COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD HX641 00405 QP1 87 .G48 The internal secreti I RECAP T H E Iran TERN A L SECRETIONS tm E V m m 9m m m Hi 5 ' Columbia Umtagttj^ mt&eCitpofMttogorK *T^ (£oU*g* of iUfgatriatiH atto 9ttrg»0tui ikjrartmettt of ^tjyatologg •Pttrrtjaaro bg ttjp ftp* 3F«np V Digitized by the Internet Archive in 2010 with funding from Columbia University Libraries http://www.archive.org/details/internalsecretioOOgley THE INTERNAL SECRETIONS UNIFORM WITH THIS VOLUME BACH, Ultra- Violet Light . . . $1.00 net BULKLEY, Cancer, Its Cause and Treatment, Vol. I . . . . . . $1.50 net BULKLEY, Cancer, Its Cause and Treatment, Vol. II $1.50 net EINHORN, Dietetics $1.25 net HELLMAN, Amnesia and Anal' gesia (Twilight Sleep) . . . . 1 1.50 net OTT, Fever . $1.50 net PAUL B. HOEBER, Publisher THE INTERNAL SECRETIONS THEIR PHYSIOLOGY AND APPLICATION TO PATHOLOGY BY E. GLEY, M. D. Member of the Academy of Medicine of Paris; Professor of Physiology in the College of France, etc. TRANSLATED FROM THE FRENCH AND EDITED BY MAURICE FISHBERG, M. D. Clinical Professor of Medicine, New York University and Bellevue Hospital Medical College; Attending Physician, Montefiore Home and Hospital for Chronic Diseases AUTHORIZED TRANSLATION NEW YORK PAUL B. HOEBER 1917 Copyright, 1917, By PAUL B. HOEBER Published April, 1917 Printed in the United States of America. PREFACE Professor Gley's book, of which a trans- lation is here offered, is believed to fill a gap in onr literature on the physiology and pathology of the endocrine glands. It ap- pears that the few available books on the subject are, in many cases, too extensive for the busy practitioner who wants to in- form himself about the present status of the theory of internal secretion and its ap- plication in every-day practice. Many, also, it would seem to the unbiased critic, err by having too optimistic a viewpoint, especially when discussing organotherapy. Professor Gley's study treats the subject in a thoroughly scientific, critical, yet not ultra-conservative, spirit, pointing out not only what we actually know in this very promising field, but also being careful to 5 6 PEEFACE indicate what we do not know and suggest- ing the proper methods to be pursued if we are to learn enough of the subject to make these glands, and their products, available in rational therapeutics. For these reasons Gley's book is given to those who are not prepared to read it in the original French. The translation has been made quite freely; no literal rendering of the French text has been attempted. Great care has, however, been taken to express the spirit of the author in clear and simple English. No additions of any consequence have been made because it was deemed best to leave the text as originally presented by the author. Several additional paragraphs sent in by Professor Grley, especially for this edition, have been incorporated with a view to bringing the work up to date, and to elucidate some points which needed am- plification. Also, an index has been added. M. F. New York, April, 1917. CONTENTS PAGE Preface 5 Introduction: The Differences between the Two Kinds of Secretions .... 11 CHAPTER I. The Concept of Internal Secretions; Its Origin and Development .... 15 I. The Precursors of the Doctrine . 16 II. The Founders of the Doctrine . 32 III. The Present Conception of Internal Secretion 59 II. Distinctive Characteristics of the Inter- nal Secretory Glands and the Princi- pal Products of Their Activities . . 77 I. Conditions Essential to Internal Secretion 77 1. Histological Conditions ... 82 2. Chemical Conditions .... 89 3. Physiological Conditions ... 92 Action of Organic Extracts . . 105 Theoretical Objections . . .113 Objections of Fact .... 115 II. Principal Distinctive Characteristics of the Products of Internal Se- cretion 134 Nutritive Substances .... 134 7 8 CONTENTS CHAPTEB PAGE Morphogenetic Substances (Harmo- zones) 134 The Hormones 143 The Parhormones .... 146 The Distinctive Characteristics of the Endocrine Products . . . 156 III. Classification of the Internal Secre- tory Glands and the Products Which They Secrete 167 III. The Function of the Internal Secretory Glands 177 I. The Normal Activities . . . .177 The Eeciprocal Glandular Actions or Humoral Correlations . . . 182 Eeciprocal Relations between the Pancreas and Adrenals . . . 194 Eeciprocal Relations between the Thyroid and Adrenals . . . 201 Eeciprocal Relations between the Thyroid and Pancreas . . . 208 Reciprocal Relations between the Thyroid and the Gonads . . 210 II. The Diseased Function . . . .213 Hypersecretion 214 Hyposecretion 219 Trophic Deviations .... 225 Index 235 INTEODUCTION THE DIFFERENCES BETWEEN THE TWO KINDS OF SECRETIONS INTRODUCTION THE DIFFERENCES BETWEEN THE TWO KINDS OF SECRETIONS The subject of secretions has always formed one of the most important chap- ters in physiology. The glands which manufacture the digestive ferments, and those which serve to eliminate the waste products of nutrition, are essential to the organism. It may be stated that there is not a single secretion whose role does not appear to be at least very useful, if not absolutely necessary, to the integrity of the vital functions. The recognition of the vast importance of the glandular organs and their products has been practically universal for the past twenty-five years. Only within this period, as a result of the 11 12 INTRODUCTION inspiration of Brown-Sequard's fundamen- tal work published in 1890, have physiolo- gists undertaken the study of the glands having an internal, or endocrine, secretion ; i.e., glands distributing the products of their activities, not through the cutaneous surface or gastro-intestinal mucous mem- brane and out of the body, but directly to the tissues, through the agency of the blood stream. THE CONCEPT OF INTERNAL SECRETION; ITS ORIGIN AND DEVELOPMENT THE CONCEPT OF INTERNAL SECRETION; ITS ORIGIN AND DEVELOPMENT "Nothing about a science is more interest- ing than the progress of that science itself." — (Laennec.) Complete knowledge of a physiological problem, like that of a living being, can be acquired only by grasping the problem at its very origin and following it through all its successive phases of development. In order to connect physiological facts, which are usually so complex, with one another, to coordinate and systematize the ideas which may be engendered by the facts, it is essential to distinguish the evolution of theory from accumulated data. In other words, nothing is more useful in studies 15 16 THE INTEENAL SECBETIONS of this sort than a good historical review of the subject. To the doctrine of internal secretions are inseparably attached the names of Claude Bernard and Brown-Sequard; the one the initiator, the other the resurrector of the doctrine, as I was the first to show. 1 I. THE PRECURSORS OF THE DOCTRINE But Claude Bernard and Brown-Sequard had their precursors; in fact, they are found in medical literature. 1. In 1897, 2 I called attention to a work 1 " Conception et classification physiologiques des glandes" (Revue scientifique, 1893, MI, 8-17) ; "ExposS des donnees experimentales sur les correlations fonc- tionnelles chez les animaux ,, (L'Anne'e biologique, 1897, I, 313-330). 2 In my article in L' Annie biologique quoted above. It is not without interest to know that Claude Bernard had read Legallois (a French physician and physiologist, celebrated for his investigations of the action of the heart and the nervous system; died in 1810). "It has been recognized for a long time," says Bernard, ("Lecons sur les . . . liquides de l'organisme," 1859, I, p. 321), "that although it were possible to admit the CONCEPT OF SECEETION 17 of Legallois, hitherto apparently forgotten, in which it is seen that, more than a cen- tury ago, this physiologist had clear no- tions of the connection which must exist between the various secretions, and the complexity of the composition of the ve- nous blood. The text runs thus : ' ' Consid- ering the homogeneity of the arterial blood and the heterogeneity of the venous blood we may conclude that ... it would be a supreme triumph of the chemistry of the living body to find connections between the arterial blood, the substances so secreted in each organ and the corresponding venous blood, in the normal as well as in the patho- logical states of various animals; to find differences between the various kinds of venous blood ; finally to discover that these homogeneity of the arterial blood, the venous blood can- not be regarded as having the same composition through- out its course. Legallois, examining this question in a purely speculative work, had already concluded that the arterial blood is everywhere identical in composition, but declared that the venous blood was not so constant," 18 THE 1NTEENAL SECEETIONS differences vary as do the corresponding secretions. "Once arrived at this degree of perfec- tion, it would often be possible to solve for the unknown in the equation: arterial blood = a secretion + the corresponding venous blood; 3 that is, given the left hand member of the equation, and the composi- tion of the corresponding venous blood, chemical science could almost determine what would be the character of the secre- tion. " 4 However keen it may have been for a physiologist of that time (1801) to recognize intuitively an essential part of the problem of the mechanism of secretion, it must nevertheless be noted that the ideas of Legallois are not specific and that they apply to all glands, not differentiating those which have since been designated as * These words were underscored by Legallois. 4 Legallois, ' ' Le sang, est-il identique dans tous les vaisseaux qu'il parcourt?" Inaugural dissertation given before the School of Medicine in Paris, Sept., 1801 ("CEuvres de Legallois," II, 209-10). CONCEPT OF SECEETION 19 glands of internal secretion. The impor- tance of this last reservation in the study of the origin of the theory of the endocrine glands is evident. 2. Following a suggestion of Max Neu- berger, 5 Biedl wishes to attribute a similar conception to another French physician, Theophile Bordeu, who lived even before Legallois. Biedl says: "In his treatise on 'L 'Analyse medicinale du sang,' which appeared in 1775, Bordeu expresses the opinion that each organ serves as a center for the preparation of a specific substance which is discharged into the blood, and that these substances are useful to the or- ganism and necessary for its integrity. The specific substances coming from their particular organs perhaps reach the blood through the medium of the lymphatics. It seemed to him to have been conclusively demonstrated that the venous blood of 5 Max Neuberger, Theophile Bordeu als Vorlauf er der Lehre der Inneren Sekretion" (Wiener Iclinische Woch., Sept. 28, 1911, XXIV, 1367). 20 THE INTERNAL SECRETIONS various regions presents important quali- tative differences." 6 Asa matter of fact, Bordeu did not express himself so clearly. The "Analyse medicinale du sang," which Biedl quotes, is a booklet whose title is rather too ambitious. I shall quote sev- eral typical passages from which it will be clear that the author's thoughts were very vague. After a series of truisms on the characteristics of each part of the liv- ing body, the author concludes : "I believe it to be certain that every organ keeps its own particular place, as I have just said, and that it lives its own independent life . . . and always diffuses around itself, in its atmosphere and province, exhalations and odors; emanations which have taken on its manners and its ways, which are, in short, true parts of the organ itself. "I do not regard these emissions as entirely useless and therefore only of 6 A. Biedl, "Innere Sekretion," 2nd Ed., Berlin and Vienna, 1913, I, p. 5. CONCEPT OF SECRETION 21 mechanical utility; I think they are use- ful and necessary for the existence of the entire organism. The seminal fluid imparts, as is well known, a manly and firm bearing to all parts of the body, since it is in a position to be pumped into and come back from the mass of humors and solids, by the work of its natural or- gans ; it confirms anew the living nature of the individual, partly subjected to the ac- tion of this fertile fluid. . . . Examine the blood that returns from each of the princi- pal regions of the body, that from the head, from the breast and from the abdomen; it is evident 7 that the blood from each of these regions has particular qualities that it has acquired in the tissues of the parts from which it returns. Finally, I accept as a fact, which has been medically verified, the assertion that each organ is continu- ously diffusing emanations into the blood ; 7 It is useless to add that these words were uttered without observation and a fortiori of all analysis. 22 THE INTERNAL SECRETIONS and if it were possible to base a deduction on some part of the anatomists' discovery of venous lymphatics, I would say that this gelatinous liquid has particular vessels so that it may be more surely brought back into the blood-stream with the individual qualities that it has acquired in the inter- nal tissues of each organ, in order to instil into the chyle, into the thoracic visceral tract, the properties and characteristics pe- culiar to the parts of which it is composed. Some one has found lymphatic veins in the testicles and has ascribed to them the function of returning the seminal fluid into the blood. It was not necessary to know of the existence of these veins to realize the fact that absorption of the seminal fluid takes place." 8 We can easily see from the above how much clearer were the ideas of Legallois. But once on a pathological basis — and this 8 Theophile Bordeu, ' ' GEuvres completes, ' ' edition Kicherand, vol. II, pp. 942-943, Paris, 1818. CONCEPT OF SECRETION 23 has not escaped Neuberger or Biedl 9 — Bordeu's progress appears to be a little more certain. "The flowing back of the bile," he says, "for example, its elaboration in the blood, its diffusion through all the tissues of the body, the color that it gives to solids and to liquids, are well known phenomena. We may indubitably conclude from this . . . that throughout life, and even when in the best of health, a constant interchange is going on between the liver and all the humors and solids of the body. The superabundance of humors present in some of the diseases to which their organs are subject, is proof of the existence of passages by which the humors pass when the organism is in a normal condition. . . . The diversity of temperaments was for- merly, not without some semblance of 9 ' ' That Bordeu has presented the pathological sig- nificance of anomalies of excretion, is shown by his re- mark: 'Physicians should follow and classify the vari- ous refluxes which take place through the fault of each organ in particular ' " (A. Biedl, loc. cit., p. 5). 24 THE INTERNAL SECRETIONS truth, attributed to an oversupply of hu- mors. I have elsewhere indicated that the various temperaments have some connec- tion with the greater or lesser activity of certain organs when compared with that of others. Thus the liver has within its do- main the bilious temperament. . . . This remark may be applied to all other organs ; each of them is master of the temperament which it governs. . . . Each organ has a marked influence on the solids, the vessels, the cellular tissue and the nerves. Each also serves as a home and laboratory for a particular humor which it sends back to the blood after having prepared and im- pregnated it and given it a definite char- acter . . . "I distinguish as many cachexias, as many minglings or principal mixtures of humors, as there are important organs and distinct humors. . . . All glands derive from the cellular tissues which surround them a large quantity of serosities, pump- CONCEPT OF SECRETION 25 ing them on, to follow the terminology of the Hippocratic school. These serosities mix with the humors specially formed and separated by the glands. Now, these serosities, not being pumped away as they should be, become superabundant; a cachexy that flows back into the humors and inundates all the neighboring parts, even as the bile is stopped in its course. It is a problem for physicians to trace and classify the various refluxes that come on because of the faulty working of some par- ticular organ." 10 From this it may be seen that the refluxes of which Bordeu speaks are not solely of glandular origin, as Biedl would seem to have him say. The context of the sentence which Biedl cites only goes to show that the XVIII century physician had crude views of the possible relations between secretions and patholog- ical disorders. It is no less curious to ob- serve — and this, above all, is the object 10 Th. Bordeu, loc. oit., pp. 947-949. 26 THE INTERNAL SECRETIONS with which I have reproduced the preced- ing quotation, although it is rather long — that he may be considered a precursor of those contemporary pathologists who hold that a certain morbid syndrome may de- pend on the hyperactivity of the nervous system which, in turn, is caused by the presence of an excessive amount of a prod- uct of secretion in the blood. Such is, as is well known, the theory or vagotonia, or hypertony of the sympathetic nervous sys- tem, which is attributed by the Viennese school to an excessive secretion of adren- alin. In 1845, J. Miiller wrote in his celebrated ''Text-book of Physiology": "The duct- less glands are alike in one particular: they either produce a definite change in the blood which circulates through them, or the lymph which they elaborate plays a special role in the formation of blood or of chyle. In every instance venous blood or lymph are the only substances which pass CONCEPT OF SECRETION 27 from the gland into the general econ- omy." X1 3. Here and there in the works of several biologists of the first part of 11 J. Muller, ' ' Lehrbuch der Physiologie, ' ' 1844. There is a little difference between this purely hypotheti- cal statement and an earlier pronouncement by Bur- dach: "The vascular or blood glands are agglomera- tions of vascular ramifications united by the primordial mass, which have neither excretory ducts nor an immedi- ate connection with the mucosa and which can be con- cerned only in the metamorphosis of the blood without the agency of an external medium. This metamorphosis may occur as the result of the passage of the blood through the glands, for it is inconceivable that that passage should be unattended by some change in the proportion of the secondary elements; or it may result from nutritional processes within the organs, or from a deposit of substance within their tissues; or it may be due to formation in the tissues of a liquid which is afterwards resolved." (C. F. Burdach, "Traite de physiologie considered comme science d 'observation. ' ' Translated into French by A. J. L. Jourdan, Paris, Bailliere, 1837-41, vol. IV, p. 83.) It is evident from this that it is hardly possible to consider Burdach and Muller as the precursors of the theory of internal secre- tion. The same may be said in regard to Henle, Kolli- ker, and even more emphatically in regard to Bordeu. (See: "Relations entre les organs a secretions internes et les troubles de ces secretions, ' ' Int. Congress of Medi- cine, London, 1913. Section Physiology, Part I, pp. 2-5.) 28 THE INTEENAL SECRETIONS the nineteenth century we note rare allusions to the functions of the vas- cular glands. Thus, Henle affirms that these glands "have no influence on ani- mal life; they may be extirpated or they may degenerate without sensation or motion suffering in the least," and he adds: "Nothing, then, would be more natural than to assign them a place among the organs which take part in the chemical processes of nutrition or of hematosis. Many facts bear witness that diseases of the spleen and thyroid are connected with general disturbances in the composition of the blood and with nutritional dis- orders. This justifies us in thinking that the blood undergoes a change in the vascu- lar glands ; that while it circulates through their interior it throws off certain sub- stances which undergo some sort of elab- oration in the parenchyma, as in the secre- tory glands. The difference consists in this: that here the products of secretion CONCEPT OF SECEETION 29 are not carried out from the gland through a duct . . ., but reenter into the blood ves- sels or lymphatics, either by absorption or exchange or by the establishment of a tem- porary means of communication between the vesicles and the blood vessels. ' ' 12 But it is easy to see that this is not the distinc- tion between the two kinds of glands recog- nized by anatomists, for he differentiated them according as to whether they have or do not have ducts conducting the secretions to the exterior. Kolliker says no more about it: "Gewebe der Blutgefassdrusen. Un- ter diesem Namen fasst man am passend- sten eine Reihe von Organen zusammen, deren Uebereinstimmendes darin liegt, dass sie in einem besonderen driisigen Gewebe aus dem Blute oder anderem Safte gewisse Stoffe bereiten, die nicht durch besondere bleibende or zeitenweise sich "J. Henle, "TraitS d'anatomie generate," trans- lated into French by A. J. L. Joubdan, Paris, 1843, vol. II, p. 586. 30 THE INTERNAL SECRETIONS bildende Ausfiihrungsgange sondern ein- f ach durch Heraussickern aus dem Gewebe abgefuhrt werden und dann in dieser oder jener Weise dem Organismus zu Gute kom- men." 13 Finally, nothing further is given in the most important contemporary- physiological treatises, for example, those by J. Miiller, Longuet, and Beclard, nor in Milne-Edwards 's great work, which was devoted to physiology and comparative anatomy. In all that period there was only a single attempt at experimental investigation, that by A. A. Berthold, of Gottingen, 14 who in 1849 removed the testicles from cocks and grafted them upon other parts of their bodies. He observed that "the ani- mals retained their male characteristics in 14 A. Kolliker, "Handbuch der Gewebelehre des Menschen, " p. 74-75, Leipzig, 1852. "Quoted by A. Biedl, loc. tit., sec. edit., 1913, p. 6. Berthold '8 -work has been published in the Archiv fur Physiologie, 1849, pp. 42-46. The experiment was only carried out on four cocks. CONCEPT OF SECRETION 31 regard to voice, reproductive instinct, fighting spirit, and growth of comb and wattles." From his experiments Berthold concluded that "the consensus is main- tained by the productive influence of the testicles ; that is to say, by their effect on the blood and, through the blood, upon the entire organism." Biedl is therefore cor- rect in saying that "A. A. Berthold was the first to demonstrate experimentally the nature and activity of a true ductless gland; he showed the influence which an organ through which the blood stream cir- culates can exert upon the composition of the blood, and thus upon the entire organ- ism." With Biedl I will add, moreover, that this discovery, far from attracting any attention, remained hidden in obscur- ity and hence had no consequences; it stimulated no further research along the same lines. 32 THE INTERNAL SECRETIONS II. THE FOUNDERS OF THE DOCTRINE The true founders of the doctrine of in- ternal secretions, such as it is, are Claude Bernard and Brown-Sequard; and in the establishment of the theory each played a part different from that of the other. 1. I believe myself to have been the first to bring to light, in 1893, and above all in 1897 (loc. cit.), the texts, often quoted since then, showing that Claude Bernard had clear ideas about the glandular organs which distribute their secretory products by means of the blood stream — into the in- terior part of the body, as he said — and these ideas came, indeed, not from infer- ences based on vague observations or from mere suppositions and assumptions reached through a priori reasoning, but, on the contrary, from a mass of experi- mental facts, solidly demonstrated. The facts which he used concern the produc- tion of grape sugar by the liver and the CONCEPT OF SECEETION 33 passage of this sugar in the hepatic veins and from there into the general circula- tion ; and once having firmly demonstrated the existence of this internal secretion, the author of this discovery is immediately led to the inevitable generalization: 15 "For a long time a false conception has been current as to what a secretory organ con- sists in. It was believed that all secretions must be poured upon an internal or ex- ternal surface, and that all secretory or- gans must necessarily be provided with an excretory duct for the purpose of convey- ing to the exterior the products of secre- tion. The case of the liver establishes in a most lucid manner that there are internal secretions, i. e., secretions which, instead of being carried to the exterior, are dif- fused directly into the blood." Further on (p. 107), he says: "It is now firmly 15 "Lemons de physiologie exp6rimeutale, " I, 96, Paris, 1855. 34 THE INTERNAL SECRETIONS established that the liver has two functions of the nature of secretion. The first, the external secretion, produces the bile, which flows to the exterior ; the second, the inter- nal secretion, forms sugar which immedi- ately enters into the blood of the general circulation. ' ' Thus we see that Bernard clearly under- stood the functional significance of the liver in producing sugar, and the physi- ological significance of this sugar, a prod- uct of secretion; and, at the same time, founded a new theory of secretion on these premises. This is not all he accomplished. The idea, of internal secretion, which he under- stood clearly at the very start of his work, appeared to be immediately connected in his mind with his conception of the nature of the blood, which he came to consider as the resultant of all the internal secretions. "All the fluids which have been examined CONCEPT OF SECRETION 35 up to the present time," he said in 1859, 16 ' ' are what are known as excreted or secreted fluids, that is, liquids manufactured by or- gans which take from the blood the elemen- tary substances necessary for the prepara- tion of the products of their secretions. All these organs pour their secretions out- side of the blood. And there is another category of organs which resemble the glandular organs, but differing from the latter in that they are not provided with excretory ducts ; they must dispose of the products of their secretion into the blood itself. These are what we have designated by the term internal secretions, in order to distinguish them from the external secre- tions, which are not poured into the blood. "I have shown that the liver is, in some ways, intermediary, because its secretions are of both types; the external secretion M "Le§ons sur les proprietes physiologiques et les alterations pathologiques des liquides de 1 'organisme, ' ' vol. II, pp. 411-412, Paris, 1859. 36 THE INTEENAL SECEETIONS being represented by the bile and the in- ternal by the sugar produced. The organs whose mode of secretion are exclusively internal are the spleen, the thyroid, the adrenals, the lymphatic ganglia, etc. " It is beyond all doubt that these organs modify the blood which passes through them and when leaving them contains sub- stances not present before it entered. We may therefore consider that the blood con- stitutes the sum total of all these secretions and it should, in my opinion, be regarded as a true product of internal secretion. ' ' Bernard attaches himself so strongly to this conception that we may wonder if he did not consider all these organs, which he classified among the internal secretory glands, as blood forming organs. In his lectures of 1859-60 at the College de France, 17 he says: "The various glands distributed throughout the entire body 17 ' ' Lemons de pathologie experimentale, ' ' 2nd Ed., p. 100, Paris, 1880. CONCEPT OF SECRETION 37 must be divided into two great classes: those which extract from the blood certain particular principles which impart to each secretion its individual characteristics; and those which, on the contrary, appear to secrete the blood itself, if I may use the ex- pression, or those which are intended to enrich the circulating blood with products manufactured in the interior of their own tissues. Such are the hematopoietic glands, among which are included the spleen, the thymus, the suprarenal capsules and other glands rich in blood vessels, and which do not possess excretory ducts. The lungs, within which the great work of oxygenating the blood goes on, represent the most complete type of this last variety of gland. Also the liver, which, if we con- sider the biliary secretion, belongs to the first class, is equally allied to the second group by the glycose it produces." The expression of Claude Bernard's opinions on the subject is in no wise different, nor 38 THE INTERNAL SECRETIONS is it more precise and complete in his fa- mous "Rapport sur les progres de la physiologie generale en France"; 18 I have quoted the entire passage in my study in L'Annee biologique of 1897 (p. 315), mentioned above. It reads as follows: "The secretory cell itself attracts, creates and elaborates all the products of secretion which it pours either on the mucous sur- faces without or directly into the blood stream. I have termed those that flow to the exterior, external secretions, and inter- nal secretions are those which are diffused into the vital interior of the body. . . . The internal secretions are far less known than the external. Their existence has been more or less vaguely suspected but is not as yet generally admitted. However, in my opinion their existence is no longer doubtful, and I think that the blood, or, in other words, the vital interior of the body, must be regarded as a product of secretion 18 Paris, 1887, pp. 73, 79, 83, 84. CONCEPT OF SECKETION 39 of the internal vascular glands. ... I con- sider the liver, in the form that it is pres- ent in the higher vertebrates, as a two-fold secretory organ. It combines, in reality, two distinct methods of secretion, and it represents two secretions : The first is the biliary secretion, which is external and flows through the bile duct into the intes- tine ; the second is the internal secretion of glycogen and is poured into the blood stream. . . . That part of the liver which secretes glycogen is composed of a large vascular gland, i. e., a gland which has no external excretory duct. In it are pro- duced the sugar constituents of the blood, perhaps also other albuminoid prod- ucts. But there exist many other vascular glands, such as the spleen, the thyroid, the suprarenal capsules and the lymphatic glands, the functions of which are as yet unknown. However, these organs are gen- erally regarded as playing some role in the regeneration of the blood plasma, as well 40 THE INTERNAL SECRETIONS as in the formation of the red and white corpuscles which float in this liquid." To sum up, we owe to Claude Bernard the first direct demonstration 19 of an in- ternal secretion — the passage into the blood of sugar formed in the liver — and the general conception of these secretions, which he understood as serving to main- tain the composition of the blood. Throughout his entire work I find no text which would seem to indicate that he meant anything else by the expression secretions internes than the concept he first expressed, viz., that they serve to maintain the composition of the blood. How differ- ent this is from the true conception ! How remote are the ideas represented by this expression to-day from those held by Claude Bernard! A word has no more meaning than the thought it expresses. 2. In order to grasp the exact value of w Berthold 's experiment, mentioned by Biedl, only constitutes an indirect proof. CONCEPT OF SECRETION 41 the ideas that Claude Bernard introduced into medical science, it is necessary to state that absolutely no interest was aroused by his work. And it is curious to note in this connection how very differently scientific ideas fare with Fortune. Some, notwith- standing that they are based on insuffi- ciently demonstrated premises and hasty deductions, at times have a rapid and bril- liant rise to fame ; others, though securely based on a sure foundation, remain in oblivion for long periods or are slow to at- tract and retain attention, until they are finally resurrected by the light of fame. The doctrine of Claude Bernard under dis- cussion belongs to the latter category. I am well aware that the theory of the glyco- gen-producing function of the liver was assailed and severely criticized by many physiologists for many years; but it was also very much admired and amply veri- fied by many others, so that, in quite a 42 THE INTERNAL SECRETIONS short space of time, its acceptance was forced upon physiologists, with the excep- tion of several rebellious spirits, as Lon- get. 20 And beginning with 1855, the year in which the "Legons de physiologie ex- perimentale " appeared, considerable work was produced which would naturally be coordinated with the experiments on the glycogen normally produced by the liver. I refer to the researches of Brown-Sequard on the physiology of the suprarenal cap- sules (1856-58) ; 21 the observations of Vul- pian (1856) on the coloring matter of the 20 See the last (third) edition of Longet's "Traits de physiologie," Paris, 1867-69, reprinted 1873, vol. II, pp. 290-296. 21 It is important to recall that Brown-Sequard, in his first manuscript (Arch. gen. de med., 1856), wrote very clearly: "The absence of the secretions of the suprarenal glands is therefore more rapidly fatal than the suppression of the urinary secretion ..." "The question of the function of the suprarenal capsules therefore depends on the following: What are the sub- stances which, when carried to these glands by the blood, are there modified, and what are the products of this modification which are carried away by the blood when it leaves the capsules?" CONCEPT OF SECRETION 43 medullary substance of the suprarenal capsules and the passage of this matter into the venous blood of the capsules ; 22 SchifT's researches on the connection of the spleen with the digestive (proteolytic) function of the pancreas (1862). But no one coordinated these facts, not even Claude Bernard. This would be most sur- prising were it not called to mind, in ac- cordance with what I have just shown, what, in reality, was his conception of the nature of the "internal secretions." It is therefore, possible that it was this, some- what narrow, conception which concealed from him the general connection existing "Vulpian had well noted the general interest of this statement: "I always noted that the droplet of san- guineous liquid issuing from the venous orifice (of the capsular vein in the sheep in Vulpian's experiments) produced the indicated reaction with sesquiehlorid of iron. This proves for the first time, and in a most de- cisive manner, the hypothesis which regards the supra- renal capsules as being like the glands termed vascular, i. e., glands pouring their products of secretion directly into the blood" (C. K. de I'Acad. des sc, Sept. 27, 1856, XLIII, 663). 44 THE INTERNAL SECRETIONS between these newly discovered facts and the normal glycemia. Towards the end of that period, how- ever, there came a biologist who under- stood the importance of the question. "The action of the glands which do not have excretory ducts," says Charles Robin, 23 "can only be studied from the physiological point of view. The nature of the products of this action can only be definitely established by the comparison of the arterial blood with the venous blood that leaves these organs, or by comparing the ingoing lymph with that which has al- ready passed through the gland. Unfor- tunately, the direct comparative analysis of the liquids which these organs receive and those which issue from them has not been done anywhere in a suitable manner ; no more than it has been done with the 28 Ch. Eobin, ' ' Legons sur les humeurs normalea et morbides," 2nd Ed., Paris, J. B. Bailliere et fils, 1874, p. 316. CONCEPT OF SECEETION 45 secreting parenchyma cells themselves." Further on, 24 Robin writes: "Each of these various glands furnishes one or more special principles of its own to the blood carried away by the corresponding vein to the principal organ to which it is con- nected. Just as the blood which enters the liver does not contain the sugar which the departing fluid holds, it is likewise found that the formation of the substances which are most certainly found in the returning blood must be attributed to the tissues of the vascular glands, which have poured them into the blood exactly as the liver un- burdens itself of sugar into the hepatic veins. ' ' 1 ' These facts are quite closely associated with the study of the constitution of the blood and lymph. 25 The studies of M. »ma., p. 318. * It is thus to be seen that this idea of the constitu- tion of the blood and lymph is always dominant. It is found in Liegeois ("Anatomie et physiol. des glandes vasculaires sanguines," Paris, 1860), as is proved by the 46 THE INTERNAL SECRETIONS Claude Bernard support them, he having given the name of internal secretions to the products poured into the blood itself by the vascular glands, in order to distin- guish them from the external secretions, the products of which are deposited with- out the blood." In a note he adds: "As far back as 1837, furthermore, Burdach, who considered the spleen, thyroid, supra- renal capsules and thymus as agglomera- tions of vascular ramifications, thought that the vascular glands could only serve for what he termed the metamorphosis of blood." Great as was the authority of following passage: "Prom all these experiments (Liegeoia has just cited Vulpian's experiments on the suprarenal venous blood and those of Beclard, Funke, Lehmann, and Gray on the splenic venous blood), we have the manifest result that in the spleen and the suprarenal capsules, modifications take place which change the constitution of the blood" (loc. cit., p. 53). "The vascular glands," says Liegeois further (p. 59), ' ' have for their principal function pouring into the cir- culation materials which change the microscopic and chemical constitution of the blood." Moreover, this work lacks facts and also a critical spirit. CONCEPT OF SECEETION 47 Charles Robin at that time, above all in France, these considerations, supported by those of Bernard, in his "Rapport sur les progres de la physiologie generale en France," did not stir many to a clear re- alization of their value, or provoke any ex- perimental researches. A little later we again find the term "in- ternal secretions," from the pen of Paul Bert. 26 "These are," he says, "products of secretion which are emptied into the blood. " 27 To this he adds nothing but these lines (p. 254) : "The liver gives us an example of a gland which not only manu- factures a liquid destined to be expelled, but also substances which are poured into the blood. ' ' So brief is this notice that we would be justified in thinking that Paul Bert did not appreciate the importance 36 "Lemons de zoologie," Paris, G. Masson, 1881. This was a work written with a view to the secondary instruction of young girls. I am indebted to Prof. V. Pachon for indicating to me this source. 27 Loc. cit., p. 248. 48 THE INTERNAL SECRETIONS of the question from the point of view of general physiology, did we not reflect that the work in which it occurs is an elemen- tary textbook. Several years after the death of Claude Bernard, Schifr* published his great work ' ' On the effects of the removal of the thy- roid body, " 28 a labor inspired by the ob- servations of J. L. and A. Reverdin (1883) and Kocher on postoperative myxedema (1883), which recalled in a most striking manner the experiments of two English physicians, W. Gull (1872) and W. W. Ord (1878), on spontaneous myxedema. It is known, further, that Schiff in 1859 had al- ready pointed out several of the successive accidents of thyroidectomy. Did he in- clude the thyroid among the vascular glands? He puts the question thus : "We may wonder if the thyroid body produces in its interior ... a substance which it de- M Revue mSdicale de la Suisse romande, Feb. 15 and Aug. 15, 1884. CONCEPT OF SECRETION 49 livers to the blood stream and which con- stitutes a nutritive element for another or- gan (nervous), or whether it acts mechan- ically by its anatomical position. To de- cide between these two alternatives, it is necessary to find a means of transplanting it, by grafting it into another part of the body. If, after this has been done, the accidents resulting from its removal are avoided or reduced to a minimum, it is evi- dent that the action of the thyroid is due to its composition and not to its anatomical relations; this will prove the thyroid to have a chemical function. ..." He then states that the grafts he attempted disap- peared by resorption ; nevertheless the ani- mals in which the thyroid body was trans- planted suffered from less severe effects, from which he concludes that "the sub- stance of the grafted organs, taken up by the blood, serves to counterbalance the untoward effects of thyroidectomy." "It would be curious to investigate if 50 THE INTERNAL SECRETIONS the macerated extract of the thyroid, in- troduced into a serous cavity, or injected into the rectum, has the same immunizing power. ' ' 29 This is all that is said. Schiff did not attempt, in the presence of all these facts, to connect them with what was al- ready known about the suprarenal cap- sules and the formation of grape sugar in the liver. As I have said elsewhere : 30 "Schiff, although always so close to the work of Claude Bernard, and whose inves- tigations on the connections between the function of the spleen and the digestive ac- tivity of the pancreas furnish some of the most favorable arguments for the doctrine of internal secretions, never even used these terms." 3. Since the time of Brown-Sequard everything has been changed. The notion of internal secretions has spread every- 29 Several years later this experiment was carried out by Gr. Vassale and myself, independently of one another. 80 E. Gley, "Essais de philosophic et d'histoire de la biologie, " p. 255, Paris, Masson and Co., 1900. CONCEPT OF SECRETION 51 where, is understood and accepted throughout, although its significance has changed in some respects. It is, in fact, possible that Brown-Sequard retained the conception introduced into science by Claude Bernard; namely, the realization that the glands "without external secre- tion ' ' have a special influence on the blood, inasmuch as they secrete substances neces- sary to its constitution; he even adds that the tissues play this role of "blood modi- fiers." But he did not stop at this point. By his experiments on the therapeutic action of testicular extract, 31 and by the generalization he induced concerning the ■ Brown-Sequard, "Des effets produits chezl'homme par des injections sous-cutanees d'un liquide retire des testicules frais de cobaye et de chien. " (C. B. de la Soc. de biol, June 13, 1889, XLI, pp. 415-449) ; "Second note sur les effets produits chez l'homme par des in- jections sous-cutanees d'un liquide retire des testicules frais de cobaye et de chien" (Ibid., pp. 420-422). The origin of Brown-Sequard 's researches on the thera- peutic effects of extracts of the genital glands is to be found in these two initial communications which were received with derisive skepticism. 52 THE INTERNAL SECRETIONS analogous action of other organic extracts, he was led to the idea that many organs secrete into the blood principles which have the property of acting in an elective manner on neighboring or distant organs. "We have called attention . . ."he says, "to a new method of therapy which con- sists in the use of subcutaneous, intraperi- toneal or intravenous injections of special principles obtained by the maceration . . . of one or another of the glandular organs of the body. We find in a note relating to our communication published by M. Gley facts confirming our ideas on one of the vascular glands, the thyroid. . . . "All the tissues, in our opinion, modify the blood by an internal secretion taken up by the venous blood. From this conclusion it necessarily follows that, if the subcuta- neous injection of the juices extracted from these tissues produces only inadequate ef- fects, it is necessary to inject the venous blood of these parts under the skin. . . . CONCEPT OF SECEETION 53 "We admit that each tissue and, more generally, each cell of the organism, se- cretes for its own use special products, or ferments, which are poured into the blood and which influence, through the inter- mediary agency of this liquid, and not through the mechanism of the nervous sys- tem, all the other cells, thus rendering all of them mutually interdependent. ' ' 32 The last sentence is characteristic and contains the germinal form of the entire theory of functional correlations of humoral origin, or of a chemical nature, as we say to-day. "These particular soluble products," writes Brown-Sequard further, 33 "pene- trate into the blood and influence, through the intermediary action of this liquid, the 82 Brown-Sequard and D'Arsonval, "Additions a une note sur 1 'injection des extraits liquides de divers organs comme methode therapeutique" (C. E. de la Soc. de bioh, April 25, 1891, XLIII, 265-68). 33 Brown-S£quard and D 'Arsonval, ' ' Eecherches sur les liquides retires des glandes et d'autres parties de l'organisme et sur leur emploi, en injections sous- cutanSes comme methode therapeutique" (Arch, de physiol, 1891, 5th series, III, 491-506; see p. 496). 54 THE INTERNAL SECRETIONS other cells of the anatomical elements of the organism. The result of this is that the various cells of the economy thus form a solidarity, and this is accomplished by a mechanism other than that of the nervous system." "All the tissues — glands or other organs — have special internal secre- tions and thereby give to the blood some- thing other than the products of their nutritive disassimilation. The internal se- cretions, either by a direct favorable influ- ence, or by preventing the occurrence of noxious reactions, seem to be of great value in maintaining the organism in its normal state. ' ' 34 Brown-Sequard added to the doctrine of Claude Bernard the notion of the action of "specific substances" secreted into the blood-stream by the various organs and, as a consequence of this, the no less impor- tant concept of functional humoral corre- lations. This greatly enriched the theory 8 * Arch, de physiol., 1891, 5th series, III, 506. CONCEPT OF SECRETION 55 of internal secretions. And hence the reason why Brown-Sequard is called the founder of the doctrine of internal secre- tions. It is certain that, had the concept of internal secretion not already existed, these new ideas, as I have already men- tioned, 35 could never have come to life, and from this point of view there is a direct connection of Claude Bernard to Brown- Sequard, but the latter certainly discov- ered something new ; he took a long stride in advance, a step in the determination of the causes of the functional mechanism. Certainly, the study undertaken by him on the dynamogenic influence of testicular extract is imperfect — I showed why in 1897 36 — and does not constitute a good ex- ample of the action of these "special inter- nal secretions" whose importance he fore- saw. ^"Traite Slementaire de physiol.," p. 1143, Paris, 1900. 88 Loc. cit., Annie biologique. 56 THE INTERNAL SECRETIONS This example was soon furnished by the researches of Gr. Vassale (1890) and Gley (1891) 3T on the amelioration of the grave disorders resulting from complete thy- roidectomy in the dog by injections of thy- roid extract, as well as the application of this method to the treatment of myxe- dema (by G. R. Murray, 1891, followed by many other physicians). It was then no longer possible to doubt the sound founda- tions of Brown-Sequard's views on the role of internal secretions in "maintaining the normal state of the organism," or in reestablishing that normal state when it is altered by disease. This was the more 87 1 will avoid overburdening these pages with biblio- graphical notes by advising the reader to refer to A. Biedl's work — capital for the study of the internal secretions — where they will be found easily ("Innere Sekretion," Berlin and Vienna, Urban and Schwarzen- berg, 1910; 2nd Ed., 1913), or also two articles by Swale Vincent, "Innere Sekretion und Driisen ohne Ausf uhrungsgang " (Ergebnisse der Physiol., 1910, IX, pp. 455-586, and 1911, XI, pp. 218-327). I will naturally give references which are not given in these two bibliog- raphies or which are not easy to discover there rapidly. CONCEPT OF SECRETION 57 strongly established several years later when there appeared the experiments of G. Glover and E. A. Schafer (1894-1895) which immediately attracted attention. Also the work of N. Cybulski and Szmono- vicz (1895), J. P. Langlois (1897), W. H. Howell (1898), etc., on the action of supra- renal extract on the cardiovascular sys- tem; those of N. Cybulski (1895), J. P. Langlois (1897), A. Biedl (1898), G. P. Dreyer (1899), etc., on the action of the venous blood of the suprarenal capsules and the numerous observations relative to the reduction in the intensity of metabolism in myxedema, or conversely, the increase in the metabolic activities of the body un- der the influence of preparations of thy- roid extract or iodothyrin. Finally, it is of importance to recall that at the time when Brown-Sequard, in 1889-1890, was giving such an impulse to the theory of internal secretions, J. von Mering and 0. Minkowski discovered the important role 58 THE INTERNAL SECRETIONS that the pancreas plays in the metabolism of sugar, and many immediately attacked the problem from other angles and showed that these changes in the carbohydrate metabolism are due to an internal secre- tion of the pancreas (R. Lepine, 1889, 1891 ; 38 E. Gley, 1891 ; 39 E. Hedon, 1892 ; 40 Vaughan Harley, 1892 ; 41 0. Minkowski, 1892; 42 J. Thiroloix, 1892 43 ). 3S B. Lupine, "Nouvelle theorie du diabete" (Lyon mid., Dec. 29, 1889, LXII, p. 621); "La pathogenie du diabete" (Bevue scient., Feb. 28, 1891, p. 273); "Sur la question du ferment glyeolytique " (C. B. de la Soc. de oiol, April 25, 1891, XLIII, 271). Lepine was the first to write the words "pancreatic internal secretion. ' ' 39 E. Gley, "Sur les troubles consecutifs a la destruc- tion du pancreas" (C. B. de I' Acad, des sc, April 6, 1891, CXII, 752); "Les decouvertes recentes sur la physiol. du pancreas" (Bev. gen. des sc., July 30, 1891, 469-76). 40 E. Hedon, "Diabete experimental" (Nouveau Montpelier med., Jan. 2, 1892, p. 27). 41 V. Haeley, "Pathogenesis of Pancreatic Diabetes" (Brit. Med. Jour., Aug. 27, 1892). a Berl. Min. Wchs., Feb. 1, 1892. 43 J. Thieoloix, "Etude sur les effets de la suppres- sion lente du pancreas" (Mem. de la Soc. de biol., Oct. 22, 1892, XLIV). CONCEPT OF SECRETION 59 I have therefore not exaggerated the part played by Brown-Sequard in repre- senting him as one of the founders and the resurrector of the theory of internal secre- tion. Such is also the opinion of numer- ous physiologists. I will only quote that of Biedl, one of those who has studied the question most completely: "In establish- ing the doctrine of internal secretions, Brown-Sequard has opened to physiology a new and fertile field of research, he has paved the way to the comprehension of many morbid disorders and has shown us a method of therapeutics which is both ra- tional and, in many cases, remarkably suc- cessful." 44 III. THE PRESENT CONCEPTION OP INTERNAL SECRETION From the initial works which followed the publications of Brown-Sequard from 1889 to 1891, it was easy to see how rapidly **Loc. cit., p. 6. 60 THE INTERNAL SECRETIONS the notion of specific functional excitants of glandular origin would develop. The original idea of Claude Bernard, that of glandular products modifying the compo- sition of the blood, on the contrary, made no progress at all. 45 The ideas of Brown- Sequard having been experimentally veri- fied, as he had foreseen, are taking posses- sion of physiology and penetrating into pathology. It may be said that these ideas have not as yet been set forth with great precision and that they lack the neces- sary support of numerous and thoroughly studied facts. But they are quickly ac- quiring this precision while facts are rap- idly accumulating which give them both "It might be maintained — though vainly — that the two ideas can be confused, in the sense that from the passage into the blood of active specific products com- ing from certain glands, there would result an actual modification in the composition of this liquid. However, Claude Bernard's sole idea seems to have been that this modification is of a chemical nature. The new notion, since added, is that of the specific, elective power of various products of glandular origin. This is properly a physiological idea. CONCEPT OF SECRETION 61 solidity and a wide scope. And the new knowledge is of an entirely new sort. "What there is characteristic about this," I said in 1897, 46 "is that we are now deal- ing with functional actions which have neither cause, nor reason, nor an end of their own; but each one of these acts de- pends on another physiological action, and this dependence appears to be always of a chemical nature, be it direct or indirect, being accomplished through the intermedi- ary action of the nervous system. It is found, for example, that a substance formed at a certain point in the organism is of such composition that it constitutes the excitant adapted to stimulate action in another organ." The same year, in the re- port that I was charged with presenting to the XII International Congress of Medi- cine, at Moscow, on the pathological physi- ology of myxedema, I wrote: "Nothing can convince us that iodothyrin has not a * L'AnnSe bid., p. 330. 62 THE INTERNAL SECRETIONS direct influence on the metabolism. If, therefore, the thyroid gland, atrophied or attacked by some form of degeneration, no longer secretes that substance, nutritional disorders promptly follow, due only to the organism's lack of a principle which nor- mally augments the intensity of the meta- bolic processes. And thus the regulation of the intracellular chemical phenomena appears to us as possibly of a directly chemical nature. There exist substances which enhance, others that moderate, these phenomena. Through the elective action of these bodies, nutritional equilibrium must be mechanically arrived at. Iodo- thyrin is one of these substances. . . . Are not the ferments secreted by the pancreas, which regulate the production of sugar by the liver and the oxydizing ferments . . . similar substances, acting in the same di- rect manner on the anatomical elements? . . . Furthermore, are there not still other substances, as the one, probably from the CONCEPT OF SECRETION 63 genital organs, which, according to the in- genious experiments of Mironoff, stimu- lates the secretion of milk at the necessary time, independently of all action of the nervous system?" Two years later, in 1899, I qualified with "specific glandular products" the "substances which result from the normal activity of many glands and which appear to play a considerable part in the regulation of the circulation. . . . Many have in fact been led, since we have understood the great importance of the internal secreting glands, to investi- gate if small quantities of the products of these glands, which pass at different times or continuously into the blood, do not ex- ercise a more or less important influence on the vasomotor centers. ". . . The fact that substances of gland- ular origin, endowed with a stimulating or depressing cardiovascular action, are normally found in the blood, shows that they play an important part in the regula- 64 THE INTERNAL SECRETIONS tion of the blood pressure ; and as the ac- tivity of the glandular organs often varies in an abnormal manner, being either exces- sively increased or diminished and some- times even suppressed, the regulation of the circulation may be proportionately dis- turbed. Herein lies an indispensable labor to be undertaken; namely, the determina- tion of the relations which exist between the normal variations of the circulation, and more especially between the blood pressure and functions of the glands like the adrenals, the thyroid, etc., the quantity of active principles they send out at vari- ous times or continuously into the blood, and the conditions which are antagonistic to the action of these substances. . . . "From all these facts it follows that the tone of the muscles of the blood vessels, in so far as it depends on an automatic stimu- lation, either direct or indirect, is main- tained not only by nervous stimulation, va- riations in the gases contained in the blood CONCEPT OF SECRETION 65 and by the products of the katabolic proc- esses, but also by specific substances nor- mally formed in various glands. " 47 To specific functional excitants in general, Starling gave, in 1905, the happy name of hormones (from op/xaw, I excite). The notion of specific functional exci- tants, or hormones, led quite naturally to that of functional correlations of humoral cause. Because these same "special solu- ble products, ' ' as Brown-Sequard said, are poured into the blood and "influence the other cells of the organism," these cells "are thus rendered into a solidarity — act- ing in unison — and by some mechanism other than the action of the nervous sys- tem" (Brown-Sequard, see above). Many occupied themselves with determining these functional correlations of a chemical nature, connecting them with one another 47 E. Gley, "Meeanisme physiologique des troubles vasculaires" (in "Traite de Path, gen." by Ch. Bou- chard, III, 133-211; see pp. 165-172). 66 THE INTERNAL SECRETIONS and at the same time differentiating them from the correlations of nervous origin, al- ready studied for many years. It was also recognized that there are still others, which form an intermediary class, the neuro- chemical correlations, or functional mani- festations provoked by nervous action, this nervous action determining a chemical ex- citation which is carried to some part of the nervous system. 48 During this time investigations followed one another, in which facts relative to the internal secretions and the action of these on the organism and its functions were ex- amined and classified. In proportion as they multiplied, the facts assumed their true value and their meaning became more precise. 49 48 This is the classification which I presented to my classes of 1908-1909 in the College of France and that I have adopted for the outline study of functional cor- relations that is given in my "Traite elementaire de physiologie," Paris, 1906-1909, p. 1142; 2nd Edit., 1910, p. 1167; 3rd Edit., 1913, p. 1181. **It would not be out of place to cite here the first CONCEPT OF SECRETION 67 While the work on functional correla- tions just indicated was being carried out, of these studies as well as the most important of those which were published later: E. Abelous, "La physiologie des glandes a secretion interne, corps thyroide et capsules surrSnales" (Bevue gin. des sc, May 15, 1893, IV, 273-278) ; E. Hedon, "Les travaux regents sur la physiol. des glandes vascu- laires sanguines" (Nouveau Montpellier Medical, 1893, II, 467-468) ; E. A. Schafer, "On Internal Secretions" {Lancet, Aug. 10, 1895, 321-324); E. Gley, "Expose des donnees experimentales sur les correlations fonc- tionelles chez les animaux" (L' Annie biol., 1897, I, 313- 330) ; " Le neo-vitalisme et la physiologie g^nerale ' ' {Bevue scient., March 4, 1911, 257-265) ; W. H. Howell, "Internal Secretions Considered in their Physiological, Pathological and Clinical Aspects" (Trans, of the Congress of American Physicians and Surgeons, 1897, IV, 70-86); H. C. Wood, "The Ductless Glands" (Amer. Journ. of Med. Sc, 1897, CXIII, 505- 13); Francis P. Kinnicutt, "The Therapeutics of the Internal Secretions" (Ibid., 1897, CXIV, 1-23); James P. Putnam, "The Clinical Aspects of the 'Internal Secretions' " (Ibid., 1898, CXV, 31-49); H. Boruttau, "Tiber den jetztigen Stand unserer Kentnisse von den Functionen der Blutgef assdriisen " (Deutsch. med. Woch., Sept. 21, 1899, XXV, 625-27) ; E. de Cyon, "Les glandes regulatrices de la circulation et de la nutrition" (Bevue gin. des sc, Sept. 30, 1901, XII, 828-35); "Die Gefassdriisen als Regulatorische Schutzorgane des Zen- tralnerven systems, " Berlin, J. Springer, 1910; A. Biedl, "Innere Sekretion" (Wiener Klinik, 1903, XXIX, 281-283); "tiber innere Sekretion" (Verhandl. 68 THE INTERNAL SECRETIONS the nature of the humoral excitants was more completely determined. der Gesellschaft deutscher Natur for scher und Aertzte, 1911); C. E. de M. Sajous, "The Internal Secretions and the Principles of Medicine," Philadelphia, 1903; G. Coronedi, ' ' Secrezioni interne e loro chimismo" (Arch, di fisiologia, 1904, II, 36-59); W. M. Bayliss and E. H. Starling, "The Chemical Correlation of the Secretory Process" (Proceedings of the Royal Soc, 1904, LXVII, 310-322); E. H. Starling, "The "Chemi- cal Correlation of the Functions of the Body," Croonian Lectures, June, 1905 (The Lancet, 1905) ; A. Magnus- Levy, " Organ therapie und Innere Sekretion" (Berlin, 1906, pamphlet of 40 pages); "Der Stoffwechsel bei Erkrankungen einiger Driisen ohne Ausfuhrgang" (in "Handbuch der Pathol, des Stoffwechsels, " 1907, II, 311-354); Swale Vincent, "Internal Secretion and the' Ductless Glands" (Lancet, August 11 and 18, 1906); "The Ductless Glands" (Science Progress, January, 1909); L. Fredericq, "De la coordination organique par action chimique" (Scientia, 1909, vol. V, Third year) ; L. Hallion, ' ' Les f onctions de secretion in- terne" (Bevue scientifique, May 8, 1909, 583-588); C. Parhon and M. Golstein, "Les secretions internes" (Paris, A. Maleine, 1909) ; A. Pi y Suner, " Correlationes fisiologicas " (Association espanola para el progreso de las sciencias, Valencia, 1910); S. J. Meltzer, "Animal Experimentation in Eelation to our Knowledge of Se- cretions, Especially Internal Secretions" (Proc. of the Pathol. Soc. of Philadelphia, Sept., 1910, N. S., XIII, 170-196); I. Ott, "Internal Secretions from a Physi- ological and Therapeutic Standpoint" (Philadelphia, E. D. Vogel, 1910); G. Fano, "La coordinazione umorale" CONCEPT OF SECRETION 69 "The exciting substances mentioned," says, for example, Starling, 50 "so far as they are known to us, are not assimilable and exert a dynamic influence on the liv- ing cells. In this respect they are analo- gous to substances which form the usual remedies of our pharmacopeias. Since it is their role to be frequently excreted, in virtue of a normally organic function, into the circulatory system by which they are conducted to each of the organs on which they exercise their specific action, they can- not therefore belong to that class of com- plex compounds, animal or vegetable in (Atti delta Soc. Italiana por il progresso delle sc, Naples, Oct., 1910) ; R. G. Hoskins, ' ' The Interrelation of the Organs of Internal Secretion ' ' (Amer. Jour, of Med. Sciences, March and April, 1911). For original views or remarks filled with new in- formation, see above all the works of Bayliss and Starling, E. de Cyon, G. Fano, E. Gley, S. J. Meltzer and E. H. Schafer. To this list must naturally be added Biedl's book and Swale Vincent's two studies (in "Ergebnisse der Physiol."), mentioned above. 00 Address delivered at the meeting of the Gesellschaft Deutscher Naturforscher und Aerzte, Stuttgart, 1906. 70 THE INTEENAL SECRETIONS origin, which we term toxins." And through the study of the remarkable prop- erties of several of these exciting sub- stances (Reizstoffe, hormones), as for ex- ample the active principle of thyroid, — iodothyrin 1 — adrenalin and secretin, physi- ology has discovered an entirely new field of investigation, which is as yet far from being completely explored. Pathology did not fail to participate con- siderably in all these researches and the progress of our knowledge of the endo- crine glands. Some important contribu- tions by pathologists helped directly in the upbuilding of the doctrine of internal se- cretions. Let us but recall what those who labored to raise this doctrine obtained from the observations of Lancereaux (1877-79) on the pancreas in diabetes and the pro- found studies of diabetes in its relations to lesions of the pancreas, beginning with the researches of J. von Mering and Minkow- ski (1889-90) ; from the comparison (P. CONCEPT OF SECRETION 71 Semon, 1884) between the description of the clinical phenomena of myxedema made by English clinicians, and the obser- vations of Swiss surgeons, J. and A. Rev- erdin, Kocher, on post-operative myxe- dema, as well as the effects of thyroid med- ication on this syndrome ; from the patho- logical anatomy of acromegaly; from Ad- dison's disease and the study of the toxic effects of adrenalin, etc. What a light is thrown by physiological experiments on all these clinical and anatomo-pathological facts, and how, reciprocally, the latter strengthen the conclusions arrived at through animal experimentation! Medi- cine has drawn its profits from this co- operation of physiology and pathology: hemophilia is explained; many of the anomalies of growth are also elucidated; the pathogeny of diabetes is cleared up; the pathology of the thyroid apparatus has been worked out; that of the hypophysis and thymus undertaken with success; the 72 THE INTERNAL SECRETIONS discovery and definition of new syndromes in which the suprarenal capsules or repro- ductive glands are concerned. Such is the sum total of the main acquisitions acquired through this work. "The following two factors," Meltzer says rightly, 51 "are re- sponsible, I believe, for the marvelous progress of this new branch of experimen- tal medicine. In the first place, the recent investigations on the ductless glands were carried out purely by biological methods of research. The second factor is to be found in the important fact that these in- vestigations had the great advantage of an harmonious cooperation of critical ani- mal experimentation, scientific clinical ob- servations and the intelligent analysis of surgical results." There is an underlying reason for this cooperation, which I re- called in my Report on Myxedema at the XII International Congress of Medicine at Moscow, to wit: "For the savant," as "Loc. tit., p. 171. CONCEPT OF SECEETION 73 Claude Bernard said, " neither medicine nor physiology is distinct; there is only one science of life, there are only the phe- nomena of life which must be explained, in the pathological state as well as in the physiological." 52 "Claude Bernard, "Introduction a l'etude de la medecine experimental, ' ' p. 257, Paris, 1865. n DISTINCTIVE CHARACTERISTICS OF THE INTER- NAL. SECRETORY GLANDS AND THE PRINCIPAL. PRODUCTS OF THEIR ACTIVITIES II DISTINCTIVE CHARACTERISTICS OF THE INTER- NAL SECRETORY GLANDS AND THE PRINCIPAL PRODUCTS OF THEIR ACTIVITIES Knowledge of the nature and functions of the internal secretory glands can only be based on the precise determination of the conditions which make of these glands a special system, and then on the discov- ery of the distinctive characteristics of the products resulting from the activities of these organs. Herein lies the primary and fundamental problem. I. CONDITIONS ESSENTIAL TO INTERNAL SECRETION Three conditions suffice to determine an internal secretion as such, but these three conditions are absolutely necessary: The 77 78 THE INTERNAL SECRETIONS first is of an histological nature ; the second results from chemical considerations; and the third is of a physiological order. That is, the cells of the vascular glands in ques- tion must present the characteristics of granular elements and these elements must be in close relation to the efferent vessels of the organ; in these cells and in the venous blood of the gland or in the efferent lymph, a specific substance must" be chemically determined; finally, the ve- nous blood of the gland must have the physiological action and properties of this specific substance. 1 Undoubtedly, for many of the organs in- cluded among the endocrine glands, all 1 For technical reasons which are easily understood, the investigation of specific products in the lymph is even more difficult than in the blood. Up to the present, we have only been able to determine the presence of specific substances in the venous blood of some glands; on the other hand, the attempts that it has at times been possible to make on the lymph have always resulted negatively. (A. J. Carlson and A. Woelfel, "On the Internal Secretion of the Thyroid" (Amer. Jour, of Physiol, 1911, XXVI, 32-67); A. J. Carlson and F. CHARACTERISTICS OF GLANDS 79 these conditions have not been satisfied. Several of the latter category are, however, most certainly such glands, even to the most exacting critic. In the case of these glands, in lien of all the conditions men- tioned above, we have a collection of facts which permits us to recognize them as en- docrine glands. In science as in all human activities, we cannot always follow implic- itly the dictates of logic. No one would think, for example, of contesting the right of the thyroid gland to a position among the endocrine glands, although there has not as yet been discovered in the venous blood of that organ any specific chemical or physiological property (Carlson, Cor- onedi, Cunningham, 2 Gley). But so spe- M. Drennan, "The Alleged Discharge of the Internal Secretion of the Pancreas into the Lymph" (Proc. of the Soc. for Exper. Biol, and Med., 1914, XI, 71-72). This, however, is no reason why we should not recog- nize, as does R. Lepine (Revue de Medecine, Feb. 10, 1914, XXXIV, p. 81-88), that it would undoubtedly be interesting to undertake studies of this sort. * Cunningham has unsuccessfully used as much as 30 80 £HE INTERNAL SECRETIONS cific are the effects of extirpation of this organ and so characteristic is the action of thyroid extract in counterbalancing the harmful effects of this deficiency, that we are forced to admit that substances con- tained in thyroid extract have an elective influence on the internal medium. 3 By an analogous, but not as yet so well founded, compromise, we are led to con- sider the spleen and the thymus as internal secretory organs, the reasons being purely physiological : The spleen because it fur- nishes the blood passing through it with a substance which transforms trypsinogen into active trypsin, as was shown by the experiments of A. Herzen (1888, 1893) ; 4 to 50 cc. of thyroid venous blood for the investigation of an action on the arterial pressure. Further mention of this work of Cunningham will be found on p. 216. 3 See also p. 111. 4 A. Herzen, "Appunti di chimiea fisiologiea" (An- nali di chim. med. e farm., 1888, VIII, IV series, Tor- ino) ; "Rate et Pancreas" (C. B. de la Soc. de biol., July 29, 1893, XLV, pp. 814-817). Herzen's opinion finds support in the experiments of Lafayette B. Men- del and Leo F. Rettgeb, (Am. Jour, of Physiol., 1902, CHARACTEEISTICS OF GLANDS 81 the thymus because its extirpation results in disordered development of the skeleton (experiments of K. Basch, 1896; Cozzo- lino, 1903; Sommer and Floerken, 1908; Ugo Soli, 1909 ; M. Lucien and J. Parisot, 1910) ; and, furthermore, because in cas- trated animals the thymus is larger (A. Calzolari, 1898 ; 5 J. Henderson, 1904; Ugo Soli, 1906 and 1909), while in animals whose thymus has been removed, the develop- ment of the male genital glands is arrested (Ugo Soli, 1909 ). 6 But the spleen and the thymus are neither histologically nor em- VII, 387-404), who have stated that injections of splenic venous blood increase the proteolytic power of the pan- creas. The defibrination, it is true, might be a cause of error, if we admit that the destruction of the leuco- cytes liberates kinase. But this objection can be an- swered by recalling Gachet's experiments (in Paehon's laboratory, These, Bordeaux, 1897) — which were nega- tive — with defibrinated arterial and venous blood. 8 The thymus, according to Calzolari, diminishes in weight at puberty, when the generative organs begin to function. 9 Noel Paton (1904) has obtained results which are the reverse of these; that is, an increase in weight of the testicles after thymectomy. 82 THE INTERNAL SECRETIONS bryologically glandular organs; they are hemolymphoid in nature. With this reser- vation, we may state that they discharge into the blood products akin to the internal secretions. (1) Histological Conditions. — Al- though without any relation to the ex- terior, being without excretory ducts, the glands called vascular, internal secretory or endocrine, are penetrated by numerous blood vessels with which their cellular ele- ments are in intimate connection and into which they deposit their secretion. Exceptions are the liver and the pan- creas, which are provided with excretory canals, but which are also glands of inter- nal secretion; their cells, so to speak, are pointed in two directions, towards the ex- cretory canals and towards the blood ves- sels. We find the same double orientation in the duodenojejunal mucous membrane, the cells of which discharge a digestive juice CHARACTERISTICS OF GLANDS 83 into the intestinal cavity, i.e., to the ex- terior, but they also, under certain con- ditions with which we are thoroughly ac- quainted, deliver to the blood the sub- stance which stimulates the pancreas to se- cretion, namely, secretin. Moreover, we may remark that it is not as yet known definitely how secretin is formed and whether this substance is really a product of glandular origin. Furthermore, it is not only in its role of secretin producer that the pancreas behaves like an endo- crine gland; it is also an absorbing organ. The histological process of the absorption of fats consists in intraprotoplasmic elabo- ration; in other words, it is a secretory process, and perhaps this is no less true of the absorption of albuminoid substances. These are the products of the decomposi- tion of those materials which reach the in- testinal mucous membrane on its free side, and the cells of this membrane deliver, by 84 THE INTERNAL SECRETIONS their internal side, fats and perhaps also albuminoids to the blood. It is also not without reason that R. Heidenhain, Oppel, Pfluger and others have compared the phenomena of absorp- tion to those of secretion. In fact, as sev- eral histologists have shown, the epithelial layer of the intestine behaves like a true granular element; it is a "granular ele- ment with two surfaces," physiologically speaking. Through its cavitary, or exter- nal, surface, it receives and elaborates the materials to be absorbed; through its in- ternal side pass out, after having been elaborated, the materials which then pass into the vascular or lymphatic circulation. These two acts undoubtedly take place, re- spectively, in the supranuclear and infra- nuclear zones of the cell. The physiologi- cal polarity of the cell imputes a morpho- logical bipolarity and also the presence, in both zones alike, of the organisms indis- pensable to glandular secretion. This ap- CHARACTERISTICS OP GLANDS 85 pears to be verified by the observation which shows the same mitochondrial for- mations in both zones, while the ordinary glandular cell is only provided with one of them. (Champy. 7 ) Absorption is thus only a particular case of the general proc- ess of secretion. And the essential re- sult of this secretion — the formation and passage into the blood of the specific al- bumins of the plasma 8 — is of the highest importance. "We may say," Champy re- marks 9 ' ' that the intestinal epithelium se- cretes the plasma, — the internal medium, — or at least the principal part of it, and it is indeed the most highly differentiated se- cretion of the organism, for this internal 7 A. Peenant and P. Bouin, "Traite d 'histologie, ' ' vol. II, p. 823, Paris, 1911. 8 It is known that the role of the intestinal wall in the formation of the proteid substances of the blood plasma can not actually be considered as beyond ques- tion. 8 Ch. Champy, ' ' Kecherches sur 1 'absorption intestinale et le role des mitochondries dans 1 'absorption et la secretion" (Arch, d'anat. microscopique, 1911, XIII, 55-170). 86 THE INTERNAL SECRETIONS medium is to the highest degree specific." There are, therefore, glands with a double secretory function, external and in- ternal. We can make still another distinction between the various endocrine glands, and one which is not devoid of interest from the point of view of the physiological sig- nificance of these organs. It has been dem- onstrated that the cells of the choroid plexuses are granular cells the activity of which regulates the composition of the ce- rebrospinal fluid, 10 contained in the cere- 10 J. W. Findlay, "The Choroid Plexuses of the Lat- eral Ventricles of the Brain, Their Histology, Normal and Pathological" (Brain, 1897, XXII, 161-203); J. Galeotti, "Studio morfologico e citologico della volta del diencefalo in alcuni vertebrati" (Biv. di patol. ner- vosa e mentale, 1897, ii, 480-517) ; H. Obeesteiner, "Anleitung beim Studium des Baus der nervosen Cen- tral-organe im gesunden und kranken Zustande, " Fourth edition, pp. 651-53. Leipzig and Vienna, 1901 ; A. Pettit and J. Gieard, "Processus secretaires dans les cellules de revetement des plexus choro'ides des ventricules lat- eraux, consecutifs a 1 'administration de muscarine et d 'ether" (C. B. de la Soc. de Uol., July 27, 1901, LIII, 825); "Sur la fonction secretaire et la morphologie des CHARACTERISTICS OF GLANDS 87 bral ventricles and in the central canal of the spinal cord. And it is known, further- more, that the cerebrospinal fluid thus formed returns to the blood by the peri- vascular sheaths (lymphatic path) and the blood vessels of the dura mater. This cerebrospinal fluid, first secreted into an exterior cavity, and then reabsorbed, is an example of an externo-internal secretion; and it might be said that the choroid plexuses are glands of external secretion, but having an internal destination (A. Pet- tit and J. Girard). 11 Conversely, there are internal secretory glands having an external destination, or, in other words, there are interno-extemal secretions. 12 A typical member of this last plexus choroides des ventricules lateraux du systeme nerveux central" {Arch, d'anat. microscopique, 1902, V, 213-264) ; F. K. Studnicka, ' ' Unters. iiber den Bau des Ependyms der nervosen Centralorgane " (Anat. Hefte, 1900, pp. 303-431). u This means that the secretion, made on the exterior, is intended to be reabsorbed. 12 Biedl has used a somewhat indefinite name — negative 88 THE INTERNAL SECRETIONS class is urea, formed in the liver, excreted into the blood and taken up by the kid- neys to be eliminated to the exterior. Such also are the phenylsulphates, if we admit that they are formed in the liver; there are also substances excreted into the he- patic blood and intended for ultimate renal excretion. No matter which gland is in question, whether properly internal or mixed (having a double secretion, inter- nal and external), or a transitory external secretion (an external secretion having an internal destination, mentioned above), or a transitory internal secretion (finally des- tined for the exterior), there is not one with cellular elements which can not be characterized as glandular. In all these cells the nucleus and a part of the proto- plasm (upper mitochondrial protoplasm, or ergastoplasm) participate in the elabo- ration of the secretory products in the internal secretion — for such a secretion. Swale Vincent has also used this terminology. CHAEACTERISTICS OF GLANDS 89 same manner as in the cells of the glands that have been best studied histologically. In brief, it is the morphological condi- tion — cellular structure and relations of the cells to the blood vessels — that is best satisfied by the endocrine glands. (2) Chemical Condition. — Every product of secretion is a cellular differen- tiation, the morphological expression of a chemical elaboration. This differentiation is a result of cytoplasmic activity; the product must be recognizable by certain chemical characteristics, both in the glan- dular cell itself and outside of it. This means, in the case of an internal secretion, which is what we are primarily concerned with at present, that the products of se- cretion must be found in the efferent blood of each gland. The presence of the products of secre- tion in the glandular cells has only excep- tionally been demonstrated. It has been shown, indeed, that there are fat globules 90 THE INTERNAL SECRETIONS in the intestinal cells and in the cells of adipose bodies, 13 and that adrenalin exists in the suprarenal cells ; in the thyroid cells, it is true, the presence of a complex product of colloid matter has been demon- strated, but do we know if this colloid mat- ter contains only the active principle of the secretion, or if it contains at all the active principle 1 ? Likewise, only in a small number of in- stances have the specific principles of the endocrine glands been identified chemically "Although the adipose bodies are not made up of epithelial cells, the adipose cell is nevertheless a glandu- lar cell and has the closest connection with its capillary plexus. This undoubtedly explains the ease with which deposits of fat are accumulated when the organism has need of them, as, for example, in jaundice. The follow- ing observation furnishes a very clear proof of this fact and at the same time of the glandular nature of adi- pose bodies: Prenant has seen mitochondria formed in three days throughout the protoplasm in the cells of adipose bodies in the nape of the neck of kittens ren- dered athreptic by defective alimentation; the cell was thus brought back to its initial condition and all the fat disappeared from it, being collected in the vessels. (Prenant told me this interesting fact by word of mouth.) CHARACTERISTICS OF GLANDS 91 in the venous blood of a given internally secreting organ. Fatty bodies have been found and even quantitatively determined in the veins of the intestine and in the tho- racic duct ; in the blood of the hepatic veins glycose and urea have been found, and in the blood of the suprarenal vein, adrena- lin. Numerous chemical investigations of the products of internal secretion are in prog- ress at the present time. This research must ultimately lead to the determination of what these substances are, what is their nature and therapeutic value. In fact, with the exception of the products which serve as nutritive materials (glycose, fats, spe- cific albumins), the products intended for excretion (as urea) and finally adrenalin, our knowledge of the chemical properties of these bodies is very limited. The most in- teresting from this point of view, as well as from the physiological standpoint, appear to be the bodies of synthetic intracellular 92 THE INTERNAL SECRETIONS origin, as adrenalin. Bnt, for the present moment, this is the only one known; in spite of the efforts of A. Ostwald, of Zu- rich, we are not yet sure if his iodothyro- globulin is the active principle of the thy- roid gland. Likewise, the chemical nature of secretin is as yet unknown. (3) Physiological Condition. — That the physiological condition be fulfilled, we must find a specific substance in the ef- ferent blood of a gland, as demonstrated by the physiological properties of this blood, collected and injected in variable quantities into another animal. Further- more, this specific substance must remain for a sufficient period of time in the gen- eral circulation, since, to reach a more or less distant organ on which it acts, it is necessary, at least in the majority of cases, that the active product secreted passes with the efferent blood of the gland into the blood of the general circulation. It is all the more necessary that its presence CHARACTERISTICS OF GLANDS 93 be speedily demonstrated, inasmuch as these glandular products, diffused through- out the blood stream, may very quickly lose their activity, either through exces- sive dilution, or as a result of a process of destruction as is the case, for example, with adrenalin (see p. 215). Their exist- ence in the general circulation may there- fore be so short, or they may be so minute in quantity, as to appear without any physiological significance. To this it could be objected, of course, that this sub- stance, soon after entering the arterial blood, does not remain there, but fixes it- self onto the organs on which it acts, this fixation being the condition for its action. Hence the difficulty of finding these sub- stances in sufficient quantity at a given moment in the arterial blood. One could, in any case — provided he was assured of their physiological destination — detect them in the blood of the left heart. Only the physiological destination of the se- 94 THE INTERNAL SECRETIONS creted product gives the true significance of a secretion (see p. 149). Now, in so far as the internal secretions are con- cerned, this destination is marked by the passage of a specific substance from the venous blood of the gland into the general circulation, and it is only the physiological properties of this venous blood, tempo- rarily acquired by the blood in general, that attest it. To recapitulate, the essential proof of an internal secretion — in addition to the clinical proof, when this is available (see below) — is the physiological proof, that is to say, the demonstration of the physio- logical properties of a specific glandular product transferred in a more or less dur- able form to the blood. This is, together with the chemical proof, whenever the lat- ter can be given, the essential proof of an internal secretion; and it is perhaps the most important for physiologists and pathologists. Far from having been fur- CHARACTEEISTICS OF GLANDS 95 nished for all the endocrine glands, its investigation, on the contrary, has been very much neglected. 1. The physiological demonstration has been given for the glands which elaborate the substances that modify chemical proc- esses and act in the manner of diastases. One of these substances, that derived from the spleen, serves to activate a ferment, 14 although the mechanism by which this is accomplished is not known; another, that derived from the pancreas, favors a proc- ess of assimilation, and we are still dis- cussing by what mechanism this takes " This interpretation is the result of the experiments of Pachon (of Bordeaux) and his pupil Gachet (1897). These experiments consisted essentially in watching the speed of digestion, which permitted the observers to note the differences between the activity of pancreatic extracts from animals whose spleen had been removed, and nor- mal animals. This also enables them to state with cer- tainty the activating property of splenic extract from an animal while digesting on pancreatic digestion. And these authors have also shown that the splenic substance endowed with such properties is a ferment. This was, therefore, the first example of one ferment having an activating influence on another. 96 THE INTERNAL SECRETIONS place; and a third, from the liver, plays the part of an antibody. Thus the experiments of Herzen and of Lafayette Mendel and Rettger have proven the influence of the blood of the splenic vein on the proteolytic activity of the pancreas. The role played by the pancreas as a gland of internal secretion was only ap- preciated as a consequence of experiments on extirpation of that organ; the only di- rect proof was furnished by experiments which I published in 1891 showing that the ligature of all the pancreatic veins was followed by glycosuria. But these experi- ments might be criticized because the dogs operated upon survived only for a limited term. The experimental grafting of the pancreas (0. Minkowski, Hedon, J. Thiro- loix, Gley and Thiroloix) supplied better demonstrations. We know, however, that Pfluger contested its significance in the last years of his life. Finally, there came the experiments of uniting two> animals, as CHARACTERISTICS OF GLANDS 97 jointed twins — parabiosis — made by J. For setback (1908-09). Two dogs were con- nected to one another, the pancreas being removed from one of them. It was found that the glycosuria which was induced in this animal remained very feeble as long as it was in symbiosis with the other. This was evidently because the substance secreted by the pancreas of the normal dog, and which acted on the assimilation of sugar, passed into the blood of the dog without a pancreas. However, it had first passed through the blood of the normal animal and was thus diluted ; hence the slight gly- cosuria. The same interpretation applies to the laborious experiments that Hedon has carried out with much perseverance during several years. Hedon saw, in fact (1909-1912), in experiments in which the circulations of diabetic and normal dogs were joined, a decided diminution of gly- cosuria taking place within several hours following the mixture of the blood of the 98 THE INTERNAL SECRETIONS two animals. Furthermore, he has stated 15 that the transfusion of pancreatic venous blood into the general circulation of a dia- betic dog, by anastomosis of a pancreatic vein with the jugular vein, considerably reduces the excretion of sugar in the de- pancreatized animal; and he has found (1911) that when venous pancreatic blood is injected into the mesenteric vein of a diabetic dog, the glycosuria of that ani- mal diminishes greatly for several hours. It is thus clear that the metabolic action of the pancreas on the sugar results from an internal secretion. The proof of the anticoagulative func- tion of the liver which was given by Gley and Pachon 16 has been completed and for- 15 C. B. de la Soc. Mol, Feb. 1, 1913, LXXIV, 238. "E. Gley and V. Pachon, "Du role du foie dans Paction anticoagulante de la peptone" (C. B. de I' Acad, des se., Aug. 26, 1895, CXXI, 383); "Influence de 1 'extirpation du foie sur 1 'action anticoagulante de la peptone" (C. B. de la Soc. de Mol, Nov. 23, 1895, XLVTI, 741) ; cf. also Arch, de physiol., 1895, 5th series, VII, 711-717, and 1896, VIII, 715-723. CHARACTERISTICS OF GLANDS 99 tified by the experiments of Delezenne. 17 They have demonstrated the presence in the venous hepatic blood of the anticoagu- lative substance which one can force the liver to produce in large quantities by the administration of various substances, such as albumoses, extracts of various organs, some serums and venens, etc. 2. In the case of the two hormones which we know best — secretin and adrena- lin — proof has likewise been given of the passage of these excitants into the venous blood of the organs that produce them. The experiments, as far as secretin is concerned, are not numerous, but we may safely consider them as sufficient. The 17 C. Delezenne, ' ' Formation d 'une substance anti- coagulante par circulation artificielle de peptone a travers le foie" (Arch, de physiol., 1895, 5th series, VIII, 655-668); "Kecherches sur le mScanisme de 1 'action anticoagulante des injections intravasculaires de peptone, de serum d'anguille et d'extraits d'organes" (in Travaux de physiol. du labor atovre du professeur Hedon, Montpellier and Paris, 1898, pp. 212-262; see page 241). 100 THE INTERNAL SECRETIONS presence of this excitant in the venous blood of a segment of the jejunum (Wert- heimer, 1903 ; 18 Fleig, 1903 19 ) and even in the general circulation (carotid blood, En- riques and Hallion, 1903) has been demon- strated. In the case of adrenalin the demonstra- tion is as perfect as is possible. Small doses of venous suprarenal blood manifest all the properties of suprarenal extract by their action on the sympathetic system and, furthermore, their action is indeed that of adrenalin itself. 20 According to my experi- ments, it is sufficient to inject 1 cc. in a kilogram weight of the animal, or even less — 0.7 cc. in some cases — into a dog to 18 It should be remarked, however, that Wertheimer's experiments were not carried out with the normal ex- citant of the duodenojejunal mucous membrane — hydro- chloric acid — which liberates the secretin of this mucosa, but with essence of mustard and with ether. 19 Fleig 's experiments were made with the use of hy- drochloric acid as the excitant of the mucous membrane. 20 1 do not think, however, that any one has as yet en- deavored to produce adrenalinic glycosuria by the injec- tion of suprarenal venous blood. CHABACTEBISTICS OF GLANDS 101 provoke a very pronounced cardiovascular reaction. As for the mammary hormone, the pres- ence in the blood of a substance exciting the secretion of milk has only been proven indirectly. First, by the experiments of MironorY, 21 which showed that after the section of all the nerves of the mammary gland in the she-goat, the breasts were nevertheless hypertrophied after the young had been brought forth ; they secreted like those of a normal animal. This fact was confirmed by the experiments of Eibbert (1897-98), which consisted in the trans- plantation of mammary gland tissue under the skin of the auricle of a female guinea- pig. The transplant took, developed and even secreted when the guinea-pigs were impregnated. 22 And it is also confirmed 21 M. Mironofp, ' ' De 1 'influence du systeme nerveux sur le fonctionnement des glandes mammaires ' ' (Arch, des sc. biol., 1895, III, 353-380). 23 These experiments have been successfully repeated on the bitch by K. Basch (Deutsche med. Woch., May 26, 1910). 102 THE INTERNAL SECRETIONS by observations on the Czech pygopagus monster, — the two connected sisters, Rosa and Josepha Blazek. When, three years ago, one of them, Rosa, became pregnant, twelve days after she had been confined the breasts of her sister Josepha were enlarged like hers and secreted milk at least as well as those of Rosa. 23 The origin of this substance that excites the secretion of milk — the galactogogue hormone — has not as yet been absolutely determined. It may come from the pla L centa (K. Basch, 1909; B. Aschner and Ch. Grigoriu, 1911), or from the myometrial glands of the uterus (Ancel and Bouin, 1911), or from the suppression of an in- hibitory stimulus of fetal origin, since al- though the development of the gland takes place during pregnancy, its secretion is not established till after the close of the gravid period, when the fetus is expelled. 88 C. Teunecek, ' ' L 'accouchement du pygopage Rosa- Josepha Blazek" (Semaine m6d., May 18, 1910, p. 229). CHARACTERISTICS OF GLANDS 103 This is the theory of Lane-Claypon and Starling. 24 In this uncertainty it would evidently be desirable that some one should discover in the venous blood of some organ the hormone which acts on the mammary gland. 25 That the waste products should play the part of excitants, they must be found in the venous blood of the organ which pro- duces them. This appears to be the case 34 The experiments of Lane-Claypon and Starling have not been confirmed in all points by C. Foa (Arch, di fisiologia, 1908, V, 520-532). The latter, moreover, sets the important question, Does the mammary gland, once it is developed, have need of a functional stimulant and does not the supply of materials necessary for the forma- tion of milk -which is brought by the blood suffice to establish and maintain the secretion? 36 E. A. Schafee has recently announced (XYIIth Intern. Congress of Medicine, London, 1913, section II, Physiology, Part II, p. 81) that the serum of normal animals — e.g., guinea-pigs — may at times have a galac- tagogue action on the cat in lactation; but he was not able to determine the conditions which make this prop- erty appear. Some, however, he adds, may be disposed to think that this " galactagogue hormone" comes from the posterior lobe of the hypophysis. For the moment, however, this is only an hypothesis. 104 THE INTERNAL SECRETIONS with urea at least (experiments of E. de Cyon, 1870; W. von Schroder, 1882, etc.). But does the urea of the blood, upon arriv- ing at the kidneys where it is eliminated, become an excitant of the renal cells 1 We know nothing which permits us to affirm this, although the diuretic action of urea, when injected in quite strong doses, is well established. Carbon dioxid, as is well known, is found not only in the blood of any particu- lar organ, but in the blood of all organs. This is (see below) one of the reasons why we (Gley, Meltzer) do not consider this substance as a true hormone. It is now to be remarked that none of the internal secretory products with a morpho- genic action — this term will be defined later on — has been found in the venous blood of the glands in which we have, on some other grounds, reasons for admitting their existence. The physiological attempts made with thyroid blood, as I have already ob- CHARACTERISTICS OF GLANDS 105 served, have up to now been fruitless. No one has ever, for anatomical reasons, at- tempted to collect the blood which comes from the hypophysis, ovaries or thymus. It should be possible to make this attempt with the testicle; and it is much to be de- sired that this be done. Definitely speaking, the sum total of our knowledge of the properties of the various sorts of glandular venous blood is very modest. While the doctrine of internal se- cretions has been expanding more and more, the solid foundation on which it rests has remained narrow, for the substances whose presence in the venous blood has been physiologically demonstrated in an indisputable manner number only four : the pancreatic substance which serves to regu- late the normal glycemia, the hepatic anti- thrombine, secretin and adrenalin. Action of Organic Extracts. — Besides the methods of study of the products of internal secretion mentioned above, there 106 THE INTERNAL SECRETIONS is another and more simple one ; in fact so simple that it has turned experimenters from the rational path, which is the inves- tigation of the physiological properties of venous blood from various sources. The other method consists in the administration of organic extracts. It is but just to recognize that there was, besides its ease, a scientific excuse for the use of this method which has spread so widely and rapidly. The first extracts to be thus studied successfully were from the thyroid and suprarenal bodies. Thyroid extract manifested, even in the first experi- ments (Gr. Vassale, Gley) and the first ap- plications to the treatment of myxedema (G. R. Murray), its specific action against disorders arising from the suppression of the thyroid secretion. From this it was to be seen that the injection of an organic ex- tract replaces immediately and for the time being the function of that organ. This led to attempts to generalize and to use ex- CHARACTEEISTICS OF GLANDS 107 tracts from other organs in the same man- ner. The unfortunate experiences, for ex- ample, in the treatment of Addison's dis- ease by suprarenal medication, or in the employment of pancreatic extracts against diabetes, did not stop these therapeutic at- tempts. Besides, the important discovery by Oliver and Schafer of the cardiovascu- lar action of suprarenal extract, confirmed a year later by the discovery of the similar action of the suprarenal blood, appeared to show the excellence of this method and it paved the way for the discovery of the specific properties of internal secretions. The result is that nearly all the investiga- tions made in the past fifteen years on this question have followed a method which, while not absolutely defective, is incom- plete and therefore inadequate. Not that several warnings have not been given. "It is necessary," I said in 1899, 26 '•In Ch. Bouchard's "Trait6 de pathologie g6n.," t. Ill, p. 169. 108 THE INTERNAL SECRETIONS "to ask oneself if all the glands in ques- tion . . . normally produce substances identical with those whose actions are man- ifested by their extracts. In fact, the sub- stances contained in the extracts may not exist in the living glandular tissue; fur- thermore, nothing proves a priori that, if they are formed in the living gland, they regularly leave it by the blood vessels in order to exercise their influence on the dif- ferent arterial regions of the organism. ... It is necessary that the demonstration given for the suprarenal bodies be also supplied for the other glands. . . . This demonstration is particularly necessary, for example, in the case of the thyroid gland." In the same year Lewandowsky 27 re- marked in connection with the suprarenal extract, that we cannot conclude anything about the action of an organ in the body from the results of injecting an extract of "Ztschr. f/- |> 0> s -*j e . taf) 0J • .id ^ 03 > ? t PS 5 „ o a) ir o c i 174 Ill THE FUNCTION OF THE INTERNAL SECRETOEY GLANDS ni THE FUNCTION OF THE INTERNAL SECRETORY GLANDS The normal and the pathological activi- ties may be considered separately. From this second point of view we are con- fronted by the pathological problems which are of the principal importance at present. I. THE NORMAL ACTIVITIES We are first called upon to answer two questions, the first of a chemical nature and the second physiological. The first is to learn out of which materials the glandu- lar elements manufacture the specific sub- stances which they secrete; or, in other words, where they obtain the substances which they use in the production of the specific secretions; and the second is to 177 178 THE INTERNAL SECRETIONS learn the causes which provoke cellular excretion, or the discharge of the gland. The influence of the nervous system on the internal secretions is then to be consid- ered, and finally that of the reciprocal ac- tions of these secretions and their prod- ucts. On this last point rest important pathological problems. 1. The first question, that of the forma- tion of specific products, has been well studied for the glands which elaborate and discharge into the blood nutritive ma- terials. We are acquainted with a consid- erable number of influences which cause an increase in the quantity of hepatic gly- cogen, that is to say, of the substance from which comes the glycose of the blood. Similarly, the liver, which receives much of ammonia salts, produces much urea. It has been known for a long time that the excessive ingestion of fats causes an in- crease in the fat deposits which are seen in adipose subjects. FUNCTION OF THE GLANDS 179 We have little evidence about the other categories of endocrine glands. In the case of the production of substances hav- ing a trophic function, the little that we know concerns the thyroid. It has been stated that the administration of foods rich in iodin, or of iodid preparations, causes an increase of the iodin present in the thy- roid. Confirmation of the first experi- ments of Baumann is still awaited. In the case of the suprarenal glands, it has been thought (Battelli, 1903) that the substances formed in muscle during ac- tivity or in the central nervous system en- gender a "proadrenalin." 2. No further progress has been made in studying the question of the glandular excitants. Quite a large number of sub- stances are known which cause the passage of antithrombin in the blood of the hepatic vein. As an example we may take the in- fluence of the albumoses, which has been thoroughly studied. It is known with the 180 THE INTERNAL SECRETIONS highest degree of certainty that secretin is discharged into the blood after contact of acids or soaps with the duodenojejunal mucous membrane. But do these sub- stances cause its formation from a "pro- secretin, ' ' which had previously existed in the mucous membrane, or do they merely liberate the secretin, already completely formed? In the case of the suprarenal se- cretion, Tscheboksaroff has observed in the laboratory of Mislavsky that an injection of physostigmin increases the amount of adrenalin which is discharged into the cap- sular vein (experiments on dogs, 1910) ; pilocarpin has not this effect. Finally, histological observations have shown that pilocarpin causes swelling of the thyroid, and the collection of colloid matter in the vesicles, this then spreading into the in- tervesicular lymphatic spaces ; the same is true after ligature of the common duct (K. Hiirthle, 1894). Hence we may suppose that the bile excites thyroid secretion. FUNCTION OF THE GLANDS 181 Undoubtedly, other facts might be added to these. They are, however, too uncertain for us to be able to consider them as dem- onstrated without the most rigorous veri- fication. Thus, it has been stated that when an organic extract is introduced into the body, it tends towards the homologous organ, hypertrophies and stimulates it. Homo stimulants have even been spoken of. Contradiction notwithstanding, it has even been maintained that these extracts, when administered in small doses, moderate the function of the homologous organ. In such a manner is the practise of organo- therapy justified by its supporters, in spite of the contradictions constantly being en- countered. 3. The influence of the nervous system on the internal secretions has been demon- strated in the cases of the glycogenic func- tion of the liver and the passage of adrena- lin into the blood. The evidence in the case of the liver is found in all treatises on 182 THE INTEENAL SECRETIONS physiology. The proofs for the second are given largely in Biedl's book and Swale Vincent's study, already mentioned, as well as in a remarkable study by G. Bayer x [and in more recent works of Crile, Can- non and others — Ed.] . Finally, it has been thought possible to prove directly the ac- tion of the nervous system on the thyroid by showing that stimulation of the laryn- geal nerves (L. Ascher and M. Flack, 1910) increases the excitability of the depressor ; it being admitted, following the researches of E. de Cyon, that the latter is dependent on the thyroid secretion. 4. The reciprocal glandular actions, or humoral interrelations, belong to the group of phenomena termed as functional hu- moral correlations. But all correlations of this sort, which are determined and char- acterized by the action of an internal secre- 1 G. Bayer, ' ' Die normale und pathol. Physiologie des chromaffinen Gewebes der Nebennieren" {Ergebnisse der pathol. Anat., 1910, XIV, 132). FUNCTION OF THE GLANDS 183 tory product on an organ of the same an- atomical system or of a distinct and more or less distant system, are not interrela- tions. The latter are characterized by the reciprocal action of two products of inter- nal secretion. Undoubtedly, confusion between these two notions tends to exist. To avoid this, however, it would suffice to use a little criticism and consider some fundamental facts in the history of internal secretions. If secretin, for example, is the specific ex- citant of pancreatic secretion, does the pancreas furnish a product of internal se- cretion acting on the intestinal secretion? And where, therefore, is the reciprocal connection between the pancreatic sub- stance which acts on the liver, the organ in which the metabolism of the carbohydrates occurs, and a substance of hepatic origin? The demonstration which follows shows how important, it is to maintain the distinc- 184 THE INTERNAL SECRETIONS tion between functional humoral correla- tions and humoral interrelations. How has the latter theory become so widely accepted? It has been admitted that there is no endocrine gland which has no mutual connections with one or several others, either of excitation or of recipro- cal antagonism. Let us now reproduce the diagram of the promoters of the theory, the Viennese pathologists, Eppinger, Falta and Rudinger (1908), 2 which sums up the principle of these actions. From this diagram it is seen that the thy- roid secretion is the excitant of the supra- renal apparatus, and adrenalin the excitant of the thyroid. Furthermore, adrenalin exercises an inhibitory influence on the 2 H. Eppinger, W. Falta and C. Eudinger, ' ' tiber der Wechselwirkungen der Driisen mit innerer Sekretion" (Zeitschr. fiir Urn. Med., 1908 and 1909, LXVI, 152, and LXVIII, 380) ; W. Falta, "tiber der Korrelationen der Driisen mit innerer Sekretion" (Lewin's Ergebnisse der Wissenschaftliche Med., 1909, I, 108-118). Cf. also Caro, ' ' Wechselwirkung der Organen mit innerer Sekre- tion" {Media. Klinilc, January 23, 1910, VI, 136-139). FUNCTION OF THE GLANDS 185 pancreas, and the secretion of the latter has the same influence on the adrenals. Also, the thyroid secretion moderates the activity of the pancreas and the internal pancreatic secretion holds the activity of the thyroid within bounds. Assuming, for Thyroid Insular Apparatus of the Pancreas Chromaffin System Inhibitory Action example, hypoactivity or suppression of the activity of the thyroid and there will result hyperfunction of the pancreas re- sulting from the disappearance of the nor- mal restraining action of the former gland upon the latter; likewise a diminution in the function of the adrenals occurs. Let there be given, on the other hand, hyper- 186 THE INTERNAL SECRETIONS activity, from some morbid influence, of the thyroid. The restraining action of the pancreas will be exercised more energetic- ally and there will result a more or less marked insufficiency of the functions of the latter gland, and at the same time hyperfunction of the chromaffin system. Analogous connections have been inves- tigated as regards the functional activity of other endocrine organs and their au- thenticity established. This is the case with the ovary, thyroid and pituitary body ; the adrenals and genital glands, etc. Isaac Ott, for example, maintains that the anterior lobe of the pituitary body has an inhibitory action on the genital glands, the testicles and ovaries, and, reciprocally, that the latter have a like action on the hypophysis. He also says that the thyroid and pituitary are mutually compensatory. 3 Such are the efforts that have been made 8 Isaac Ott, ' ' Internal Secretions from a Physiological and Therapeutical Standpoint," Phil., 1910; see p. 125. FUNCTION OF THE GLANDS 187 to generalize the conception of humoral interrelations. Both parts of the vegetative nervous system share in these reciprocal actions. They are the autonomous and the sympa- thetic systems. It is known, for example, that the product of the adrenal secretion is the excitant of the sympathetic nervous system. We might therefore say that adrenalin is sympathicotropic, and the product of the thyroid secretion, which acts on the tone of the vagus (F. Kraus, 1908), is vagotropic, or, better, autonomo- tropic. Thus adrenalin produces the same effects as a stimulant of the sympathetic system; whenever it encounters a motor fiber of this system, it produces a motor effect ; if it strikes an inhibitory fiber of the same system, the effect is of an inhibitory character. But there are some organs which possess a double enervation, auton- omous and sympathetic. In this case, as 188 THE INTERNAL SECRETIONS has been well said by G. Fano, 4 these or- gans "possono reagire a sostanze iniettate dall'esterno o elaborate dalP organismo ragginngondo effetti molto notevoli perche a quelle stimolazioni tossiche possono risponderi non solo liberando le determi- nant! d'una funzione ma pure contempor- aneamente inibendo quelle condizioni an- tagonistic!^ che si opporrebbero alia sua facile e completa attuazione." The first question to be discussed is if all the actions started by endocrine products are the re- sults of the stimulation or inhibition of sympathetic or autonomic nerve fibers. It is evident that we may say, for example, that the action by which glycogen is col- lected in the liver is regulated by the sym- pathetic, and that the internal secretion of the pancreas is regulated by the vagus. But there is no proof that these secretions cannot take place under purely humoral influences, and there are proofs that the * Loo. cit. FUNCTION OF THE GLANDS 189 mobilization of sugar in the liver in the form of glycogen and the accumulation of the latter are diastatic phenomena. Like- wise, the formation of fibrinogen in the liver, and of antithrombin in the same gland, take place independently of the nervous system. And it would be easy to cite other instances of the same nature. It is no less important to discuss another question which concerns the connections between the vegetative nervous system and reciprocal glandular activities. We have been led to admit (Eppinger and Hess, 1909-1910) that a certain rise in the nor- mal tone of the pneumogastric (constitu- tional vagotonia) or of the sympathetic (sympathicotonia) may be observed in various subjects. Hypertonia of the vagus nerves, i. e., vagotonia, is caused by the excessive secretion of autonomotropic hor- mones accompanied by a deficient secretion of sympathicotropic hormones. This is a constitutional anomaly and quite a variety 190 THE INTEENAL SECEETIONS of disorders may arise from it. The vic- tims of this anomaly show a particular sensibility to autonomotropic poisons, like atropin and pilocarpin, and a lesser sen- sibility to sympathicotropic poisons, as adrenalin. The reverse is true in sympa- thicotonia, which furnishes us with a com- plete series of diagnostic signs. But the proofs of the existence, and a fortiori of the action, of autonomotropic (thymicolymphatic and pancreatic) hor- mones are altogether insufficient. Is there a physiologist who has actually recognized a hormone in a thymus extract, in the sense that the word hormone should be used (see p. 136) ? The theory is therefore based on an unstable foundation. Furthermore, the facts on which it rests are either uncertain or altogether inexact and the pharmaco- dynamic criterion to which has been at- tributed so high a diagnostic value is far from being infallible. Some most useful points on these various questions will be FUNCTION OF THE GLANDS 191 found in several recent studies. 5 In any case, the question if nervous actions par- ticipate in reciprocal glandular activities, and to what degree this occurs, is as yet far from solved. However, it is of importance to examine the theory of humoral interrelations in it- self, and we shall do this immediately. What are the facts on which it is based? They are anatomo-pathological data, clini- cal observations and some animal experi- ments. At the bedside we analyze a syn- drome in which disorders depending on the alteration of an endocrine gland appear to predominate. At the autopsy we actually S K. Peteen und I. Thorling, "Unters. iiber das Vorkommen von 'Vagotonus und Sympathicotonus ' " (Zeitschrift fur Tclin. Med., 1911, LXXIII, 27-46); J. Bauer, ' ' Zur Funktionspriif ung des vegetativen Nerven- systems" (BeutscTies Arch, fur Tclin. Med., 1912, CVII, 39); P. Fleischmann, "tiber die Wechselbeziehungen der Driisen mit innerer Sekretion" (Med. Klinilc, Feb. 4, 1912, p. 177); N. Pende, "Sulla vagotonia constituzion- ale e morbosa di Eppinger ed Hess e su alcuni recenti metodi d'indagine semiologica del sistema nervoso sim- patieo" (II Tommasi, April 30, 1912, VII, 265). 192 THE INTERNAL SECRETIONS find this change, but, besides, there are dis- covered lesions of other endocrine glands by which it is believed possible to explain disorders which were not accounted for by the lesion of the organ primarily attacked. By combining clinical facts and post mor- tem observations, a connection between the various organs studied is finally arrived at. The question is, What is the nature of this connection? Are we dealing with a synergic, reciprocal relation, like that maintained by Eppinger, Falta and Rudin- ger ! Or have we simply concomitant phe- nomena, provoked by the same cause acting on divers organs? The second notion, which results solely from the consideration of clinical facts, has given rise to the establishment of syn- dromes of pluriglandular insufficiency, due to several French pathologists (H. Claude, 1907-1908; L. Renon, 1908; L. Re- non and Arthur Delille, 1908, etc.). The conception of these syndromes has led to FUNCTION OF THE GLANDS 193 associative opotherapy, the simultaneous administration of several organic extracts (L. Benon, 1908), which has been much vaunted. However, the anatomo-patho- logical method is subject to errors of interpretation. The statement concern- ing lesions in various organs does not prove that there normally exists any as- sociation whatsoever between these or- gans. There have been found lesions of the testicles in individuals affected with cirrhosis of the liver, and likewise follow- ing resection of the liver or ligature of the bile duct. Has any one, therefore, drawn the conclusion that there is a re- lation between the bile duct and the testicles ? Is it probable that the retention of toxic substances, following lesions of the liver, causes parenchymatous altera- tions here and there, but more markedly in the testicles ? Similarly, are we justified in maintaining that the lesions found in a number of organs of thyroidectomized ani- 194 THE INTERNAL SECRETIONS mals are directly due to the loss of the thy- roid function 1 Are they not rather one of the effects of the intoxication and meta- bolic disorders which occur in these ani- mals? The tendency at present to consider the study of hormones as being nothing else than the investigation of reciprocal ac- tions, or humoral interrelations is there- fore little justified. If, as I have already said, 6 interrelations enter into the group of functional humoral correlations, it is necessary that all the latter be interrela- tions. This is what is shown by the actual facts. Reciprocal Relations between the Pancreas and the Adrenals. — Let us con- sider the reciprocally antagonistic rela- tions admitted to exist between the pan- creas and the adrenals. In favor of the •E. Glet, "Correlations fonctionelles et inter-rela- tions humoraleB ' ' (Bev. ge"n6rale des sciences, July 30, 1913, p. 537). FUNCTION OF THE GLANDS 195 idea of an inhibitory action of the pan- creas upon the adrenals, it has been main- tained that following the suppression of the former organ the action of adrenalin is more marked. The following was ob- served by 0. Loewi: 7 He removed the pancreas and then noticed that the ad- ministration of adrenalin was followed by dilatation of the pupil, which does not occur in a normal animal. Loewi ob- served in ten out of eighteen diabetics a marked dilatation of the pupil following the administration of adrenalin, while in thirty healthy subjects this phenomenon was noted but twice. To explain this ef- fect it is suggested that the pancreas se- cretes a substance antagonistic to adrena- lin. The latter acts on the pupil through the intermediary of the sympathetic. The antagonistic substance inhibits the sympa- 7 O. Loewi, ' ' Eine neue Funktion des Pankreas unci ihre Beziehung zum diabetes mellitus" (Wiener Min. Woch., 1907, p. 747). 196 THE INTERNAL SECRETIONS thetic or stimulates the constrictor, so that when the pancreas is destroyed this action can no longer be exercised and the adrena- lin is free to produce its full effects. These observations of Loewi are cer- tainly exact. Is the interpretation correct? In this connection we should mention that Bittorf 8 (1911) carried out Meltzer's re- action with the blood serum of ten dia- betics and in no case did he find an aug- mentation in the quantity of adrenalin in the blood. Furthermore, in diabetic ani- mals and in man, permanent dilatation of the pupil has never been observed. But why not decide the question on a surer and more solid basis — that of direct experi- ence? Has any one found an increase in the proportion of adrenalin in the supra- renal blood of depancreatized animals'? The experiment has not even been at- 8 A. Bittorf, "1st beim Diabetes Mellitus eine Ueber- fonktion der Nebennieren nachweisbar?" (Mimchencr med. Woch., 1911, No. 42). FUNCTION OF THE GLANDS 197 tempted as yet. Researches on this point have been begun in my laboratory. It has been maintained that the supra- renal capsules have a reciprocally inhibi- tory action on the function of the pancreas. The following is the experiment performed by R. Pemberton and J. E. Sweet (1908, 1910), according to whom this action is even manifested on the external pancreatic secretions: A preliminary injection of adrenalin prevented the action of secretin. This antagonism of the two \ substances was not found by Gley (1911). 9 Ziilzer 10 observed glycosuria following the extirpa- tion of the pancreas cease after ablation of the two suprarenals. Also, Frouin 11 9 When an antagonism is stated to occur, it is due to the temporary anemia of the pancreas, resulting from the vasoconstriction produced by the adrenalin (Willis Edmunds, 1910; Wertheimer, 1911; Gley, 1911). 10 G. ZtJlzer, M. Dohrn, and A. Maexer, ' ' Neuere Un- ters. iiber den experimentellen Diabetes" (Deutsch. med. Woch., 1908, p. 1380). "A. Frouin, "Ablation des capsules surrenales et diabete pancr^atique ' ' (C. B. de la Soc. de biol., Feb. 8, 1908, LXIV, p. 216). 198 THE INTERNAL SECRETIONS has published the results of two analo- gous experiments in which pancreatic dia- betes in a dog was diminished after the ablation of one suprarenal capsule and two- thirds of the other. But Ziilzer 's dogs only survived twenty-four to thirty-six hours. Under these conditions, what does a dimi- nution in the elimination of sugar signify 1 ? Is it not a well known fact that in animals suffering from malnutrition, cachectic ani- mals or those near death, diabetes is at- tenuated or may even disappear? We should not forget the somewhat paradoxi- cal but just expression of Claude Bernard that "in order to be diabetic, one must look well." Now, decapsulated animals are in a state of organic decay. The recent experiments of Athanasiu and his pupil Gradinesco 12 have, moreover, shown that 13 Cf. J. Athanasiu and Gradinesco, "Les capsules surrenales et les eehanges entre le sang et les tissus ' ' (C. B., August 9, 1909), and A. V. Gradinesco, "Der Einfluss der Nebennieren auf den Blutkreislauf und den Stoffwechsel" (Arch. f. die ges. Physiol., 1913, CLII, pp. 187-253). FUNCTION OF THE GLANDS 199 adrenalin, by the tonic influence that it ex- erts on the endothelium of the blood capil- laries, regulates the material exchanges be- tween the blood and the interstitial plasma of the tissues, so that if the secretion of this product is abolished these exchanges are put in a state of profound disorder and their reduction appears to be the cause of death following ablation of the adrenals. It would therefore seem that one passes by the facts too boldly when he maintains that there exists — alongside of a " posi- tive adrenal diabetes," due to a hyperac- tivity of the suprarenal glands which pro- duce more adrenalin, leading, under the in- fluence of this substance, to hyperglycemia and glycosuria — a "negative diabetes," from the suppression of the permanently moderating influence exercised by the pan- creas on the suprarenal capsules, and that in the classic pancreatic diabetic (J. von Mering and Minkowski, Lancereaux), this 200 THE INTERNAL SECRETIONS last factor plays its role. Following the destruction of the pancreas, adrenalin would be secreted in excess and thus the pancreatic diabetic would in reality be an adrenalin diabetic (Ziilzer). As G. Bay- er 13 justly remarks, the physiological an- tagonism between the two glands and the fact of the hyperactivity of the chromaffin system after extirpation of the pancreas could only be accepted if there were found : (a) Histological signs of increased func- tion in the suprarenal glands of depan- creatized animals ; (b) abnormal quantities of adrenalin in the blood of depancreatized animals and diabetic human beings ; (c) in the same animals signs of hyperactivity of the chromaffin system, as elevation in the arterial pressure. Such a demonstration has not as yet been furnished. The facts amassed by Viennese pathologists only show that the loss of the pancreas has, under certain conditions, the same effect u Loo. tit. FUNCTION OF THE GLANDS 201 as excitation of the adrenals, that is, in- creased secretion of adrenalin. Thus the result is the same as after section of the inhibitory nerves of the heart or stimula- tion of the accelerating nerves. Section of the vagus does not provoke acceleration of the heart beat because increased activity of the sympathetic follows, but because the normal inhibitory influence is suppressed. Likewise, the pancreas and the suprarenals act oppo singly on the accumulation of sugar. That does not prove that the ac- tion of one is determined by the suppres- sion of the action of the other, and con- versely. Reciprocal Relations between the Thyroid and the Adrenals. — Is it very well established that the thyroid and adrenals exert reciprocal stimulation on one another? According to the experi- ments of Eppinger, Falta and Rudinger, 14 adrenalin no longer causes glycosuria in u Loc. tit., 1908. 202 THE INTEBNAL SECEETIONS thyroidectomized animals; 15 if these ani- mals be administered thyroid prepara- tions the action of adrenalin is reestab- lished. 16 From this there follows im- mediately the explanation of the glyco- suria observed very frequently in exoph- thalmic goiter; in fact, nothing in the theory is more simple, if it is true that exophthalmic goiter depends on hyperfunc- tion of the thyroid, which hyperactivity is followed by an increased secretion of ad- renalin, one of the effects of which will be 15 The same would not be true after thyroparathyroi- dectomy. Eppinger, Falta and Kudinger admit in fact that there is an antagonism between the thyroid and the parathyroids and that their actions on the sympathetic nervous system are the reverse of one another, the thyroid secretion exciting and the other inhibiting the nerves of this system. The proofs brought to the sup- port of this conception are insufficient and it is far from being established. Moreover, F. Kraus and E. Hirsch have noted (1909) that thyroparathyroidectomized dogs and rabbits become exquisitely glycosurie under the influ- ence of adrenalin. 16 According to F. Kraus and Eahel Hirsch, on the con- trary, adrenalin does not produce glycosuria in the dog if thyroid extract is administered at the same time. FUNCTION OF THE GLANDS 203 glycosuria. Now, contrary to the experi- ences of the Viennese pathologists, the ex- periments of Underhill and Hilditch, 17 and of Underhill 1S have shown that glycosuria is exquisitely produced after thyroidec- tomy under the influence of adrenalin. Moreover, E. P. Pick and F. Pineles 19 (1908) observed that the same is true in the rabbit; in the young she-goat, on the contrary, glycosuria was prevented by the operation. It is, in fact, possible that among thyroidectomized animals there are some that are incapable of reacting to ad- renalin. We know how much the metabo- lism is disordered in these animals and the "Frank P. Underhill and W. W. Hilditch, "Cer- tain Aspects of Carbohydrate Metabolism in Eelation to the Complete Eemoval of the Thyroids and Partial Para- thyroidectomy" (Amer. Jour, of Physiol., 1909, XXV, p. 67). 18 Frank P. Underhill, ' ' The Production of Gly- cosuria by Adrenalin in Thyroidectomized Dogs" (Ibid., 1911, XXVII, pp. 331-339). 19 E. P. Pick and F. Pinecles, " Tiber die Beziehungen der Schilddriise zur physiol. Wirkung des Adrenalins" (Biochem. Zeit, 1908, XII, p. 473). 204 THE INTERNAL SECRETIONS disorders are variable in intensity ; if they are profound it is not astonishing that the animal thus attacked cannot become hyper- glycemic or glycosuric, which has already been mentioned above. This interpretation finds support in a series of experiments made by H. Ritzman 20 (1909) which show that, in athyroid cats, when the phenomena of intoxication are acute, adrenalin does not provoke glycosuria; if the disorder is ameliorated it reappears. The cause of the absence of glycosuria does not, there- fore, lie in the lack of thyroid secretion, but in a change of the general condition. 21 Let us suppose the case to be the reverse of that just examined. Hyperthyroidism brings after it a stimulation of the chro- maffin system followed by emaciation and 20 ' ' iiher den Mechanismus der Adrenalinglycosurie ' (Arch. f. Exper. Path, und Pharmalc., 1909, LXI, p. 231) 21 It is interesting to state in this connection that A Bonanni (Arch, italiennes de biologie, 1912, LVIII, pp 157-172) has noted that the glycosuria which is pro voked by carbon dioxid is not produced in debilitated animals. FUNCTION OF THE GLANDS 205 glycosuria, which are so frequently found in these conditions of thyroid hyperfunc- tion. But is the reality of these conditions firmly established? It is a point that we will investigate immediately. I would like to go immediately to the pith of the question. We might, to judge by the reciprocal connections between the chromaffin system and the thyroid, insti- tute direct experiments. It is not always possible to carry out such experiments; the investigator is often obliged to attack the problem by indirect methods and he can only arrive at the solution sought for by successive and gradual approximations. In the case in question, on the contrary, the direct study is easy; the experiments of Cybulski, J. P. Langlois, J. P. Langlois and L. Camus, Biedl, Dreyer and above all, those of Tscheboksaroff 22 have taught us M N. Cybulski, " Tiber die Funktion der Nebenniere" (Wiener med. Woch., 1896, pp. 215 and 255); J. P. Langlois, "Sur les fonctions des capsules surrenales, ' ' These de doctorat es sciences, Paris, 1897; L. Camus 206 THE INTERNAL SECRETIONS that the suprarenal blood can be collected in quantities large enough to discover in it the action of adrenalin through the proc- ess of injecting this blood into another animal. With a view to studying this ques- tion, we can call to mind many other ex- periments. But there are two series which, it appears, should be mentioned first: (a) Is the thyroid secretion really an excitant of the suprarenal? And does the supra- renal blood therefore contain more adrena- lin after the injection of thyroid extract? (b) Do extracts of suprarenal glands of thyroidectomized animals which have suc- cumbed to the operation contain less ad- renalin? On these two points I have col- and J. P. Langlois, "Secretion surrenale et pression sanguine" (C. B. de la Soc. de biol., March 3, 1900, p. 210) ; A. Biedl, "Beitrage zur physiol. der Nebennieren. Die Innervation der Nebennieren" (Arch, fur die ges. Physiol., 1897, LXVII, p. 443) ; George P. Dreyer, "On Secretory Nerves to the Suprarenal Capsule" (Am. Jour, of Physiol., 1899, II, pp. 203-219) ; M. Tscheboksaroff, "tiber sekretorische Nerven der Nebennieren" (Arch. fur die ges. Physiol., 1910, CXXXVII, pp. 59-122). FUNCTION OF THE GLANDS 207 lected a large number of facts. 23 These facts prove that the adrenals of thyroidec- tomized animals do not contain less active adrenalin than those of normal animals and, furthermore, that the suprarenal blood does not become richer in adrenalin after the injection of thyroid extract in physiological doses than after that of any other organic extract, at least of those which have been tested in the experiments of Gley and Quinquaud, viz., hepatic, pan- creatic, testicular and renal. Hence the experiments so far carried out do not appear to favor either the the- ory of the reenforcing reciprocal action of the thyroid and the adrenals, or the theory 23 See E. Gley and Alf. Quinquaud, "Contribution a 1 'etude des interrelations humorales, I. — Action de l'extrait thyroidien et en general des extraits d 'organs sur la secretion surrenales" {Archives Internationales de physiologie, January 31, 1914, XIV, pp. 152-174) ; "Con- tribution a 1 'etude des interrelations humorales. II. — Valeur physiologique de la glande surrenale des animaux ethyroideV' (Ibid., pp. 175-194). See also E. Gley and Alf. Quinquaud, C. B., June 30, 1913, CLVI, p. 2013. 208 THE INTERNAL SECRETIONS of the inhibitory reciprocal action of the pancreas and the adrenals. Would it not be the same with the other interrelations that have been so easily admitted! Reciprocal Relations between the Thykoid and the Pancreas. — The third case is the interrelation between the thy- roid and the pancreas. According to Lorand, 24 extirpation of the thyroid sup- presses glycosuria in depancreatized ani- mals. Why, by what mechanism 1 ? The answer given is that following the loss of the inhibitory influence exercised by the pancreas on the thyroid gland, the thyroid secretion is increased in these depancrea- tized animals, which is followed by a sec- ondary augmentation in the quantity of adrenalin. 25 Hence if the thyroid is re- 21 A. Lorand, "Lea rapports du pancreas (Hots de Langerhans) avec la thyroide" (C. B. de la Soc. de biol., March 19, 1904, LVI, p. 488). 28 We have already seen that it does not matter if the injection of thyroid extract in physiological doses does not augment at all the adrenalin content of the FUNCTION OF THE GLANDS 209 moved, the secretion of adrenalin dimin- ishes and at the same time the hyper- glycemia and the glycosuria disappear. This explanation does not take into ac- count several important facts. The first is that in thyroidectomized animals glyco- suria has several times been found; the above theory does not explain this — in any case it is seen that the question is com- plex. Similarly, cases of myxedema with diabetes have been found. Besides, let us suppose that the facts are always so. It is to be recalled that thyroidectomized ani- mals suffer from disordered metabolic ex- changes, which are profoundly diminished, and that consequently glycosuria, 26 no mat- ter by what cause it is provoked, may very well be diminished for this reason alone. This is the observation which has already suprarenal blood. The reasoning is therefore funda- mentally wrong. "No one has even attempted to investigate how the various sorts of glycosuria run their course following thyroidectomy. 210 THE INTERNAL SECRETIONS been made with regard to the connection between the pancreas and the adrenals. Another argument has also been invoked, viz., the increase in volume of the thyroid in depancreatized dogs, combined with aug- mentation of the colloid substance. 27 Taken by itself, this statement does not mean very much. Licini, more prudent than others, has asked himself whether this is a compensatory phenomenon or is it due to the suppression of a specific secretory product of the pancreas; or perhaps, we may add, is it a more general phenomenon resulting from reactions against the intoxi- cations which may result from disorders in the nitrogenous metabolism which are presented by depancreatized dogs. Reciprocal Relations between the Thyroid and the Gonads. — The same un- certainty exists in connection with the rela- 27 C. Licini (a pupil of Kocher), "Der Einfluss der Extirpation des Pankreas auf die Schilddriise ' ' (Zeitschr. fur Chirurgie, 1909, CI, p. 522). FUNCTION OF THE GLANDS 211 tions between the thyroid and the ovaries. The ovaries exercise an inhibitory action on the thyroid; in fact, the latter becomes hyperactive after castration, and there is an increase of colloid matter. This is the cause, it is said, of the large number of cases of exophthalmic goiter after the menopause. Is it necessary to point out how very injudiciously statistical methods are applied here? The loss of the thyroid function should be followed, reciprocally, by hyperfunction of the ovary. The latter has not been proven at all. It is true that Champy and myself noted that thyroidec- tomy in the rabbit is followed by hyper- trophy of the insterstitial gland of the ovary. But von Eiselsberg 2S showed long ago that thyroidectomy causes atrophy of the genital organs. The truth is that these 28 Fe. von Eiselsbeeg, " tiber vegatative Storungen im Wachstume von Thieren nach frtihzeitiger Schilddrusen- exstirpation " (Arch, fur Min. Chirurgie, 1895, XLIX, pp. 207-234). Cf. also a preliminary note in Berliner Min. Woch., 1892, No. 46, p. 1178. 212 THE INTERNAL SECRETIONS statements of a morphological nature do not permit of drawing any conclusions as to the direct connections between the or- gans involved. Other interrelations are no better es- tablished. It is commonly thought that when an increase in volume is observed, one may conclude a concomitant augmen- tation of function. But it is necessary to prove first that a hypertrophy really cor- responds to functional hyperactivity. It is high time that a physiological study be made of the organs thus stated to be al- tered, as well as of the properties of the blood in diseases attributed to disorders of internal secretion. Without this physi- ological study hypotheses are being too liberally formulated. That there are connections between the various glands is one of the fundamental facts maintained by the doctrine of inter- nal secretions, and to deny them would be to deny a part of the doctrine of internal FUNCTION OF THE GLANDS 213 secretions itself. But what I criticize is the insufficiently demonstrated theory of reciprocal relations. H. THE DISEASED FUNCTION From the physiological point of view, the diseases of the endocrine organs may be divided into two large classes, — those at- tributed to hyperfunction, and those to hy- pofunction. Moreover, this is the distinc- tion most naturally made by pathologists. The notion of insufficiency has been real- ized by physicians, one might say, from time immemorial. But it has now been de- veloped to such a point that pathologists like Chaufrard have been led to think that this notion dominates pathology. The no- tion of excessive functioning is more recent and has not as large a range as before the discoveries relative to the internal secre- tions and their disorders. Some reflections of a physiological na- 214 THE INTEBNAL SECBETIONS ture on the value of these two notions may not be out of place here. As for the clini- cal questions which confront us at this point in large number, I have neither the means nor the intention to examine them. ( 1 ) Hypersecretion. — I have mentioned above that the substances having a trophic role, and hormones, act in minimal doses. It is therefore sufficient for the glands to discharge very small quantities of them into the blood. This is one of the reasons why it is so difficult to discover their pres- ence in the blood of efferent veins of the glands, at least when we are not dealing with extremely active products, like secre- tin and, above all, adrenalin. Furthermore, these substances disappear very rapidly in the blood. For this reason, is it possible for an ex- cess to remain in the blood? A gland may indeed show exaggerated function. In or- der that a morbid syndrome be established FUNCTION OF THE GLANDS 215 in connection with this hyperfunction, still another condition is necessary; namely, that the product liberated in excess should not be liable to destruction in the blood or tissues. In the conditions described as resulting from glandular hyperactivity, no one has ever investigated if this second condition, necessary though it is, is ful- filled. In view of properties continuously manifested, it is most assuredly true that there are hormones which are constantly being produced. The best example appears to be that of adrenalin. But these hor- mones are formed and secreted only in very small amounts. In order to admit that a permanent state of hypersecretion exists, it would first be necessary to dem- onstrate that these destructive mechanisms have ceased to act. Just as the excess of digestive ferments is absorbed or elimi- nated, so the endocrine products disappear rapidly in the blood — secretin in several 216 THE INTERNAL SECRETIONS minutes, adrenalin almost immediately after it has been injected. 29 Besides, have the states of hypersecre- tion just described indeed been proven to exist? Hyperthyroidism, of which so much has been spoken, has never really been repro- duced experimentally, neither by Cunning- ham, nor by Gley, nor, in the last few years, in the researches methodically pursued by Carlson and by Coronedi. 30 No one has, by repeated injections of pituitary extract, caused symptoms of acromegaly to appear, no more than symp- " Experiments of J. de Vos and M. Kochmann on the rabbit. One-third and even two-thirds of the minimal fatal dose of adrenalin disappeared almost immediately after the injection (Arch, intern, de pharmacodyna/nvie, 1905, XIV, pp. 81-91). *°B. H. Cunningham, "Experimental Thyroidism" {Jour, of Exper. Med., 1898, III, pp. 147-243); A. J. Caelson, J. E. Rooks, and J. F. MacKie, "Attempts to Produce Experimental Hyperthyroidism in Mammals and Birds" (Am. Jour, of Physiol., 1912, XXX, pp. 129- 159) ; G-. Coronedi, "TJn coup d'ceil d 'ensemble sur mes experiences actuelles relatives a la glande thyroide" (Arch, italiennes de Biologie, 1912, LVTI, pp. 252-262). FUNCTION OF THE GLANDS 217 toms of exophthalmic goiter have been pro- voked by injections of thyroid extract. It will be remarked that the experiments of Bircher on the reproduction of Graves ' dis- ease by intraperitoneal implantation of hy- pertrophied thymus are of an entirely dif- ferent nature. 31 Does hypersecretion of epinephrin itself, of which so much has been spoken during the last few years, surely exist? Its real- ity in exophthalmic goiter is well contest- able. While Meltzer's reaction has been obtained in the blood of many patients suf- fering from exophthalmic goiter, yet the serum of the blood has not the cardiovas- cular properties of adrenalin (M. Cleret and E. Gley, 32 1911) ; on the contrary its 31 E. Bircher, ' ' Zur experimentellen Erzeugung des Morbus Basedoweii ' ' (ZentraTbl. fur Chirurgie, Feb. 3, 1912, XXXIX, pp. 138-140). 82 E. Gley and M. Cleret, ' ' Kecherches sur la patho- genie du goitre exophtalmique. I. Action cardiovascu- laire du serum sanguin des malades atteints de goitre exophtalmique" {Jour, de physiol. et de pathol. gen- erate, 1911, XIII, pp. 928-944). Cf. also M. Cleret 's 218 THE INTERNAL SECRETIONS action is clearly hypotensory. The hyper- tension observed in many renal affections has also been considered as a sign of ad- renalinemia. But Meltzer-Ehrmann's re- action is not given by the serum of these sufferers and, furthermore, Janeway has been unable to discover any vaso-constric- tive substance in the blood of six patients with hypertension. In this investigation, neither defibrinated blood nor serum should be used, for these are liquids in which substances having a vaso-constric- tive action are formed. 33 Also the facts governing the alleged increase of adrena- lin in various pathological conditions can no longer be accepted without reserve. thesis ("Etude sur la pathogenie du goitre exophtal- mique, " Paris, 1911), in which can be found the criti- cism of what I have called the thyroido-suprarenal theory of exophthalmic goiter. 33 J. M. O'Connor, "tJber den Adrenalingehalt des Blutes" (Arch. f. exper. Pathol, unci Pharmak., 1912, LXVII, pp. 195-232).— Th. Janeway and E. A. Park, "The Question of Epinephrin in the Circulation and its Relation to Blood Pressure" (Jour, of Exper. Med., 1912, XVI, p. 541). FUNCTION OF THE GLANDS 219 Moreover, in Lucien and Parisot's 34 re- cent work will be found the reasons why we have no right to surmise a relation of cause and effect from the simple anatomo- pathological fact of suprarenal hypertro- phy, and the clinical phenomenon of ar- terial hypertension. (2) Hyposecretion. — There are also reasons for asking if it is possible that a state of hypofunction of the endocrine glands is ever produced. This question is connected with that of profuse or excessive functioning, so widespread throughout the organism. Just as machines, says Meltzer, are constructed in such a manner as to pos- sess a resisting force superior to that re- quired of them, so must the animal 35 or- ganism have on hand a superabundance of tissues and energy. There is an ex- 34 M. Ltjcien and J. Pakisot, ' ' Glandes surrenales et organes ehromaffines " (Paris, ¥. Gittler, 1913). "Meltzer (loc. cit.) wrote human. Is it not preferable to say animal^ The reader will permit me to take this liberty. 220 THE INTERNAL SECRETIONS cess of digestive secretions, excessive ac- tion of the heart and respiratory move- ments. Similarly, we have surplus endo- crine secretions. Let us recall the fact that minimal doses of products secreted by the ductless glands suffice to fulfil the role as- signed them. Facts pertaining to this point are avail- able in abundance. A small fragment of the pancreas, adrenals or thyroid, insignifi- cant in weight when compared to the total mass of the organ — it has been estimated that a twelfth of the pancreas is sufficient to prevent glycosuria — preserves animals from the fatal consequences of the extirpa- tion of these glands. Undoubtedly, in the case of the pancreas it has several times been observed by Hedon, Sandmeyer, Thir- oloix and others, that animals in whom a small fragment of the gland has been left, either intentionally or inadvertently, finally became diabetic. One is tempted to believe that the fragment became insuffi- FUNCTION OF THE GLANDS 221 cient. Is it not surprising that a portion of an organ that, although very small, has sufficed for a long time to maintain the function of the organ, should suddenly lose its ability to fulfil its office, although one would think that the increased demand call- ing for hypertrophy would increase its functional capacity? Sooner than accept this hypothesis, could we not suppose the intervention of purely mechanical causes — adhesions and sclerosis, for example — gradually rendering the circulation in the remaining fragment of the organ difficult, which, furthermore, has perhaps preserved but a few small blood vessels. Another pertinent fact in this connection is the following: The suprarenal glands are more or less severely attacked by vari- ous microbic toxins, and the extract of glands coming from infected animals ap- pears much less active than that from nor- mal glands. However, the arterial pres- sure of these animals is not always very 222 THE INTERNAL SECRETIONS low. This was recognized in the case of rabies in my laboratory by R. Porak. 36 Thus the small quantity of adrenalin still secreted by these altered glands almost suffices to maintain the vascular tone. It is more difficult than is generally appreciated to render the liver insufficient; the blood continues to contain sugar and urea. At autopsies, cirrhotic livers have been found in subjects in whom the organ had ap- peared to function normally. 37 While we thoroughly understand insuf- ficiencies of organs furnishing mechanical labor, as the heart, or organs having quan- titative chemical functions, as the liver and 38 E. Porak, ' ' Des alterations f onctionelles des glandes surrenales dans la rage" (C. E. de la Soc. de biol., Dec. 7, 1912, LXXIII, p. 601). 37 Almost the same is true in the case of the kidney. Greatly altered kidneys are found in very many cadavers, although the urine of the subjects had always been normal and they had never presented any serious sign of renal insufficiency. It is likewise with the blood which certain pathologists (Widal and his pupils, for example) are investigating for signs of renal or hepatic insuffi- ciency. FUNCTION OF THE GLANDS 223 the kidneys, it is difficult, for reasons which have just been indicated, to under- stand insufficiencies of endocrine glands, since the latter furnish but minute quan- tities of extraordinarily active substances and we must suppose them almost entirely destroyed in order that they should not have the ability to furnish the small quan- tity of secretion absolutely necessary for the vital functions. This does not mean, however, that we must deny a priori the reality of these insufficiencies, but that we should be more stringent than heretofore in accepting demonstrations of this reality. Explanation has been much abused in at- tempting to account for disorders of hypo- secretion and also, generally speaking, for the disorders of all the internal secretions. This has reached such a point that when a syndrome cannot be explained by assuming either hypersecretion or hyposecretion of an endocrine gland, the two factors are brought in. Has it not been said — in 224 THE INTEENAL SECRETIONS acromegaly, for example — that there is at the same time partial "hyperpituitarism" and "hypopituitarism"? Would it not be right to apply to this sort of considerations and to these pathological explanations of glandular disorders what Vulpian wrote concerning pathological explanations by vaso-motor disturbances, at a time when it seemed to physicians that the discoveries of physiologists about the action of the vascular nerves could explain all morbid phenomena? "It was soon admitted that the greater part of the morbid disorders of the organism had for their origin or mechanism a functional modification of the vaso-motor nerves. Fever, inflammation, hemorrhages, dyspepsias, the chief neu- roses, . . . tetanus, various forms of paralysis, diabetes, albuminuria, etc., all these pathological states, or at least their principal symptoms, were due to a pertur- bation of the vaso-motor apparatus. . . . "For my part, I have always fought FUNCTION OF THE GLANDS 225 against this deplorable tendency to apply prematurely facts from experimental phys- iology, as yet uncertain, to pathology. The greater part of the assertions thus made, without any critical spirit, are, besides, absolutely lacking in proof. They are purely theoretical conceptions, the results of the sort of speculations that can be made as one desires. ' ' 38 (3) Trophic Deviations. — It appears certain, however, that there are certain dis- eases depending on alterations of the en- docrine glands. I have posed the question, Can toxic products not be formed in the endocrine glands, the more or less active absorption of which causes morbid syn- dromes? This question confronts at once experimental pathology, pathological chem- istry and the clinician. The notion is un- doubtedly hypothetical, but there are some facts which render it interesting. ""Vulpian, "Legons sur l'appareil vaso-moteur, ' ' vol. i, preface, x, Paria, Germer Bailliere, 1875. 226 THE INTERNAL SECRETIONS Among the theories proposed to explain exophthalmic goiter, there is one, dysthy- roidism, which furnishes an example of tro- phic deviations with concomitant func- tional disorders. I do not mean by this that the theory of dysthyroidism should from now on be considered as proved ; what I do mean is that if it were definitely es- tablished, it would show the pathological importance of functional deviations. It ap- pears to be demonstrated that the thyroid tissue also can be altered by various influ- ences; it has been observed that in many infectious diseases the thyroid secretes an abnormal colloid matter which does not possess its normal staining reactions (M. Gamier, 1899) ; this is dysthyroidism. It would be interesting to investigate if this altered tissue still manifests the physiolog- ical properties of normal thyroid sub- stance. Unfortunately, we have as yet no absolutely characteristic test for proving the activity of the substance of the thyroid. FUNCTION OF THE GLANDS 227 Speaking generally, this sort of studies appears to me to be very useful to patholo- gists. Anatomo-pathological investigation, by which the presence of lesions may be ascertained, must be surpassed. What should really interest the physician and the therapeutist is a knowledge of the func- tional capacity of the diseased organ; the lesion is of little importance as long as the organ fulfils its function. But, in order to make sure of this last point, physiological research is necessary. There are many af- fections considered as glandular or pluri- glandular in which physiological research has been completely neglected and which are only known through post mortem find- ings. And is not the interpretation of these findings uncertain 1 ? Let us take for an example the reaction of hyperplasia, often found in the endocrine glands; at the time when connections between these glands were first beginning to be perceived, this reaction was attributed to a specific 228 THE INTERNAL SECRETIONS vicarious function (hypertrophy of the hypophysis after thyroidectomy, for ex- ample). At present the tendency is to con- nect it with the suppression of a normally antagonistic action. Would it not be pos- sible that the suppression of an endocrine gland should be followed by a special in- toxication, which would provoke in other glands a reaction bordering on hyper- plasia? In order to judge, we must have recourse to investigative procedures other than the anatomo-pathological. Patholo- gists are now engaged in the field of physi- ological exploration, thanks, above all, to the progress made in our knowledge of the chemistry of the blood; but they should also make use of the other methods of physiology. Is not the same true of the adrenals I Is it not generally admitted that the effects of extirpation of these organs do not re- produce exactly the symptoms of Addi- son's disease? Are there not cases of Ad- FUNCTION OF THE GLANDS 229 dison's disease in which the arterial pres- sure is not particularly low? And does not the pigmentation of the skin, so character- istic in this syndrome, prove that the me- tabolism of the adrenals has undergone al- terations because of the influence of the morbid cause ? 39 And has not Pende 40 re- cently attempted to explain the disorders of acromegaly by positing a vitiated pitu- itary secretion, "qualitatively different from the physiological secretion"? Insuf- ficiency or even loss of function may there- fore not constitute the entire disease; the symptoms may depend on the disordered metabolism of the organ. Hence we see that various toxic sub- stances — exogenous as well as endogenous poisons — may act on the glandular cells. 59 See O. von Fubth, "Probleme der physiol. und der pathol. Chemie," Leipzig, 1912, Bd. 1, pp. 418-419. 40 N. Pende, "Studio di morfologia e di fisiopatologia dell 'apparato ipofisario, con speciale riguardo alio neuroipofisi ed alia patogenesi dell 'acromegalia" (II Tommasi, June 10, 1911, pp. 364-369). 230 THE INTERNAL SECRETIONS There are some that fix the cell, then it may degenerate and atrophy. Does not atro- phy of the cells cause passage into the blood of toxic substances that have been re- ceived by them and more or less modified, and at the same time of cellular proteins, products of autolysis or degeneration, themselves toxic f Let us but recall what occurs in cancerous cachexia, resulting from the liberation of endocellular fer- ments (F. Blumenthal). 41 These liberated poisons are different according to the or- gan in which this process occurs. Hence the different syndromes. In some of these syndromes it may be that there is nothing depending on an actual insufficiency of the gland attacked, the parts which remain un- affected still assuring enough of the spe- cific function; but the metabolism of the gland itself is changed and this is perhaps 41 F. Blumenthal, "Die chemischen Vorgange bei der Krebskrankheit ' ' (Ergebnisse der Physiol., 1910, X, pp. 363-428). FUNCTION OF THE GLANDS 231 enough to cause trouble. At least, we may indicate this opportunity for investigation. The problem is complex. Physiology has furnished the foundations and traces its limits; the solution will be the result of extensive analysis, in which physiology will play its part, but which will no less re- sult from the convergent efforts of clini- cal science, experimental pathology and chemistry. INDEX INDEX Absorption, 83 and secretion, 84 Acromegaly, 71 not produced experimen- tally, 216 Addison's disease, 71 and extirpation of adre- nals, 228 Adrenalin, 91, 92 action of, 161 and dilatation of the pupils, 195 and nutritive exchanges, 199 and sympathetic nervous system, 187 and vagotonia, 26 effect of successive in- jections of, in depancreatized ani- mals, 196 in venous blood, 100 Adrenalinemia, 218 Adrenals, action when dis- eased, 221 Albumoses and secretin, 179-80 Anaphylaxis, 119 Ancel, 102 Aschner, 102 Autonomotropic hormones, existence of, 190 Basch, 81, 101 Bayer, 200 Bayliss, 146 Beclard, 30, 46 Bernard, Claude, 16, 43, 46, 47, 50, 73 ideas of, on internal se- cretions, 32 ff. influence of work of, 40- 41 summary of contribu- tions of, 40 Bert, Paul, 47 Berthold, 30, 31 Bibliography, 56, 66-69 Biedl, 19, 20, 23, 25, 30, 31, 57, 59, 87, 109, 154 Bile, absorption of, into blood, 23 and thyroid secretion, 180 Blazek, pygopagus monster, 102 Blood, absorption of bile into, 23 of seminal fluid into, 22 and secretions, relations of, 17 et seq. influences of diseases of spleen on, 28 of thyroid on, 28 modification of, by inter- nal secretions, 51 et seq. relations of, to secretory glands, 32 235 236 INDEX Blood, specific glandular products in, 63, 93, 94 venous, secretion in, 99 Blood glands, 27, 37 Blood pressure, regulation of, by internal se- cretions, 63-65 Bones, growth of, 137, 138, 139 Bordeu, Theophile, as dis- coverer of internal secretions, 19 ff. as pathologist, 23, 25, 27 Bouin, 85, 102 Brown-Sequard, 12, 16, 32, 42, 50, 56, 65 founder of doctrine of secretions, 55, 59 fundamental work of, 51-54 Burdach, 27, 46 Cachexias, 24 Calzolari, 81 Cannon, 182 Carbon dioxid, as excitant, 146-147 as a hormone, 104 classification and func- tion of, 150-151 Carlson, 79 Castration and respiratory exchanges, 159 Cellular excretions, physio- logical rdle of, 152- 153 Cerebro-spinal fluid, 86-87 Cesa-Bianchi, 119, 120 Champy, 85, 115, 120 Chromaffin system, hyper- activity of, 200 Classification of endocrine glands and prod- ucts, 167 ff. chemical, 168 tables, 172 ff. of endocrine products, gaps in, 169 physiological, 169 Coronedi, 79 Corpora lutea, vasodila- tator action of, 124 Cozzolino, 81 Crile, 182 Cunningham, 79 Cybulski, 57 Cyon, E. de, 104 Dale, 161 Delezenne, 99 Development, phenomena of, 166-67 Diabetes, 71 and the adrenals, 197- 198 "negative," 199 relations of lesions of pancreas to, 70 Dreyer, 57 Dysthyroidism, theory of, 226 Ehrlich, 164 Endocrine glands, connec- tions between, 183 ff. diseased function of, 213 ff. normal activities of, 177 ff. study of, 12 with double enervation, 188 INDEX 237 Endocrine products, action of, in minimal doses, 220 ff. classification of, 167 ff. distinctive characteris- tics of, 156 ff. likenesses and differ- ences of, 168 tables of, 172-74 Enriques, 100 Epigenesis, 159 Epinephrin, hypersecretion of, 217 Eppinger, Falta and Kud- inger, diagram of, 184-85, 201 Eppinger and Hess, 189 Ergastoplasm, 88 fitienne, 122 Excretory products, as ex- citants, 148 Findlay, 86 Fleig, 100 Floerken, 81 Foa, 103 Forschback, 97 Founders of doctrine of internal secretions, 32 v. Frankl-Hochwart, 123 Frouin, 197 Functional correlations, 156 Functional humoral corre- lations, 54 Funke, 46 Gachet, 81 Galactogogue action, glands having, 117 Galactogogue hormone, 102 Galeotti, 86 Girard, 86, 87 Gland, conception of, 147, 148 Glands, blood, 27, 37 secretory, relations of blood to, 32 two classes of, 37 with double secretory function, 86 Glandular discharge, excit- ants of, 179 ff. Glandular products, speci- fic, 94 Gley, 52, 55, 56, 58, 79, 96, 98, 106, 115, 120, 216 Glover, 57 Glycose, 91 Glycosuria, after thyroi- dectomy, 203 and the adrenals, 197 extirpation of thyroid in, 208-10 in exophthalmic goiter, 202 Grigoriu, 102 Gull, 48 Gray, 46 Hallion, 100 Harley, 58 Harmozones, 134, 142, 156 Hedon, 58, 97, 98 Heidenhain, 84 Henderson, 81 Henle, 27, 28 Herring, 123 Herzen, 80, 96 Hippocratic school, 25 Homostimulants, 181 Hormonal, 129, 130 dangers of, 131 Hormone, 65, 131, 132, 143 ff. 238 INDEX Hormone, chemical, 143- 144 galactogogue, 102 mammary, 101 physiological, 143-144 Hormones, 157 action of, in minimal doses, 214 characteristics of, 158 general action of, 167 local action of, 165 specificity of, 159 transitory action of, 164 Howell, 122 Humoral interrelations, theory of, 191 Hypersecretion of glandu- lar products, 214 Hyperthyroidism, 216 Hypertony of sympathet- ic nervous system, 26 Hyposecretion of endocrine products, 219 ff. reality of, 222-225 Internal medium, 85 Internal secretions, 35 ff. chemical condition of, 89- 92 concept of, 15, 47 ff. present, 57 ff. conditions necessary for, 77 ff. definition of, 35 distinctive characteristics of, 134 ff. founders of doctrine of, 32 histological condition of, 82-89 physiological condition of, 82 Internal secretions, pre- cursors of doctrine of, 16 regulating development, 137-140 Internal secretory glands, characteristics of, 77 ff. Intestinal mucous mem- brane, 82, 83 Iodothyrin, 61 Iodothyroglobulin, 92 Kocher, 48 Kolliker, 27, 29 Kraus, 187 Laennec, 13 Lambert, 109 Lancereaux, 70 Lane-Claypon, 103 Langlois, 57 Legallois, ideas of, indefi- nite, 18 views of, on glands, 17 Lepine, 58 Lewandowsky, 108 Licini, 210 Liegeois, 45 Liver, 37 as endocrine gland, 33 functions of, 39 secretion of, 32 Loewi, 195-96 Longuet, 30, 42 Lorand, 208 Lucien, 81 Lungs, 37 Lymph, role of, 26 Lymphatic path, 87 Lymphatic veins, 22 INDEX 239 Mammary hormone, 101 Meltzer, 72, 148, 151, 152 Mendel, 96 Mering, von, 57, 70 Milne-Edwards, 30 Minkowski, 57, 58, 70, 97 Mironoff, 63, 101 Morphogenetic substances, 104, 134, 157 necessity of, for term, 135-136 Miiller, 26, 27, 30 Murray, 56 Myxedema, 56 Nervous system, and inter- nal secretion, 181 and thyroid, 182 Neuberger, 19, 23 Neurochemical correlations, 66 Nutritive materials, 91, 134 Nutritive transmutations, 149 Obersteiner, 86 Opotherapy, associative, 193 Oppel, 84 Ord, 48 Organic extracts, action of, 105 ff. advantages from use of, 133 effects of large doses of, 127 errors involved in use of, 108 factors involved in use of, 116 objections of fact to use of, 115 Organic extracts, pharma- codynamic action of, 126 theoretical objections to use of, 113 value of, 106 Ostwald, A., 92 Ott, 117 Pachon, 95, 98 Pancreas, 58, 95 action when partially ex- tirpated, 220-21 and adrenals, reciprocal relations between, 195 and spleen, relations of, 43, 50 proof of internal secre- tion, 96-98 relations of, with thy- roid, 185 relations of lesions of, to diabetes, 70 Parabiosis, 97 Parathyroids, antitoxic mechanism of, 171 Parhormones, 146, 154 Parisot, 81, 122 Pathology and endocrine glands, 70 Paton, 81 Patta, 115 Pettit, 86, 87 Pfliiger, 84 Phenylsulphates, 88, 151 Physiological differentia- tion, evolution of, 162-164 Physiological investigation of endocrine glands, necessity for, 227- 229 240 INDEX Pick and Pineles, 203 Pituitary, action of, 161 effects of extirpation of, 137 Pituitary extract, action of, on bladder, 123 Pluriglandular insufficien- cy, syndromes of, 192 Poisons, exogenous and endogenous, 229-30 Preformation, theory of, 159 Prenant, 85 " Proadrenalin, " 179 Prostate, secretion of, 144 Reciprocal glandular ac- tions, 182 ff. and interrelations, 182- 183 Refluxes, 25 Renon, 191-92 Rettger, 96 Reverdin, A., 48, 71 Reverdin, J. L., 48, 71 Ribbert, 101 Robin, 44, 45, 47 Roger and Josuet, 123 Schafer, 57, 103, 107, 117, 123 Schiff, 43, 48, 50 Schroder, von, 104 Scott, 117 Secretin, 92 correlations established by, 165, 166 in venous blood, 99 sources of, 161 Secretion, internal, concept of, 15 et seq. present, 59 et seq. Secretion, internal, found- ers of doctrine of, 32 precursors of doctrine of, 16 Secretions, blood and, rela- tions of, 17 et seq. externo-internal, 87 importance of, 12 interno-external, 87 kinds of, 11 Secretory glands, relations of blood to, 32 Secretory products, desti- nation of, 149 Seminal fluid, absorption of, into blood, 22 Semon, 71 Soli, 81 Sommer, 81 Specific glandular prod- ucts, 63, 94, 178-179 and katabolism, 64-65 detection of, in blood, 93 Spleen, 80, 95, 96 and pancreas, relations of, 43, 50 diseases of, and influ- ence on blood, 28 Starling, 65, 69, 103, 146 Status lymphaticus, 128, 130 Studnicka, 87 Substitution therapy, 170 Suprarenal extract, cardio- vascular action of, 107 Suprarenin, 158 Szmonovicz, 57 Sympathetic nervous sys- tem, hypertony of, 26 Sympathicotonia, 189 INDEX 241 Tachyphylaxia, 119 crossed, 120 importance of, 121 Temperaments, 24 Testicles, extirpation and grafting of, 30 extract of, 55 lymphatic veins in, 22 Tigerstedt, 145 Thiroloix, 58, 97 Thymus, 80 and growth of bone, 160 Thyroid gland, and adre- nals, reciprocal rela- tions between, 201 and gonads, reciprocal relations between, 210 ft. and nutrition, 62 and pancreas, reciprocal relations between, 208 ft. as excitant of adrenals, 206-207 as internal secretory gland, 80 diseases of, influences of, on blood, 28 function of, 48, 49 relations with pancreas, 184-86 removal of, 48, 56 transplantation of, 49 Thyroid secretions, 70 and vagus, 187 Thyroidectomy, metabolic disorders after, 209 Trophic deviations in en- docrine glands, 225 ff. Trunecek, 102 Underhill and Hilditch, 203 Urea, 91, 104 as excitant, 146, 147 classification of, 146 Uric acid, 151 Vagotonia, 26, 189 disorders arising from, 190-91 Vascular glands, 27, 37 Vassale, 56 Vegetative nervous system and reciprocal glan- dular activities, 187, 189-90 Veins, lymphatic, 22 Venous blood, properties of, 105 Vincent, 88, 122 Vulpian, 42 Waste products as excit- ants, 103 Waterman, 125 Wertheimer, 100 Wilson, 159 Ziilzer, 132 MEDICAL MONOGRAPHS Published by PAUL B. HOEBER 67-69 East 59th St., New York This catalogue comprises only our own publications. It will be noticed that particular care has been exercised in the selec- tion of Monographs of timely interest. We are always glad to consider the publication of new and original medical worlcs. Correspondence ivith Authors is invited. ,\ ADAM: Asthma and Its Eadical Treatment. By James Adam, M.A., m.d., f.r.c.p.s. Hamilton. Dispensary Aural Surgeon, Glasgow Eoyal Infirmary. 8vo, Cloth, viii+184 Pages, Illustrated $1.50 net. ADLEE: Primary Malignant Growths of the Lungs and Bronchi. By I. Adler, a.m., m.d., Professor Emeritus at the New York Polyclinic, Consulting Physician to the German, Beth-Israel, Har Moriah, and People's Hospitals, and Mon- tefiore Home and Hospital. 8vo, Cloth, xii+325 Pages, 1 Colored and 16 Halftone plates $2.50 net. AMEEICAN JOURNAL OF EOENTGENOLOGY, THE. Official Organ of the American Eoentgen Eay Society. Edited by James T. Case, m.d., Battle Creek, Mich. Pub- lished Monthly (Volume IV, No. 1. Published January, 1917). $5.00 per year. ANNALS OF MEDICAL HISTOEY. Edited by Francis E. Packard, m.d. Associate Editors: Drs. Harvey Cushing, George Dock, Mortimer Frank, Fielding H. Garrison, Abra- ham Jacobi, Howard A. Kelly, Arnold C. Klebs, Sir William Osier, Lewis S. Pilcher, David Eiesman and Edward C. Streeter. Published quarterly, $6.00 per year. 1 2 EOEBEB'S MEDICAL MONOGRAPHS ARMSTRONG: I. K. Thebapy, with Special Reference to Tuberculosis. By W. E. M. Armstrong, m.a., m.d. Dublin. Bacteriologist to the Central London Ophthalmic Hospital, Late Assistant in the Inoculation Department, St. Mary's Hospital, Padding, W. 8vo, Cloth, x-j-93 Pages, Illustrated $1.50 net. BACH: Ultra-Violet Light by Means op the Alpine Sun Lamp. By Hugo Bach, m.d., Bad Elster, Saxony, Germany. Authorized Translation from the German. 114 Pages, HIub- trated $1.00 net. BIGG: Indigestion, Constipation and Liver Disorder. By G. Sherman Bigg, Fellow of the Koyal College of Surgeons; Fellow of the Royal Institute of Public Health ; Late Surgeon Captain, Army Medical Staff; Surgeon Allahabad, India, 12mo, Cloth, viii+168 Pages $1.50 net. BEAUN AND FRIESNER: Cerebellar Abscess: Its Eti- ology, Pathology, Diagnosis and Treatment. (See Friesner & Braun) $2.50 net. BBOCKBANK: The Diagnosis and Treatment op Heart Disease. 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