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Fundamental Concepts in Endocrine Diagnosis and Therapy
Mayo Clinic Number
THE MEDICAL CLINICS OF
NORTH AMERICA Number 4
July. 1940
Volume 24
FUNDAMENTAL CONCEPTS IN ENDOCRINE DIAGNOSIS AND THERAPY EDWlN
J.
KEPLER AND LAWRENCE
M.
RANDALL*
The present status of endocrinology.-The youth of
endocrinology as a specialized division of medicine is attested by the fact that even such basic terms as "hormone" and "endocrine" did not appear in tnedicalliterature until the beginning of the present century. Since then endocrinology has become one of the most rapidly growing of all the specialties. Entire laboratories have· devoted all their resources to the investigation of endocrine problems (especially those centering about the pituitary body, adrenal glands and the gonads), and journals have been given over to the publication of their results. Growth not only has been rapid but asymmetric. Clinicians have been unable to follow the pace set by the workers in research. For example, in one of the recent issues of a journal devoted exclusively to endocrinologic matters, less than onefifth of the space was assigned to clinical papers. Not only has the field been dominated by experimentalists but, as so often is the case with a rapidly growing branch of science, results have not always been either conclusive or mutually compatible. It should not be inferred from the foregoing remarks that endocrinology is not making genuine advances. Some of the recent discoveries will rank among the great medical achievements of all time. The biochemists, in particular, have been forging ahead. From the thyroid gland, the adrenal cortex and medulla, the islets of Langerhans and the gonads, they
* With
the assistance of the other contributors to this symposium. 941
942
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
have extracted crystalline substances that provide the means for replacement therapy of a high degree of effectiveness. The chemical formulas of many of these compounds have been ascertained and in some instances synthesis has been accomplished. In the case of the parathyroid glands and the posterior lobe of the pituitary body, extracts have been prepared which can be used clinically. Only the extracts of the anterior lobe of the pituitary body are still crude and on the whole unsatisfactory for clinical use, and there seems little likelihood that good preparations will be available in the near future. As new substances were prepared, new terms became necessary. Some of the terms proved to be unsatisfactory and were subsequently dropped or modified; others that did survive were so cumbersome that they had to be abbreviated. Endocrinologic literature therefore became difficult to read. This fact, in conjunction with the inherent intricacies of the subject matter and the limited critique of the profession when dealing with innovations, has made self-education in endocrinologic matters a particularly difficult problem for most physicians. Another of the several consequences of the present state of affairs has been that even the well-informed practitioner often approaches his diagnostic endocrine problems with a sense of inferiority and views his therapeutic achievements with a feeling of frustration. There has developed, therefore, a demand for a simple, concise and authoritative synopsis of . endocrinology which will enable the physician without specialized training to treat his endocrine patients at least rationally, if not always successfully. Unfortunately, there are no authorities, the subject is still complex, knowledge is limited, and treatment is often unsatisfactory. Probably at least another decade will elapse before the totality of endocrine therapy attains the satisfactory status that now is obtained, for example, in the treatment of myxedema. Need for accurate diagnosis.-The old adage that effective therapy is based on accurate diagnosis is particularly applicable to modern endocrinology. Fifteen years ago, when with the exception of desiccated thyroid or thyroxin, insulin, adrenalin (epinephrine hydrochloride), and pituitrin, the only
ENDOCRINE DIAGNOSIS AND THERAPY
943
available endocrine preparations were relatively inert mixtures that accomplished little except to dep~ete the patient's pocketbook, the consequences of injudicious therapy often were not particularly serious. This situation no longer exists. "Organotherapy" has been displaced by "chemotherapy." Hormonal compounds whose dosage is measured in milligrams are on the market. Their therapeutic potentialities are almost equalled by their capacity to do harm. It has become imperative that the physician who prescribes these substances make an accurate diagnosis, and that he have a clear conception of their pharmaceutic effects, their indications and their therapeutic limitations. In the ensuing series of papers it will be noticed that in some instances the question of therapy has been given scant .attention. The omission has been deliberate, because there are a number of endocrine diseases that are very poorly understood and for which there is no satisfactory treatment. When dealing with such conditions we have felt that it is more important that the physician appreciate the limitations of what is known rather than that he be encouraged to institute uncertain or worthless treatment. Experimental therapeutics had best be left in the hands of the experimentalists. There are also certain conditions in which there is no unanimity of opinion regarding the merits of several therapeutic procedures. In such instances it is now manifestly impossible to present in didactic form the best method. Finally, there remains a number of diseases that have been studied carefully over long periods. Here medical opinion has had a chance to crystallize and therapy has been fairly well standardized and stereotyped. In dealing with this group of diseases we have felt that we were justified in stressing therapy at the expense of physiologic and diagnostic considerations. Before proceeding with a discussion of the diseases of the individual ductless glands we feel that some attention should be given to certain general principles that seem to apply to the endocrine system as a whole. These principles may have to be modified or discarded in the future, and they do not necessarily apply with equal force to each member of the system. Nevertheless, irrespective of their ultimate worth, for the time being they do serve to correlate a vast amount of physiologic and
944
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
clinical factual material that is otherwise detached and meaningless. Hormones.-In many respects the glands of internal secretion are similar to chemical manufacturing plants. Raw chemical materials are brought to the glands, new compounds are manufactured, and these in turn are transported elsewhere for use. These new compounds are known as "hormones," which is a term that is derived from the Greek and means "I rouse to activity." Hormones have the property of setting up definite and specific types of physiologic activity in cells or receptors which have the capacity* to respond to the presence of the hormone. Some hormones seem to influence the activity of most, if not all, of the cells of the body; the effects that are produced by others are limited to certain organs or even to certain cells within an organ. In the main there are two types of hormones that are synthesized by the ductless glands: 1. Hormones of the first type influence primarily intracellular and extracellular chemical reactions and thereby serve to keep the chemical interchanges of the body constant within physiologic limits. Thyroxin is a good example of such a hormone. In the absence of thyroxin, the utilization of oxygen by the cells decreases, and the production of heat by the body under basal conditions is diminished by about 40 per cent. The decreased ability of the cells to use oxygen at the normal rate produces in turn a wide variety of interesting side effects, the end result of which in man is the reduction of life to a mere vegetative existence. It is important to notice that chemical interchanges involving oxygen do continue, but that such interchanges are no longer within the prescribed limits that are essential to health. 2. Hormones of the second type co-ordinate the function of certain cells and organs with other organs or with the needs and activities of the organism as a whole. In this group belong, for example, the secretory products of the gonads and the anterior lobe of the pituitary. The response of the female breast to hormonal influences that are present during pregnancy and lactation exemplifies the co-ordination of the function of
* Not only do the different tissues vary among themselves in their capacity to respond to the presence of a hormone, but they may possibly vary in this respect from time to time as the result of either local or distant influences.
ENDOCRINE DIAGNOSIS AND THERAPY
945
one organ with the physiologic activity of the entire organism. Many, but not all, of the hormones in this group produce structural as well as chemical changes. If we were to accept Cannon's view that the adrenal medulla secretes epinephrine (adrenalin) during periods of emergency, we should have an example of a hormone which is co-ordinating the function of anatomically unrelated structures for a common purpose, namely, defense.
Terms relating to diseases of the endocrine glands.
-Diseases of the endocrine glands are usually, but not always, accompanied by quantitative changes in the secretory activity of the diseased organ. In some instances there is evidence to suggest that qualitative abnormalities of secretion may occur. In such cases it is thought that the gland synthesizes an abnormal chemical molecule which has hormonal properties that may differ materially from those manifested by the normal hormone. Some of the clinical phenomena which occur in conjunction with tumors of the adrenal cortex can best be explained by such a hypothesis. The self-explanatory terms hypofunction and hyperfunction are used to designate quantitative departures from normal secretory activity. The terms dysfunction and malfunction are often used so loosely that they cease to have exact meaning. Sometimes they imply the production of an abnormal hormonal molecule. Again the terms seem to refer to secretory activity that may be essentially normal in both quality and quantity, but which is poorly timed in relation to the needs of the body as a whole or to the activity of other members of the endocrine system. Very often these- terms are used to cover a multitude of endocrine sins, in which case they are about synonymous with the expression frequently used by patients: "I must have something wrong with my glands." They should not be used as descriptive or diagnostic terms unless the precise meaning that is intended is specifically defined. The term imbalance is of use in gynecologic endocrinology to. desigQate abnormal quantitative and possibly qualitative relationships among the various hormones that are involved in the maintenance of the menstrual cycle. When this term is used to describe nongynecologic endocrinopathies, the implied meaning is not always clear. VOL. 24-60
946
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
Finally, not infrequently terms such as endocrine dyscrasia are applied to conditions (for example, simple obesity) that are characterized by certain stigmas that are somewhat suggestive of an underlying endocrine disorder. In many of these conditions it is impossible with present methods to demonstrate by means of quantitative measurements any abnormality of the endocrine system. When such problems are encountered there is little to be gained by the use of a diagnostic term which incriminates either the endocrine system or its individual members.
Lesions most commonly associated with abnonnalities of secretory activity.-It is frequently stated that abnormal
secretory activity of an endocrine gland cannot be estimated by its histologic appearance. This statement is only partially true, because in most instances bona fide endocrine disease is usually found to be attended by some histopathologic change in the particular organ at fault. The severity of the clinical symptoms, however, may not always be commensurate either with the gross or the microscopic pathologic findings. For example, the physician occasionally sees instances of severe exophthalmic goiter associated with comparatively slight alterations in the histologic appearance of the thyroid gland. In spite of such lack of correlation that may be obtained in certain diseases, in the main it may be stated that organic endocrine diseases are usually associated with structural changes in the gland at fault. In this connection it should be recalled that the endocrine glands, even though they are anatomically normal, cannot function unless they are supplied with adequate raw materials (minerals, vitamins and other foodstuffs) from which hormones can be synthesized. Furthermore, the function of certain endocrine organs, notably the anterior lobe of the pituitary body and the gonads, is dependent to a considerable extent on the general health of the body. Bearing in mind, then, the limitations of the conclusions that can be drawn from pathologic findings, one can summarize the lesions that are most commonly found in conjunction with abnormalities of secretory activity as follows: 1. Glandular hyperjunction is usually associated with (a)
ENDOCRINE DIAGNOSIS AND THERAPY
947
diffuse 'hyperplasia* or hypertrophy of the entire gland, or with (b) adenomatous or malignant tumors. Such tumors often are functioning entities whose secretory activity is not under the control of those mechanisms which regulate the secretion of the normal gland. Hence, they continue to secrete without regard to the requirements of the body for their hormones. 2. Primary glandular hypofunction is frequently found in conjunction either with (a) hypoplastic lesions, or (b) destructive lesions of the glandular parenchyma, such as atrophy, fibrosis, destructive hemorrhage, acute inflammations, tuberculosis and other chronic inflammatory processes, granulomatou.s lesions, hemochromatosis, amyloid disease, metastatic malignancy and non functioning or infiltrating neoplasms. Most of the glands have relatively large factors of safety, so that most of the parenchyma has to be destroyed before symptoms of hypofunction make their appearance. Furthermore, there is a great deal of evidence to suggest that as progressive lesions destroy more and more of the gland, the residual healthy glandular tissue compensates by becoming hypertrophic. This phenomenon can best be observed in the case of the paired ductless glands. Secondary glandular hypofunction occurs as the result of anterior pituitary insufficiency. The latter may follow either as the result of an organic lesion of the pituitary body or as the result of metabolic disorders, poor hygienic conditions or systemic disease elsewhere in the body. Rela.tion of adenomatous tissue to endocrine function.-An understanding of the peculiar relationship of adeno... We have used the term "hyperplasia" somewhat loosely to designate the nonneoplastic parenchymatous enlargement of a ductless gland. Unquestionably in some instances the term "parenchymatous hypertrophy" would be preferable; in others, our knowledge of the histopathology is not sufficient to justify the selection of either term in preference to the other. The word "adenoma" is a generic term that has been used to denote any benign epithelial tumor with a gland-like structure. It has been applied to a variety of lesions that exhibit such adenoma-like morphology. In addition the term often connotes a pathologic process which has a histologic resemblance to the' architecture and a secretory resemblance to the physiology of the tissue from which the tumor arose. The rigid denotation of the word is gradually giving way, especially in endocrinologic literature, to its more useful connotation. In the ensuing series of papers the term shoul! not be interpreted in its strict morphologic sense.
948
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
matous tissue to endocrine glandular function is so important that it is worth while to recapitulate: 1. Adenomas without clinical evidence of hyperfunction are frequently found at necropsy. This finding does not imply that such adenomas were not functioning. It usually does signify that the sum total of hormone that was made by the adenomatous and nonadenomatous tissue was not excessive. 2. The outstanding characteristic of hyperfunctioning adenomas is their tendency to function irrespective of the needs of the body. Apparently, they are not inhibited by the normal mechanisms that regulate glandular secretory activity. 3. When adenomatous tissue hyperfunctions, the remaining nonadenomatous glandular tissue from which the adenoma was derived tends to hypofunction and may become functionally inadequate or even actually atrophic. Such atrophic tissue usually regenerates if the adenoma is removed, but until regeneration or renewal of function does occur there may be a period in which the body suffers from an inadequate supply of the hormone that had been manufactured by the adenoma. The temporary diabetes that follows the removal of a hyperfunctioning tumor of the islets of Langerhans illustrates this point nicely. More important, however, are the cortical adrenal insufficiency and the tetany that occur after the removal of adrenal cortical tumors and tumors of the parathyroid bodies. The application of this principle to adenomas of the thyroid gland has not been demonstrated. Fundamental principles of treatment.-The mechanism that determines the secretory activity of the endocrine organs is not known. It is frequently stated that the anterior lobe of the pituitary body is a "master gland" that "controls" the functional activity of the remaining members of the endocrine system. We do not feel that the available evidence at present justifies the unqualified acceptance of this conception of anterior pituitary function. The problems involved have more than academic significance, because there has been a tendency to look upon (and treat accordingly) the anterior pituitary body as the primary cause of a number of both endocrine and nonendocrine diseases of unknown etiology. On the whole, the therapeutic accomplishments that have sprung from this philosophy have been singularly unsuccessful.
ENDOCRINE DIAGNOSIS AND THERAPY
949
The fundamental principles of the treatment of endocrine disorders are relatively simple. They may, however, be exceedingly difficult to apply. With few exceptions, the effective treatment of hyperfunctioning lesions is surgical. If the lesion is a benign or operable neoplasm, the surgical removal of the tumor usually results in cure. On the other hand, if the lesion is hyperplastic in character, the surgical reduction of the mass of hyperplastic tissue is less likely to be of benefit except in cases of exophthalmic goiter. If, for various reasons, surgical treatment is inadvisable (as is the case with certain types of pituitary tumor), roentgen therapy may reduce the mass of hypetfunctioning tissue. Attempts to depress the hormonal output of hyperplastic or neoplastic tissue are frequently made by administering large amounts of a hormone that is thought to be directly or indirectly antagonistic to the gland that is diseased. The rationale behind this type of therapy at first sight appears highly logical. However, it does not take cognizance of the crucial fact that the lesions which are responsible for the symptoms are probably no longer amenable to control mechanisms. In addition to the weakness of the theory, there remains the very valid objection that, on the whole, this type of therapy has yielded either unsatisfactory or equivocal results. This statement is not vitiated by the fact that menopausal symptoms can be treated successfully by estrogenic substances. The menopause is not a "disease" and its attending symptoms are not the result of hyperplastic or neoplastic disturbances of the ovaries or the anterior pituitary body. If an endocrine gland is destroyed or incapacitated by disease, the resulting symptoms of hypofunction usually can be controlled by the administration of its hormone. Such replacement therapy is limited necessarily by the availability or" potent hormonal preparations and to some extent by the degree of similitude of the effects produced by the administration of the hormone to the normal action of the gland itself. For example, the treatment of severe diabetes mellitus is not always entirely satisfactory because of the differences between periodic injections of insulin and the secretion of insulin by the normal pancreas. In spite of its limitations, replacement therapy is of great value in many of the various endocrine insufficiencies.
95 0
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
Thus far, however, it has been of very little value in the treatment of severe degrees of anterior pituitary insufficiency such as the physician sees, for example, in instances of chromophobe pituitary tumor. Replacement therapy should be sharply distinguished from simulating therapy. The former is indicated when an endorine gland is hopelessly damaged as the result of disease; the latter, when a gland is anatomically capable of functioning but for various reasons does not do so. The anterior lobe of the pituitary body and the ovaries seem to be particularly sensitive to extraneous influences which interfere with normal function, and it is in such conditions that stimulating therapy has the greatest usefulness. Hygienic regimens, vitamin and dietary therapy and "stimulating" doses of roentgen rays are among the measures in this category that are frequently used. When administered to experimental animals, the various extracts that have been prepared from the anterior lobe of the pituitary body seem to have specific stimulating properties on some of (the other endocrine organs. With few exceptions comparable results have not been obtained in clinical medicine. The hormonal "pituitary-like" substances that are present in the blood and urine during pregnancy have been prepared for clinical use. These substances have the property of stimulating ovarian and testicular function. They have been shown to be of value in the treatment of certain gynecologic disorders (see Dr. Randall's article), and in the treatment of undescended testes and delayed puberty in boys. Here again a word of caution is necessary because of the tendency to prescribe them in cases in which both the diagnosis and the necessity of treatment have been indeterminate. Indiscriminate endocrine therapy of this type not only may be physically injurious, but it is often the instigator of severe anxiety states. Furthermore, it is always expensive. If the use of any of these substances is contemplated, it is advisable to bear in mind the fact that hormones act on specific receptors and that the response to stimulation by anterior pituitary or anterior-pituitary-like hormones will be dependent on the capacity of the cells in the receptor to respond. Replacement therapy should not be used indiscriminately. It does not stimulate either a normal or a diseased gland to
~
ENDOCRINE DIAGNOSIS AND THERAPY
951
produce'its own hormone, and as a general rule, therefore, it should not be administered when the objective in view is an increase in the ability of,a gland to deliver its own product. In fact, long-continued administration of a hormone in large amounts may actually inhibit the secretory activity of any healthy tissue which is secreting that hormone, so that the end result is a situation comparable to disuse atrophy. Fifteen years ago the subject of glandular therapy was discussed in a series of articles prepared under the auspices of the Council on Pharmacy and Chemistry of the American Medical Association. The introductory article was written by Dr. Frank Billings. After commenting on the difficulties in the "differentiation between the morbid .conditions due to deficiencies of secretions of the internal glands and deficiencies in growth, development and other morbid conditions due to want of sunlight and a properly balanced diet" and on the lack of knowledge of the specific glandular principles that were "contained in the preparations used orally, subcutaneously, intravenously or as enemas," he concluded his discussion with the following remarks: "It must therefore be admitted that, at present, substitutional organotherapy in the treatment of conditions alleged to be due to deficiencies of the glands of internal secretion, with the exception of the thyroid and pancreas, cannot be utilized in general practice with the hope that definite results will be obtained. This should not, however, deter experimental substitutional organotherapy by clinicians on animals and patients under conditions that will insure scientific accuracy. The experimental studies might well include the transplantation of glands including the gonads, with the hope that this type of organotherapy may become of real benefit when rationally indicated and utilized. "The brilliant results attending the use of preparations of the thyroid, including thyroxin, and of insulin afford reasonable belief that other important glands of internal secretion will be found to yield active principles that will arm us with specific agents for the correction of morbid conditions due to deficiencies of secretion of the respective glands. In the meantime, recognizing our responsibility to the public in this as in other matters that affect the welfare of the people, we should not continue to patronize and support those manufacturers of glandular remedies who make statements of specific virtues posSessed by pluriglandular preparations that are without foundation of fact. . The existence and continued pernicious influence of the manufacturers of glandular products who publish statements of their therapeutic value without the support of established physiologic and clinical facts will depend on whether the medical profession will patronize them. A decided forward step would
952
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
be taken if physicians were to limit their use of animal organ preparations to those admitted to the United States Pharmacopoeia and the current edition of New and Nonofficial Remedies. "The endeavor has been made to present in this introductory statement the present status of organotherapy as based on exiSting knowledge of the physiology, both normal and pathologic, of the glands of internal secretion. The judgment and the conclusions formed in regard to problems in biology that are not fully understood today may require a change of opinion and verdict in the future. Therefore, the opinions and judgment expressed in this brief statement in regard to the value of organotherapy today may require readjustment tomorrow."
That remarkable progress has been made in the intervening years is immediately apparent, and that the fundamental philosophy of Dr. Billings regarding endocrine therapy is as sound today as it was the day on which it was written needs no comment.
THE MEDICAL CLINICS OF
NORTH AMERICA Number 4
July. 1940
Volume 24
FUNDAMENTAL CONCEPTS IN ENDOCRINE DIAGNOSIS AND THERAPY EDWlN
J.
KEPLER AND LAWRENCE
M.
RANDALL*
The present status of endocrinology.-The youth of
endocrinology as a specialized division of medicine is attested by the fact that even such basic terms as "hormone" and "endocrine" did not appear in tnedicalliterature until the beginning of the present century. Since then endocrinology has become one of the most rapidly growing of all the specialties. Entire laboratories have· devoted all their resources to the investigation of endocrine problems (especially those centering about the pituitary body, adrenal glands and the gonads), and journals have been given over to the publication of their results. Growth not only has been rapid but asymmetric. Clinicians have been unable to follow the pace set by the workers in research. For example, in one of the recent issues of a journal devoted exclusively to endocrinologic matters, less than onefifth of the space was assigned to clinical papers. Not only has the field been dominated by experimentalists but, as so often is the case with a rapidly growing branch of science, results have not always been either conclusive or mutually compatible. It should not be inferred from the foregoing remarks that endocrinology is not making genuine advances. Some of the recent discoveries will rank among the great medical achievements of all time. The biochemists, in particular, have been forging ahead. From the thyroid gland, the adrenal cortex and medulla, the islets of Langerhans and the gonads, they
* With
the assistance of the other contributors to this symposium. 941
942
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
have extracted crystalline substances that provide the means for replacement therapy of a high degree of effectiveness. The chemical formulas of many of these compounds have been ascertained and in some instances synthesis has been accomplished. In the case of the parathyroid glands and the posterior lobe of the pituitary body, extracts have been prepared which can be used clinically. Only the extracts of the anterior lobe of the pituitary body are still crude and on the whole unsatisfactory for clinical use, and there seems little likelihood that good preparations will be available in the near future. As new substances were prepared, new terms became necessary. Some of the terms proved to be unsatisfactory and were subsequently dropped or modified; others that did survive were so cumbersome that they had to be abbreviated. Endocrinologic literature therefore became difficult to read. This fact, in conjunction with the inherent intricacies of the subject matter and the limited critique of the profession when dealing with innovations, has made self-education in endocrinologic matters a particularly difficult problem for most physicians. Another of the several consequences of the present state of affairs has been that even the well-informed practitioner often approaches his diagnostic endocrine problems with a sense of inferiority and views his therapeutic achievements with a feeling of frustration. There has developed, therefore, a demand for a simple, concise and authoritative synopsis of . endocrinology which will enable the physician without specialized training to treat his endocrine patients at least rationally, if not always successfully. Unfortunately, there are no authorities, the subject is still complex, knowledge is limited, and treatment is often unsatisfactory. Probably at least another decade will elapse before the totality of endocrine therapy attains the satisfactory status that now is obtained, for example, in the treatment of myxedema. Need for accurate diagnosis.-The old adage that effective therapy is based on accurate diagnosis is particularly applicable to modern endocrinology. Fifteen years ago, when with the exception of desiccated thyroid or thyroxin, insulin, adrenalin (epinephrine hydrochloride), and pituitrin, the only
ENDOCRINE DIAGNOSIS AND THERAPY
943
available endocrine preparations were relatively inert mixtures that accomplished little except to dep~ete the patient's pocketbook, the consequences of injudicious therapy often were not particularly serious. This situation no longer exists. "Organotherapy" has been displaced by "chemotherapy." Hormonal compounds whose dosage is measured in milligrams are on the market. Their therapeutic potentialities are almost equalled by their capacity to do harm. It has become imperative that the physician who prescribes these substances make an accurate diagnosis, and that he have a clear conception of their pharmaceutic effects, their indications and their therapeutic limitations. In the ensuing series of papers it will be noticed that in some instances the question of therapy has been given scant .attention. The omission has been deliberate, because there are a number of endocrine diseases that are very poorly understood and for which there is no satisfactory treatment. When dealing with such conditions we have felt that it is more important that the physician appreciate the limitations of what is known rather than that he be encouraged to institute uncertain or worthless treatment. Experimental therapeutics had best be left in the hands of the experimentalists. There are also certain conditions in which there is no unanimity of opinion regarding the merits of several therapeutic procedures. In such instances it is now manifestly impossible to present in didactic form the best method. Finally, there remains a number of diseases that have been studied carefully over long periods. Here medical opinion has had a chance to crystallize and therapy has been fairly well standardized and stereotyped. In dealing with this group of diseases we have felt that we were justified in stressing therapy at the expense of physiologic and diagnostic considerations. Before proceeding with a discussion of the diseases of the individual ductless glands we feel that some attention should be given to certain general principles that seem to apply to the endocrine system as a whole. These principles may have to be modified or discarded in the future, and they do not necessarily apply with equal force to each member of the system. Nevertheless, irrespective of their ultimate worth, for the time being they do serve to correlate a vast amount of physiologic and
944
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
clinical factual material that is otherwise detached and meaningless. Hormones.-In many respects the glands of internal secretion are similar to chemical manufacturing plants. Raw chemical materials are brought to the glands, new compounds are manufactured, and these in turn are transported elsewhere for use. These new compounds are known as "hormones," which is a term that is derived from the Greek and means "I rouse to activity." Hormones have the property of setting up definite and specific types of physiologic activity in cells or receptors which have the capacity* to respond to the presence of the hormone. Some hormones seem to influence the activity of most, if not all, of the cells of the body; the effects that are produced by others are limited to certain organs or even to certain cells within an organ. In the main there are two types of hormones that are synthesized by the ductless glands: 1. Hormones of the first type influence primarily intracellular and extracellular chemical reactions and thereby serve to keep the chemical interchanges of the body constant within physiologic limits. Thyroxin is a good example of such a hormone. In the absence of thyroxin, the utilization of oxygen by the cells decreases, and the production of heat by the body under basal conditions is diminished by about 40 per cent. The decreased ability of the cells to use oxygen at the normal rate produces in turn a wide variety of interesting side effects, the end result of which in man is the reduction of life to a mere vegetative existence. It is important to notice that chemical interchanges involving oxygen do continue, but that such interchanges are no longer within the prescribed limits that are essential to health. 2. Hormones of the second type co-ordinate the function of certain cells and organs with other organs or with the needs and activities of the organism as a whole. In this group belong, for example, the secretory products of the gonads and the anterior lobe of the pituitary. The response of the female breast to hormonal influences that are present during pregnancy and lactation exemplifies the co-ordination of the function of
* Not only do the different tissues vary among themselves in their capacity to respond to the presence of a hormone, but they may possibly vary in this respect from time to time as the result of either local or distant influences.
ENDOCRINE DIAGNOSIS AND THERAPY
945
one organ with the physiologic activity of the entire organism. Many, but not all, of the hormones in this group produce structural as well as chemical changes. If we were to accept Cannon's view that the adrenal medulla secretes epinephrine (adrenalin) during periods of emergency, we should have an example of a hormone which is co-ordinating the function of anatomically unrelated structures for a common purpose, namely, defense.
Terms relating to diseases of the endocrine glands.
-Diseases of the endocrine glands are usually, but not always, accompanied by quantitative changes in the secretory activity of the diseased organ. In some instances there is evidence to suggest that qualitative abnormalities of secretion may occur. In such cases it is thought that the gland synthesizes an abnormal chemical molecule which has hormonal properties that may differ materially from those manifested by the normal hormone. Some of the clinical phenomena which occur in conjunction with tumors of the adrenal cortex can best be explained by such a hypothesis. The self-explanatory terms hypofunction and hyperfunction are used to designate quantitative departures from normal secretory activity. The terms dysfunction and malfunction are often used so loosely that they cease to have exact meaning. Sometimes they imply the production of an abnormal hormonal molecule. Again the terms seem to refer to secretory activity that may be essentially normal in both quality and quantity, but which is poorly timed in relation to the needs of the body as a whole or to the activity of other members of the endocrine system. Very often these- terms are used to cover a multitude of endocrine sins, in which case they are about synonymous with the expression frequently used by patients: "I must have something wrong with my glands." They should not be used as descriptive or diagnostic terms unless the precise meaning that is intended is specifically defined. The term imbalance is of use in gynecologic endocrinology to. desigQate abnormal quantitative and possibly qualitative relationships among the various hormones that are involved in the maintenance of the menstrual cycle. When this term is used to describe nongynecologic endocrinopathies, the implied meaning is not always clear. VOL. 24-60
946
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
Finally, not infrequently terms such as endocrine dyscrasia are applied to conditions (for example, simple obesity) that are characterized by certain stigmas that are somewhat suggestive of an underlying endocrine disorder. In many of these conditions it is impossible with present methods to demonstrate by means of quantitative measurements any abnormality of the endocrine system. When such problems are encountered there is little to be gained by the use of a diagnostic term which incriminates either the endocrine system or its individual members.
Lesions most commonly associated with abnonnalities of secretory activity.-It is frequently stated that abnormal
secretory activity of an endocrine gland cannot be estimated by its histologic appearance. This statement is only partially true, because in most instances bona fide endocrine disease is usually found to be attended by some histopathologic change in the particular organ at fault. The severity of the clinical symptoms, however, may not always be commensurate either with the gross or the microscopic pathologic findings. For example, the physician occasionally sees instances of severe exophthalmic goiter associated with comparatively slight alterations in the histologic appearance of the thyroid gland. In spite of such lack of correlation that may be obtained in certain diseases, in the main it may be stated that organic endocrine diseases are usually associated with structural changes in the gland at fault. In this connection it should be recalled that the endocrine glands, even though they are anatomically normal, cannot function unless they are supplied with adequate raw materials (minerals, vitamins and other foodstuffs) from which hormones can be synthesized. Furthermore, the function of certain endocrine organs, notably the anterior lobe of the pituitary body and the gonads, is dependent to a considerable extent on the general health of the body. Bearing in mind, then, the limitations of the conclusions that can be drawn from pathologic findings, one can summarize the lesions that are most commonly found in conjunction with abnormalities of secretory activity as follows: 1. Glandular hyperjunction is usually associated with (a)
ENDOCRINE DIAGNOSIS AND THERAPY
947
diffuse 'hyperplasia* or hypertrophy of the entire gland, or with (b) adenomatous or malignant tumors. Such tumors often are functioning entities whose secretory activity is not under the control of those mechanisms which regulate the secretion of the normal gland. Hence, they continue to secrete without regard to the requirements of the body for their hormones. 2. Primary glandular hypofunction is frequently found in conjunction either with (a) hypoplastic lesions, or (b) destructive lesions of the glandular parenchyma, such as atrophy, fibrosis, destructive hemorrhage, acute inflammations, tuberculosis and other chronic inflammatory processes, granulomatou.s lesions, hemochromatosis, amyloid disease, metastatic malignancy and non functioning or infiltrating neoplasms. Most of the glands have relatively large factors of safety, so that most of the parenchyma has to be destroyed before symptoms of hypofunction make their appearance. Furthermore, there is a great deal of evidence to suggest that as progressive lesions destroy more and more of the gland, the residual healthy glandular tissue compensates by becoming hypertrophic. This phenomenon can best be observed in the case of the paired ductless glands. Secondary glandular hypofunction occurs as the result of anterior pituitary insufficiency. The latter may follow either as the result of an organic lesion of the pituitary body or as the result of metabolic disorders, poor hygienic conditions or systemic disease elsewhere in the body. Rela.tion of adenomatous tissue to endocrine function.-An understanding of the peculiar relationship of adeno... We have used the term "hyperplasia" somewhat loosely to designate the nonneoplastic parenchymatous enlargement of a ductless gland. Unquestionably in some instances the term "parenchymatous hypertrophy" would be preferable; in others, our knowledge of the histopathology is not sufficient to justify the selection of either term in preference to the other. The word "adenoma" is a generic term that has been used to denote any benign epithelial tumor with a gland-like structure. It has been applied to a variety of lesions that exhibit such adenoma-like morphology. In addition the term often connotes a pathologic process which has a histologic resemblance to the' architecture and a secretory resemblance to the physiology of the tissue from which the tumor arose. The rigid denotation of the word is gradually giving way, especially in endocrinologic literature, to its more useful connotation. In the ensuing series of papers the term shoul! not be interpreted in its strict morphologic sense.
948
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
matous tissue to endocrine glandular function is so important that it is worth while to recapitulate: 1. Adenomas without clinical evidence of hyperfunction are frequently found at necropsy. This finding does not imply that such adenomas were not functioning. It usually does signify that the sum total of hormone that was made by the adenomatous and nonadenomatous tissue was not excessive. 2. The outstanding characteristic of hyperfunctioning adenomas is their tendency to function irrespective of the needs of the body. Apparently, they are not inhibited by the normal mechanisms that regulate glandular secretory activity. 3. When adenomatous tissue hyperfunctions, the remaining nonadenomatous glandular tissue from which the adenoma was derived tends to hypofunction and may become functionally inadequate or even actually atrophic. Such atrophic tissue usually regenerates if the adenoma is removed, but until regeneration or renewal of function does occur there may be a period in which the body suffers from an inadequate supply of the hormone that had been manufactured by the adenoma. The temporary diabetes that follows the removal of a hyperfunctioning tumor of the islets of Langerhans illustrates this point nicely. More important, however, are the cortical adrenal insufficiency and the tetany that occur after the removal of adrenal cortical tumors and tumors of the parathyroid bodies. The application of this principle to adenomas of the thyroid gland has not been demonstrated. Fundamental principles of treatment.-The mechanism that determines the secretory activity of the endocrine organs is not known. It is frequently stated that the anterior lobe of the pituitary body is a "master gland" that "controls" the functional activity of the remaining members of the endocrine system. We do not feel that the available evidence at present justifies the unqualified acceptance of this conception of anterior pituitary function. The problems involved have more than academic significance, because there has been a tendency to look upon (and treat accordingly) the anterior pituitary body as the primary cause of a number of both endocrine and nonendocrine diseases of unknown etiology. On the whole, the therapeutic accomplishments that have sprung from this philosophy have been singularly unsuccessful.
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The fundamental principles of the treatment of endocrine disorders are relatively simple. They may, however, be exceedingly difficult to apply. With few exceptions, the effective treatment of hyperfunctioning lesions is surgical. If the lesion is a benign or operable neoplasm, the surgical removal of the tumor usually results in cure. On the other hand, if the lesion is hyperplastic in character, the surgical reduction of the mass of hyperplastic tissue is less likely to be of benefit except in cases of exophthalmic goiter. If, for various reasons, surgical treatment is inadvisable (as is the case with certain types of pituitary tumor), roentgen therapy may reduce the mass of hypetfunctioning tissue. Attempts to depress the hormonal output of hyperplastic or neoplastic tissue are frequently made by administering large amounts of a hormone that is thought to be directly or indirectly antagonistic to the gland that is diseased. The rationale behind this type of therapy at first sight appears highly logical. However, it does not take cognizance of the crucial fact that the lesions which are responsible for the symptoms are probably no longer amenable to control mechanisms. In addition to the weakness of the theory, there remains the very valid objection that, on the whole, this type of therapy has yielded either unsatisfactory or equivocal results. This statement is not vitiated by the fact that menopausal symptoms can be treated successfully by estrogenic substances. The menopause is not a "disease" and its attending symptoms are not the result of hyperplastic or neoplastic disturbances of the ovaries or the anterior pituitary body. If an endocrine gland is destroyed or incapacitated by disease, the resulting symptoms of hypofunction usually can be controlled by the administration of its hormone. Such replacement therapy is limited necessarily by the availability or" potent hormonal preparations and to some extent by the degree of similitude of the effects produced by the administration of the hormone to the normal action of the gland itself. For example, the treatment of severe diabetes mellitus is not always entirely satisfactory because of the differences between periodic injections of insulin and the secretion of insulin by the normal pancreas. In spite of its limitations, replacement therapy is of great value in many of the various endocrine insufficiencies.
95 0
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
Thus far, however, it has been of very little value in the treatment of severe degrees of anterior pituitary insufficiency such as the physician sees, for example, in instances of chromophobe pituitary tumor. Replacement therapy should be sharply distinguished from simulating therapy. The former is indicated when an endorine gland is hopelessly damaged as the result of disease; the latter, when a gland is anatomically capable of functioning but for various reasons does not do so. The anterior lobe of the pituitary body and the ovaries seem to be particularly sensitive to extraneous influences which interfere with normal function, and it is in such conditions that stimulating therapy has the greatest usefulness. Hygienic regimens, vitamin and dietary therapy and "stimulating" doses of roentgen rays are among the measures in this category that are frequently used. When administered to experimental animals, the various extracts that have been prepared from the anterior lobe of the pituitary body seem to have specific stimulating properties on some of (the other endocrine organs. With few exceptions comparable results have not been obtained in clinical medicine. The hormonal "pituitary-like" substances that are present in the blood and urine during pregnancy have been prepared for clinical use. These substances have the property of stimulating ovarian and testicular function. They have been shown to be of value in the treatment of certain gynecologic disorders (see Dr. Randall's article), and in the treatment of undescended testes and delayed puberty in boys. Here again a word of caution is necessary because of the tendency to prescribe them in cases in which both the diagnosis and the necessity of treatment have been indeterminate. Indiscriminate endocrine therapy of this type not only may be physically injurious, but it is often the instigator of severe anxiety states. Furthermore, it is always expensive. If the use of any of these substances is contemplated, it is advisable to bear in mind the fact that hormones act on specific receptors and that the response to stimulation by anterior pituitary or anterior-pituitary-like hormones will be dependent on the capacity of the cells in the receptor to respond. Replacement therapy should not be used indiscriminately. It does not stimulate either a normal or a diseased gland to
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ENDOCRINE DIAGNOSIS AND THERAPY
951
produce'its own hormone, and as a general rule, therefore, it should not be administered when the objective in view is an increase in the ability of,a gland to deliver its own product. In fact, long-continued administration of a hormone in large amounts may actually inhibit the secretory activity of any healthy tissue which is secreting that hormone, so that the end result is a situation comparable to disuse atrophy. Fifteen years ago the subject of glandular therapy was discussed in a series of articles prepared under the auspices of the Council on Pharmacy and Chemistry of the American Medical Association. The introductory article was written by Dr. Frank Billings. After commenting on the difficulties in the "differentiation between the morbid .conditions due to deficiencies of secretions of the internal glands and deficiencies in growth, development and other morbid conditions due to want of sunlight and a properly balanced diet" and on the lack of knowledge of the specific glandular principles that were "contained in the preparations used orally, subcutaneously, intravenously or as enemas," he concluded his discussion with the following remarks: "It must therefore be admitted that, at present, substitutional organotherapy in the treatment of conditions alleged to be due to deficiencies of the glands of internal secretion, with the exception of the thyroid and pancreas, cannot be utilized in general practice with the hope that definite results will be obtained. This should not, however, deter experimental substitutional organotherapy by clinicians on animals and patients under conditions that will insure scientific accuracy. The experimental studies might well include the transplantation of glands including the gonads, with the hope that this type of organotherapy may become of real benefit when rationally indicated and utilized. "The brilliant results attending the use of preparations of the thyroid, including thyroxin, and of insulin afford reasonable belief that other important glands of internal secretion will be found to yield active principles that will arm us with specific agents for the correction of morbid conditions due to deficiencies of secretion of the respective glands. In the meantime, recognizing our responsibility to the public in this as in other matters that affect the welfare of the people, we should not continue to patronize and support those manufacturers of glandular remedies who make statements of specific virtues posSessed by pluriglandular preparations that are without foundation of fact. . The existence and continued pernicious influence of the manufacturers of glandular products who publish statements of their therapeutic value without the support of established physiologic and clinical facts will depend on whether the medical profession will patronize them. A decided forward step would
952
EDWIN
J.
KEPLER, LAWRENCE M. RANDALL
be taken if physicians were to limit their use of animal organ preparations to those admitted to the United States Pharmacopoeia and the current edition of New and Nonofficial Remedies. "The endeavor has been made to present in this introductory statement the present status of organotherapy as based on exiSting knowledge of the physiology, both normal and pathologic, of the glands of internal secretion. The judgment and the conclusions formed in regard to problems in biology that are not fully understood today may require a change of opinion and verdict in the future. Therefore, the opinions and judgment expressed in this brief statement in regard to the value of organotherapy today may require readjustment tomorrow."
That remarkable progress has been made in the intervening years is immediately apparent, and that the fundamental philosophy of Dr. Billings regarding endocrine therapy is as sound today as it was the day on which it was written needs no comment.