,, „ „ separation of the stalk, 158. ,, ,, ,, in hibernation, 87. „ ,, ,, „ hypopituitarism, 236, 241. Features, alterations in, in acromegaly, 226. Feet, enlargement of, in acromegaly, 220. Felis domestica, 66. Fits in hypopituitarism, 244. Formamine, see Hexamethylenamine. Fowls, brooding, pars anterior in, 83. Gadus morrhua, 45. Gait in acromegaly, 226. Gallus clomesticus, 52. Genital organs, after combined partial removal of the partes anterior and posterior, 157. „ „ „ removal of the pars posterior, 153, 195. ,, ,. atrophy of, after compression of stalk, 158. „ ,, ,, „ ,, partial removal of pars anterior, 150, 165, 195. „ ,, ,, ., „ separation of stalk, 158. „ „ „ ,, in acromegaly, 220. „ „ „ „ ,, hypopituitarism, 236, 241. Glycogenolytic substance in pars posterior, 109, 140, 177. Glycosuria in acromegaly, 226, 232. ,, caused by artificial tumours, 172. ,, „ „ experimental operations on pituitary, 140, 169. „ „ , r faradization of pituitary, 171. ,, ,, ,, indirect stimulation, 175. Goitre, exophthalmic, causing secondary lesions of pituitary, 264. „ parenchymatous, causing secondary lesions of pituitary, 264. Gonads, affections of, in primary lesions of pituitary, 248. ,, lesions of, causing secondary lesions of pituitary, 266. (See also Genital organs.) Graafian follicles, atrophy of, after partial removal of pars anterior, 196 ,, ,, ,, „ ,, compression of stalk, 196. „ ,, ,, „ „ separation of stalk, 196. Grafts, extirpation with implantation of, 170. ,, immediate results of, 120. Guinea-pig, 65. Gustatory phenomenon hi hypopituitarism, 244. Hsematoxylinophil cells in pars anterior, 29. (See also Cells basophil.) Haemorrhage, accidental, treatment with infundibulin in, 315. Hair, alterations of, in acromegaly, 226. ,, loss of, in hypopituitarism, 244. Hands, enlargement of, in acromegaly, 220. „ splaying of, in acromegaly, 224. Head, enlargement of, in acromegaly, 220. Headache, pituitary, in acromegaly, 226, 288. ,, ,, ,, ,, an indication for operation, 286. „ „ ,, ,, surgical treatment of, 297. INDEX 337 Headache, pituitary, in hypopituitarism, 243. ,, after administration of pituitary extract, 325. Heart, effect of infundibulin on rhythm of, 106. Hedgehog, 71. Hemiachromatopia, cause of, 255. Hemianopia in acromegaly, 226. „ „ hypopituitarism, 243. ,, bitemporal, cause of, 255, 257. Hexamethylenamine in the preparation for operation, 129, 286. Hibernation, dystrophia adiposogenitalis, 87. „ pituitary in, 85. „ pluriglandular inactivity in, 85. Hormonopoietic organs, affections of, causing secondary lesions in pituitary, 262. ,, „ effects of diseases of, 211. ,, ,, implication of, in acromegaly, 220. „ „ interrelation of, with pituitary, 182. ,, ,, results of removal of, on pituitary, 182. „ „ „ „ ,, pituitary on, 204. Hour-glass contraction of uterus after use of infundibulin, 318. Hyaline bodies in pars nervosa, see Cells, wandering. Hydrocephalus as cause of hypopituitarism, 245. „ „ „ ,, secondary lesions of pituitary, 259. Hyperglycemia, 124, 226. Hyperhypophysism , see Acromegaly. Hyperpituitarism, see Acromegaly. Hyperplasia of pituitary, effects of, in adult life, 219. „ „ „ early life, 219. Hyperthyroidism, effects of infundibulin on, 327. „ causing secondary changes in pituitary, 264. Hypoglycemia, 241. Hypophysial angle, 3. Hypohypophysism, see Hypopituitarism. ' Hypophysis ', definition of, 2. Hypopituitarism, 236. acromegaly as precursor of, 233. amenorrhoea in, 241. blindness in, 243. blood -pressure in, 241. bullet-wound as cause of, 238. carbohydrate-tolerance in, 241. colour-vision in, 243, 244. compression of stalk causing. 159. diplopia in, 243. dystrophia adiposogenitalis after puberty in, 241. ,, „ before puberty in, 241. embryonic rests as cause of, 246. endothelioma in, 236. epileptiform seizures in, 243. extracts, pituitary, in, 324. extremities, tapering, in, 244. glandular administration in, 280. gustatory phenomenon in, 244. hair, loss of, in, 244. headaches in. 21."!. hemianopia in, 243. hibernation resembling, 87. hydrocephalus as cause of, 244. hypoglycemia in, 241. 22 338 THE PITUITARY Hypopituitarism, infantilism in, 236. „ irritability in, 243. „ lassitude in, 241. „ Lorain type of infantilism in, 236. „ menstruation, scanty, in, 241. ,, memory, loss of, in, 244. ,, obesity in, 241. ,, olfactory phenomenon in, 244. „ overgrowth with adiposity and genital inactivity in, 236. „ pars anterior, atrophy of, in, 247. „ pathology of, 244. „ pituitary extracts in, 324. psychology in, 243. „ puberty, after, 241. ,, ,, before, 236. „ scanty menstruation in, 241. „ sella turcica in, 236. „ ,, „ deformation of, in, 243. „ separation of stalk causing, 159. ,, sex-characteristics, secondary female, production of, in, 249. „ sexual infantilism in, 236. „ skin, smooth, in, 244. ,, sterility in, 241. „ stunted growth with sexual infantilism and adiposity in, 236. „ subnormal temperature in, 241. „ symptoms and incidence of, 226. „ thermic reaction in, 166, 241. „ torpidity in, 243. „ types of, occurring after puberty, 240. „ „ ,, ,, before puberty, 236. „ ,, feminine in, 241. ,, vision in, 243. „ ,, colour, in, 243. „ vomiting in, 246. Incidence of acromegaly, 219. ,, „ hypopituitarism, 236. Indications for administration of pituitary extracts, 304. „ ,, operation, 286. Induction of labour, effects of infundibulin on, 311. Infantilism, after experimental operations on the pituitary, 165. „ in hypopituitarism, 236. „ Lorain type of, in hypopituitarism, 236. ,, sexual, in hypopituitarism, 236. „ „ with stunted growth, and adiposity in hypopituitarism, 236. Infections causing hyperplasia of pituitary, 270. „ ,, ,. ,, „ with increase in skeletal growth, 271. „ „ necrosis of pituitary, 271. „ „ secondary lesions of hypophysis, 270. „ effects of experimentally produced, 211. ,, „ ,, generalized, in Man, 270. „ ,, „ localized, in Man, 270. Infundibular process, development of, 9. Infundibulin, absorption of, 105. „ action of pepsin on, 101. ,, ,, ,, trypsin on, 101. „ in cerebrospinal fluid, 102. „ definition of, 2 INDEX 339 Infundibulin, ingestion of, 105. ,, injection of, 105. » »> -., intravenous, immediate results of, 105. a » » jj „ „ „ on alimentary tract, 112. " » » 59 jj „ ,, ,, blood -pressure, 108. " J9 » j> 9> ,, ,, ,, bladder, 110. " » »s >» jj „ „ „ cardiac rhythm, 106, " !> j» 59 55 9; „ ,y cerebrospinal secre- tion, 103. " 99 9; ;, „ ,, „ ,, circulatory system, 105. " 99 9? j, „ „ „ „ dilator muscles of iris, 119. " 99 59 95 99 95 9; -5 intestines, 112, 55 99 99 5s „ „ „ „ kidneys, 109. 95 99 99 95 ,5 „ „ „ mammary glands, 114. 55 -j 59 55 55 95 95 55 pancreatic secretion, 119. 55 55 55 55 55 >, „ „ pulmonary arteries, 108. 59 5. 99 55 55 ,, ,5 55 respiratory system, 109. 95 55 99 99 55 55 55 55 Spleen, 108. 99 59 99 99 99 ,, „ ,, stomach, 114. » 59 99 99 55 ,, „ „ urinary system, 109. « 99 99 95 55 „ ,, „ uterus, 111. •j „ „ repeated, 106. „ origin of, 96. „ pressor effects of, 306. „ ,, in abortion, 317. ,, ,, ,, accidental haemorrhage, 315. „ ,, on alimentary tract, 321. „ „ in asthenia, 309. „ ,, on bladder, 322. ,, ,, in Caesarean section, 317. „ „ on circulatory system, 306. ., ,, in collapse, 307. „ „ contraindications to use of, in obstetric practice, 319. „ „ in diabetes insipidus, 326. ,, ,, gynaecological uses of, 320. „ „ hour-glass contraction of uterus after use of, 318. „ „ in hyperthyroidism, 327. „ „ ill effects of, in obstetric practice, 318. ,, ,, in induction of labour, 311. „ ,, on kidneys, 321. „ ,, ,, mammary glands, 322. ,, ,, in menopausal flushings, 309. „ „ ,, monorrhagia, 320. ,, „ ,, osteomalacia, 327. „ ,, obstetrical uses of, 310. „ „ in paralytic distention of stomach and intestine, 321. „ ,, ,, placenta previa, 315. „ „ „ post partum haemorrhage, 317. ,, ,, rigidity of cervix after use of, 318. ,, ,, in sepsis, 308. „ ,, „ serum-sickness, 308. „ „ shock, 306. 340 THE PITUITARY Infiindibulin, pressor effects of. on spleen, 323. „ ,, in subinvolution, 317. „ „ tetanic spasms after use of, 319. „ „ on urinary system, 321. „ ,. in uterine inertia, primary, 314. ,, „ „ ,, ,, secondary, 314. ,, ,, on uterus, 310. ., „ uterus, rupture of, after use of, 318. ,, toxic effects of, 123. Ingestion of pituitary extracts, late results of, 122. Injections of pituitary extracts, late results of, 122. „ intravenous, of infundibulin, immediate results of, 105. ,, repeated, of infundibulin, effects of, 106. Jnseclivora, 71. Interstitial cells, degeneration of, after partial removal of pars anterior, 196. „ „ ,, ,, „ compression of the stalk, 196. „ ,, ,, ,, ,, separation of the stalk, 196. Intestines, effect of infundibulin on, 112. ,, paralytic distension of, effects of infundibulin on, 321. Intracranial methods of operation, 287. Iris, dilator muscles of, effect of infundibulin on, 119. Irritability in hypopituitarism, 243. Juxtaneural epithelium, definition of, 2. ,, „ one layer of, in opossum, 59. (See also Pars intermedia.) Kidneys, effects of infundibulin on, 109, 321. ,, cortical necrosis of, causing changes in pituitary, 272. Lacerta viridis, 51. Lassitude in hypopituitarism, 241. Lemur, 73. Lemur catta, 73. Lemuridce, 73. Lepus cuniculvs, 65. Lesions of pituitary, primary, 218. ,, coincidental, and suprarenals, 249. ,, gonads, affections of, in, 248. ,, nerve, fourth, paresis of, in, 258. ,, „ sixth, paresis of, in, 258. ,, „ third, paresis of, in, 258. „ nystagmus in, 258. ,, oj)tic tracts, injuries to, in, 255. „ pineal, affections of, in, 251. „ producing no pituitary symptoms, 253. ,. vision, disturbances of, in, 226, 243, 253. „ suprarenals, affections of, in, 249. ,, thymus, affections of, in, 250. „ thyroid, affections of, in, 250. secondary, 259. ,, bacterial emboli causing, 271. „ cretinism causing, 262. „ diabetes insipidus caused by, 269. ., dystrophia adiposogenitalis caused by, 269. ,, exophthalmic goitre causing, 264. „ gonads, lesions of, causing, 266. ,, hormonopoietic organs, affections of causing, 262. INDEX 341 Lesions of pituitary, secondary, hj T drocephalus causing, 259. „ ,, „ infections causing, 270. ,, „ ,, metastases causing, 269. „ ,, „ niyxoedema causing, 264. „ „ „ neighbouring pathological conditions causing, 259. „ „ ,, pancreas, lesions of, causing, 268. „ ,, „ parenchymatous goitre causing, 264. ., ,, „ suprarenals, lesions of, causing, 268 „ ,, ,, thymus, lesions of, causing, 267 ,, „ „ thyroid, lesions of, causing, 262. Lipoid particles in pars anterior, 93. Lobe, anterior, see Pars anterior. „ lateral, of Ecaudata, 49. ,, middle, of petromyzon fluviatilis, 41. ,, posterior, definition of, 2. ,, „ extract of, 2, 302. Lobus infundibuli of petromyzon fluviatilis, 41. Localized acromegaly, 222. Lorain type of infantilism in hypopituitarism, 236. Lumbar puncture in preparation for operation, 287. Lymphatics of pars anterior, 32. „ ,, ,, intermedia, 34. Macacus rhesus, 75. Macula, 255. Maculopapillary bundle, 255. Magnesium excretion in acromegaly, 229. Mammalia, 55. „ Carnivora, 66. „ ,, Felis domestica, 66. „ „ Canis familiaris, 66. „ Insectivora, 71. „ „ Erinaceus europceus, 71. „ Man, 76. „ Marsupialia, 58. „ „ Didelphys mrginiana, 58. 5 , Monotremata, 55. ., „ Ornithorhynchus anatinus, 55. „ Primates, 73. ,j „ Cynocephalus, 76. „ „ Lemur catta, 73. „ ,, Macacus rhesus, 75. „ „ Simiidce, 75. „ Rodentia, 65. „ „ Muscurdinus avcllanarius, 65. „ „ Cavia familiaris, 65. „ ,, Lepus auriculas, 65. „ „ M us domestic us, 65. „ Ungulata, 60. ., „ Bos taunts, 60. „ „ Ovis aries, 61. ,, „ Sus domesticus, 61. Mammary glands, effect of infundibulin on, 114, 322. Man, 76. Marswpialia, 58. Masculinity in women in acromegaly, 220. Measurements, surgical and anatomical, in regard to sella turcica, 284. Memory, loss of, in hypopituitarism, 244. 342 THE PITUITARY Menopausal flushings, effects of infundibulin on, 309. Menorrhagia, effects of infundibulin on, 320. Menstruation, scanty, in hypopituitarism, 241. Metabolism in acromegaly, 227. Metastases, causing secondary lesions of pituitary, 269. Monkeys, 75. Monotremata, 55. Morphology of pituitary, 3. Muscardinus avellanarius, 65. Mus domesticus, 65. Myxoedema causing secondary lesions of hypophysis, 264. Nails, alterations of, in acromegaly, 226. Nasal, inferior, routes in operations, 291. „ superior, routes in operations, 291. Necrosis, cortical, of kidneys causing changes in pituitary, 272. „ of pituitary, infections causing, 271. Nerve, fibres, sympathetic, in pars anterior, 32. „ fifth, ophthalmic division of, 24. „ fourth, 24. „ ,, paresis of, 258. „ sixth, paresis of, 258. „ third, 24. „ „ (oculomotor), involvement in acromegaly, 226. „ „ paresis of, 258. Neuroglia-cells of pars nervosa, 36. Neutrophil cells in pars anterior, see Cells, neutrophil. Nitrogen excretion in acromegaly, 229. Nose, mucous membrane of, in acromegaly, 226. Nystagmus in lesions of pituitary, 258. Obesity in hypopituitarism, 241. Obstetrical uses of infundibulin, 310. Oculomotor nerve, see Nerve, third. Olfactory phenomenon in hypopituitarism, 244. Operations, experimental, on pituitary, 126. „ ,, „ procedures in, 80. buccopharyngeal route in, 298. extracranial methods in, 291. hexamethylenamine in the preparation of patient for, 286. indications for, 286. intracranial methods in, 287. lumbar puncture in preparation of patient for, 287. nasal (transphenoidal) routes in, 291. „ „ „ ,, inferior, 292. „ „ ,, ,, submucous resection in, 293. „ ,, ,, ., superior, 291. orbital and orbitonasal routes in, 298. orbitofrontal route in, 289. overhanging-brain position in, 287. preparation of patients for, 286. results of, 299. selection of route of approach in, 286. temporal and bitemporal routes in, 288. Opossum, 58. Optic chiasma, 24, 255. » ,, anatomy of, 254. " 5, injuries to, in primary lesions of hypophysis, 255. INDEX 343 Optic chiasma, involvement of, in acromegaly, 266. Orbital and orbitonasal routes, 298. Orbitofrontal route, 289. Ornithorhynchvs anatinus, 55. Osteoblasts, hypersensitive, in acromegaly, 220. Osteomalacia, effect of infundibulin in, 327. Ovarian extracts in hyperpituitarism, 281. Ovaries, effects of compression of stalk on, 196. „ ,, ,, partial removal of pituitary on, 195. ,, „ ,, removal of, on pituitary, 192. „ ,, „ separation of stalk on, 196. ,, hypoplasia of, effects of pituitary extracts on, 326. Overgrowth with adiposity and genital inactivity in hypopituitarism, 236 t Overhanging-brain position in operations, 287. Oris aries, 61. Ox, 60. Pancreas, infundibulin, effects of, on secretion of, 119. ,, lesions of, causing secondary lesions of hypophysis, 268. ,, pituitary, relationship to, 203. Parahypophysis, vascular supply of, 26. Parenchymatous goitre causing secondary lesions of hypophysis, 264. Pars anterior, atrophy of, in hypopituitarism, 24.7. „ „ ,, uterus after partial removal of, 146. ,, blood-channels in, 44, 49, 63. ,, blood-sinuses in, 28. „ in brooding fowls, 87. „ changes in, in acromegaly, 231. „ chief cells in, 85. „ chromophil cells in, 85. „ chromophobe cells in, 85. ., colloid formation in, 92. „ definition of, 2. „ effects of removal of ovaries on, 192. „ ,, ,, „ „ suprarenals on, 198. ,, ,, „ „ ,, thyroid on, 182. „ in hibernation, 85. ,, histological anatomy of, 32, 83. „ hyperplasia in accessory, causing acromegaly, 234. „ hypertrophy of, in acromegaly, 230. „ lipoid particles in, 93. „ lymphatics of, 32. „ neutrophil cells in, 85. ,, in pregnancy, 83. „ principal cells in, 85. „ removal of, 145. „ secretion of, 91. „ significance of types of cells in, 89. ,, somnolence after removal of, 148. „ sympathetic nerve-fibres in, 32. „ syncytial confluence of cells in, 85. „ trabecule in, of sheep, 61. „ types of cells in, 89. „ type? of cells in, in acromegaly, 233. intermedia, 33. „ definition of, 2. „ effects of removal of ovaries on, 192. .» „ ,, ,, ,, thyroid on, 189. 344 THE PITUITARY Pars intermedia, effects of removal of, on suprarenals, 198. „ histology of, 94. „ lymphatics of, 24. nervosa, 35. channelling by pars intermedia of, in ornitliorhynclius anatinus, 56. definition of, 2. effects of removal of ovaries on, 192. „ „ „ ,, suprarenals on, 198. ,, „ ,, „ thyroid on, 189. histology of, 95. ,, „ hyaline bodies in, 97. „ „ ,, ,, ,, destination of, 97. neuroglia-cells of, 36. pigment in, 37. posterior, absence of, in Elasmobranchii, 43. „ definition of, 2. „ extract of, see Infundibulin. Pathological conditions, neighbouring, as cause of secondary lesions in pituitary, 259. „ processes, interpretation of, 211. Pathology of acromegaly, 232. ,, „ hypopituitarism, 244. „ ,, pituitary, histological facts concerning, 215. Pathophysiological investigations, 126. „ methods, 80. Pepsin, action of, on infundibulin, 101. Petromyzon fluviatilis, 41. Petromyzonles, 40. Phalanges, tufting of terminal, in acromegaly, 224. Pharynx, mucous membrane of, hi acromegaly, 226. Phosphorus excretion in acromegaly, 229. Physiological investigations, 82. „ methods, 79. Physiology of the pituitary, 79. „ ,, ,, „ comparative, 214. Pig, 61. Pigment in pars nervosa, 37. Pineal, affections of, in primary lesions of hypophysis, 251 . Pisces, 41. „ Elasmobranchii, 45. ,, „ Raia batis, 43. „ „ Squalus acanthias, 45. „ „ Torpedo marmorata, 44. „ Teleostei, 45. ,, „ Anguilla vulgaris, 46. „ ,, Gadus morrhud, 45. ' Pituitary ', derivation of, 1. Placenta prsevia, effects of infundibulin in, 315. Pluriglandular affections in primary hypophysial lesions, 248. ,, syndrome, acromegaly as, 234. Polyuria in acromegaly, 226. „ „ diabetes insipidus, treatment of, 326. ,. after experimental operations on pituitary, 140, 169, 171. ,, ,, grafting of the pars posterior, 121. „ „ injections of extracts of pars posterior, 109. ,, caused by metastases in the pituitary, 269. Posterior lobe, definition of, 2. „ ,, partial removal of, 153. ,, „ total removal of, 153. INDEX 345 Postoperative symptoms after removal of pituitary, 140. Postpartum haemorrhage, effects of infundibulin on, 317. Potassium excretion in acromegaly, 229. Pouch of Rathke, 4. ,, „ Seessel, 4. Pregnancy, disorders of, effects of, on pituitary, 211. ,, pars anterior in, 83. „ cells, see Cells, pregnancy. Preparation of patient for operation, 286. Primates, 73. Primordial ova, degeneration of, after partial removal of pars anterior, 196. Principal cells in pars anterior, see Cells, 'principal. Prognathism in acromegaly, 224. Psychology in acromegaly, 226. ,, „ hypopituitarism, 243. Pulmonary arteries, effects of infundibulin on, 108. Rabbit, 65. IiarJieittlorhln/pophyse, 8. Raia batis, 43. Rana esculenta, 48. „ sylvatica, 48. Rat, 65. Recessus hypophyseus, of petromyzon fluviatilis, 41. Removal of pituitary, 127. ,, ,, „ control experiments in regard to, 140. „ ,, „ method of producing anaesthesia in, 129. ,, ,, ,, . operative technique in, 129. ,, „ ,, postoperative symptoms after, 140. ,, ,, ,, preliminary procedures in, 129. „ ,, „ surgical procedures in, 131. ,, ,, ,, (See also Pars anterior and Pars posterior, removal of.) Reptilia, 51. „ Alligator mississippiensis, 51. „ Lacerta viridis, 51. „ Testudo europcea, 52. „ Testudo grceca, 52. Respirator}' system, effects of infundibulin on, 109. Results of experimental extirpation of pituitary and injury of stalk, 164. „ „ surgical operations, 299. Rhythm, cardiac, effect of infundibulin on, 106. Rigidity of cervix after use of infundibulin, 318. Ring-tailed lemur, 73. Rodentia, 65. Routes of approach, selection of, 286. „ buccopharyngeal, 298. „ nasal inferior, 291. „ ,, superior, 291. ,, orbital and orbitonasal, 298. „ orbit of rontal, 289. ,, temporal and bitemporal, 288. Rupture of uterus after use of infundibulin, 318. Saccus vascuhsus, 45. ,, ,, function of, 45. ,, ,, structure of, 45. Salamandra maculosa, 49. Scotoma, central, cause of, 255. 346 THE PITUITARY Secretion-bodies, see Cells, wandering. Sella turcica, 18. „ „ craniopharyngeal canal, in relation to, 22, „ „ deformation of, in acromegaly, 222. ,, „ „ „ ,, hypopituitarism, 24)5. „ ,, enlargement of, in acromegaly, 222. „ „ in hypopituitarism, 236. „ ,, nerve, fourth, in relation to, 24. ,, „ ,, fifth, ophthalmic division of, 24. „ ,, ,, sixth : in relation to, 24. „ „ „ third, in relation to, 24. „ ,, measurements in regard to, 284 ,, ,, optic chiasma, in relation to, 22. ,, „ sphenoidal cells, in relation to, 22. Sepsis, effects of infundibulin in, 308. Serum-sickness, effects of infundibulin in, 308. Sex-characteristics, secondary, production of, in acromegaly, 220. „ „ „ ,, ,, ,, hypopituitarism, 249. Sexual infantilism in hypopituitarism, 236. Sexuality, increased, in acromegaly, 220, 248. Sheep, 61. Shock, effects of infundibulin in, 306. Simiidce, 75. Sinuses, frontal, enlargement of, in acromegaly, 222. ,, sphenoidal, see Sphenoidal. Skate, 43. Skeletal growth, infections causing hyperplasia of pituitary with, 271. Skin, coarseness of, in acromegaly, 220, 226. „ pigmentation of, in acromegaly, 226. ,, smooth, in hypopituitarism, 244. Sodium excretion in acromegaly, 229. Somnolence, see Torpidity. Sphenoidal cells in relation to sella turcica, 22. „ sinuses, anatomical anomalies of, 284. Spleen, effects of infundibulin on, 108, 323. Squalus acanthias, 45. Squint, external, cause of, 258. Stalk of pituitary, compression and separation of, 158. „ „ „ ,, „ ,, ,, dystrophia adiposogenital, caused by, 159. „ „ ,, results of injury to, 164. Staphylococcus inoculations, effect of, on pituitary, 207. Sterility in acromegaly, 220. „ ,, hypopituitarism, 241. Stimulation of pituitary in situ, 170. „ „ „ „ direct, 171. „ „ ,, ,, ,, artificial tumours causing, 171. ,, „ ,, ,, „ faradization causing, 171. „ ,, ,, ,, ., glycosuria caused by, 172. ,, ,, ,, ., indirect, 175. ,, ,, ,, ,, >> glycosuria caused by, 175. „ „ ,, ,, ,, of superior cervical ganglion, 175. Stomach, effects of infundibulin on, 114. ,, paralytic distension of, effects of infundibulin on, 321. Strengths of pituitary extracts, 302. Streptococcus inoculations, effects of, on pituitary, 209. Stunted growth with sexual infantilism and adiposity hi hypopituitarism, 236. Subinvolution, effects of infundibulin on, 317. INDEX 347 Subnormal temperature in hypopituitarism, 241. Superciliary ridges, enlargement of, in acromegaly, 222. Supplementation with pituitary extracts, 180. Suprarenals, affections of, in primary lesions of hypophysis, 249. „ effects of removal of, on pituitary, 198. „ ,, „ „ ,, pituitary on, 198. „ lesions of, causing secondary lesions of hypophysis, 268. Surgical anatomy, 282. ,, treatment of pituitary lesions, 282. Sus domesticus, 61. Sympathetic nerve-fibres of pars anterior, 32. Symptoms of acromegaly, 219. ,, ,, hypopituitarism, 236. ,, lesions in pituitary as cause of, in acromegaly, 234. S yncyt ial cells in pars anterior, see Cells, syncytial. Technique, operative, in experimental removal of pituitary, 129. „ ,, „ surgical operations on pituitary, 282. Teeth, separation of, in acromegaly, 226. Teleostei, 45. Temporal and bitemporal routes for operation, 288. Testudo europcea, 52. „ grceca, 52. Tetanic spasms after use of infundibulin, 319. Thermic reaction in experimentally produced dystrophia adiposogenitalis, 166. „ ,, „ hypopituitarism, 241. Thymus, affections of, in primary lesions of hypophysis, 250. ,, lesions of, causing secondary lesions of hypophysis, 267. ,, relationship of, to pituitary, 203. Thyroid, affections of, in primary lesions of hypophysis, 250. ,, hypoplasia of, effects of pituitary extracts on, 326. ,, lesions of, causing secondary lesions of hypophysis, 262. „ removal of, effects on pituitary of, 182. „ ,, „ ,, „ anterior lobe of, 188. „ „ „ „ ,, production of colloid bodies of, 182. „ „ „ ,, ,, „ ' hyaline ' bodies of, 182. „ „ „ ,, ,, pars intermedia of, 189. „ ,, ,, „ ,, pars nervosa of, 189. Tinnitus aurium, in acromegaly, 226. Tongue, enlargement of, in acromegaly, 226. Torpedo marmorata, 44. ,, „ pars anterior of, blood -channels in, 44. Torpidity in acromegaly, 226. ,, ,, hypopituitarism, 243. ,, ,, after experimental operations, 140, 169. Tortoise, 52. Toxaemias of pregnancy, changes of pituitary in, 272. Tract, optic, involvement of, in acromegaly, 226. „ alimentary, effects of infundibulin on, 112, 321. Treatment of pituitary lesions, 280. ,, medical, 280. „ „ of hypopituitarism, 280. „ surgical, 282. Trypsin, action of, on infundibulin, 101. 'I'ii I a r cinereum, 24. Tubercle bacilli, effects on pituitary of inoculations with, 209. Tumours, artificial, causing direct stimulation of pituitary, 171. „ ,, glycosuria caused by, 172. 348 THE PITUITARY Typhoid bacilli, effects on pituitary of inoculations with, 207. Type, feminine, in hypopituitarism, 241. Ungulala, 60. Urinary excretions in acromegaly, 229, 230. ,, system, effects of infundibulin on, 109, 321. Urotropin, see Hexame.thylenamine. Uterine cannula, 111. Uterus, effects of infundibulin on, 111, 310. „ hour-glass contraction of, after use of infundibulin, 318. „ inertia of, primary, effects of infundibulin on, 312. ,, „ secondary, effects of infundibulin on, 314. ,, rupture of, after use of infundibulin, 318. Vascular supply of pituitary, 24. „ „ external, 26. ,, „ „ of parahypophysis, 26. ., ,, internal, 24. Vision in acromegaly, 226. ., disturbances of, in primary lesions of pituitary, 253 ,, in hypopituitarism, 243. Voice, deepening of, in acromegaly, 220. Vomiting in acromegaly, 226. ,, ,, hypopituitarism, 243. Water-vascular system in Ammoccetes, 41. Weight of pituitary, 14. „ „ „ variations in, according to age, 17. PRINTED BY WILLIAM CLOWES AND SONS, LIMITED, LONDON AND BECCLES. Date Due K-//-3X .7 cH CW i«- \ 9 . RC658 B41 cop # i Bell Pituitary.