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Chronic Endocrine Disorders
CHRONIC ENDOCRI.NE DISORDERS WILLARD
O. THOMPSON, M.D., F.A.C.P.*
MOST endocrine disorders are chronic in the sense that they commonly persist until specific treatment is carried out and those involving hypofunction of glands of internal secretion usually recur when specific treatment is omitted. It will, therefore, be impossible in the space allotted to cover in detail the whole field of chronic disorders of the endocrine glands. Emphasis will be placed on those disturbances with which the practicing physician is most often confronted. THE THYROID
Hypothyroidism.-Once a deficiency of the thyroid develops, it usually persists throughout life and its manifestations will usually reappear gradually when the administration of desiccated' thyroid is discontinued. The signs and symptoms that develop on omission of treatment are always similar in the same patient except in the case of cretinism. In this condition the administration of thyroid may produce such great changes in the patient that some manifestations of thyroid deficiency which follow the· omission of treatment may vary at different ages in the same patient. DIAGNOsIs.-Cretinism and myxedema are not commonly encountered by the average physician, with the result that the diagnosis is often not made until the disease has been present for a considerable length of time. Perhaps the single most important consideration in cretinism is the problem of early diagnosis. The brain doubles in size during the first year of life,. and complete absenc.~ of thyroid function for only a few months of this period means that the function of the brain will never be completely normal. It is, therefore, extremely important to think of the possibility of cretinism in any infant who is very sluggish, eats poorly, cries very little and does not grow at an adequate rate. It is not possible in most instances to corroborate the diagnosis in infancy and childhood with basal metabolism determinations. Facilities are available in only a few places for carrying out this test in young children and the standards are not as well worked out as in older people. The dose of desiccated thyroid must therefore be determined empirically and varies from JAo grain U.S.P. material daily at the age of six months to one grain daily at the age of fourteen years. From the Department of Medicine, University of Illinois College of Medicine, and the Presbyterian Hospital, Chicago. *' Professor of Medicine (Rush), University of Illinois College of Medicine; Associate Attending Physician, Presbyterian Hospital, Chicago. 467
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To the trained observer the diagnosis of full blown myxedema is not difficult. To the average physician, however, it presents some difficulty because of its rarity. It is still confused with chronic nephritis, particularly the nephrotic variety, with anemias of various sorts and with Simmonds' disease (pituitary cachexia). It is sometimes confused with chronic nephritis because some older patients with myxedema may have hypertension, transient albuminuria .and secondary anemia. The characteristic myxedematous facies is absent in chronic nephritis as well as the dryness of the skin, thickness of the tongue and slow, thick characteristic speech. Some patients with myxedema develop edema of dependent portions of the body and in some it may be extreme and result in marked ascites, thereby causing the disease to be confused with nephrosis in which the basal metabolism is also often very low. However, the concentration of serum protein is normal in'myxedema, and there is no reversal of the albumin-globulin ratio as in nephrosis. Some degree of secondary anemia is commonly present in patients with myxedema, and occasionally myxedema and pernicious anemia coexist in the same patient. The anemia per se, however, does not produce the clinical appearance of myxedema. It is usually necessary to give specific treatment for both anemia and myxedema in order to correct them. Occasionally patients with myxedema are thought to have a brain tumor because of the presence of ataxia and a high concentration of protein in the cerebrospinal fluid. The cerebrospinal fluid does not show other abnormalities. During the administration of thyroid the concentration of protein in the fluid promptly drops to within normal limits. TREATMENT.-Myxedema develops insidiously over a period of many years. Two serious errors may be made in treatment: (1) The' initial dose of desiccated thyroid may be too large so that unpleasant and sometimes harmful effects are produced. There is great 'danger in older people of inducing a coronary thrombosis by the initial administration of too large doses. (2) Failure to continue treatment. The treatment of primary hypothyroidism may be outlined as folJows:! 1. Administer the minimum amount of desiccated thyroid necessary to maintain a normal level of metabolism. The average dose required for maintenance in adult thyroidless individuals is from 1% to 2 grains of U.S.P. thyroid daily (0.18 to 0.23 per cent iodine). The dosage for cretins is noted above. 2. Begin with a small dose (1 grain daily in adults) and increas.e gradually after several weeks until the correct amount is being administered. 3. Changes in the dose should be made slowly because of slow adjustmeilt. At least two months is required for complete adjustment to any dose.
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4. Avoid large initial doses in all patients, particularly in those with arteriosclerosis and coronary disease. In such patients the initial dose should not exceed ~ grain daily, and it may be necessary to adjust the metabolism at a slightly subnormal level because of the inability of the heart to meet the demands placed upon it by a normal level. 5. Thyroxin has no advantage over desiccated thyroid in the treatment of myxedema except in rare instances. Any attempt to correct the disease quickly by the initial administration of thyroxin intravenously not only may make the patient very uncomfortable because of muscle tenderness but may be very harmful. If' an initial dose of desiccated thyroid is too large, muscle tenderness may be so great that the patient is unable to sleep. From the standpoint of hypometabolism, the problem that confronts the physician most is the matter of diagnosis and treatment in patients who have a moderate depression of the basal metabolism (from minus 15 to minus 25 per cent) but who do not appear to be myxedematous. In some of these patients there is present a mild hypothyroidism that is primary in type; in others there is a mild hypothyroidism that is secondary to a deficiency of the anterior lobe of the pituitary. In others the cause of the low metabolism cannot be determined at the present time. In many of them it is possible to determine the presence or absence of hypothyroidism only by a· therapeutic test with thyroid. If the patient is improved when given the minimum amount of desiccated thyroid that is necessary to. raise the basal metabolism to normal, it may be assumed that some hypothyroidism is present and the administration of desiccated thyroid necessary. However, if the patient does not improve, its administration is futile and may even make the patient worse. ,~' '1' :
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not entirely clear. In some instances inadequate removal of the thyroid plays a role, but in others rapid regeneration of thyroid tissue occurs in spite of adequate subtotal thyroidectomy. In some patients, records show that the disease is not completely abolished by three or four subtotal thyroidectomies. In such patients it would appear that the cause of the disease is acting with great intensity and is not eliminated by the thyroidectomy. It should be pointed out that postoperative thyrotoxicosis usually represents a persistence of the disease and only occasionally a recurrence. This means, of course, that once the basal metabolism drops to within normal limits following the thyroidectomy and remains there for as long as one month when the patient is not receiving iodine, it is unlikely that the patient will ever be thyrotoxic again. In rare instances a recurrence may be observed months or years after the operation. Thyrotoxicosis following subtotal thyroidectomy behaves in the same manner as the untreated disease and is characterized in some patients by remissions and relapses. The management of the condition differs only slightly from that of the untreated disease. TREATMENT.-In most instances it is desirable to perform a subtotal thyroidectomy after adequate preparation of the patient. In a few others it may be possible to maintain the basal metabolism within normal limits by the administration of iodine until the disease disappears. It should be pointed out that the danger of complications, notably recurrent laryngeal nerve paralysis and parathyroid tetany, is much greater with the second and third than with the first thyroidectomy. In some instances in which one vocal cord is paralyzed and most of the palpable thyroid tissue is present on the opposite side, it may be desirable to use roentgen-ray therapy instead of resorting to further surgery. In general, however, the treatment of toxic goiter by irradiation of the gland is a very unsatisfactory procedure. Of great interest are recent experiments on the control of toxic goiter by nonsurgical methods, particularly by the use of radioactive iodine and by the administration of thiourea and tbiouracil. Sometimes during the prolonged administration of the thyrotropic factor of the pituitary, the basal metabolism will drop to within normal limits after an initial rise. There are many reasons for believing that the treatment of toxic goiter will eventually be accomplished by medical and not surgical procedures. However, these recent observations are still in the experimental stage and the best routine method of managing ~he disease still remains the performance" of a subtotal thyroidectomy after adequate preoperative preparation of the patient. THE PARATHYROIDS
Hypofunction and hyperfunction of the parathyroid glands are not very common and when they develop are usually cared for in special
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clinics. However, both conditions may be encountered by any practicing physician. He must, therefore, be somewhat familiar with their signs and symptoms. Hypoparathyroidism (Tetany).-Hypofunction of the parathyroids in most instances follows the removal of the parathyroid glands at the time of a thyroidectomy. It occasionally follows the removal of too much parathyroid tissue during a parathyroidectomy for hyperparathyroidism. In rare instances, a spontaneous form of the disease is seen which corresponds to spontaneous myxedema. The disease may vary greatly in severity, depending upon the extent of hypofunction. Acute and chronic forms are observed. Acute manifestations of the disease are noted when the function of the parathyroids is suddenly withdrawn, as following a parathyroidectomy. As time goes on, one of two things may happen. Some regeneration of parathyroid tissue may occur so that the hypofunction may be partially or completely relieved. It is more common for some degree of hypofunction to persist. The body gradually adapts itself to the loss of parathyroid function so that the symptoms of the disease in its chronic form are not so severe as in the acute form. DIAGNOSIS.-The most important clinical signs of tetany are numbness and tingling of the extremities, which mayor may not be accompanied by pain; the signs of Chvostek and Trousseau; lowering of the concentration of calcium in the serum; and increase in the concentration of phosphorus while the phosphatase remains normal. The excretion of both calcium and phosphorus is low in the urine and normal in the stools. Erb's phenomenon, which is caused by increased nervous excitability, can be elicited only by special equipment which is rarely used in the practice of the average physician. In general, the intensity of signs and symptoms is proportional to the degree of lowering of the concentration of the serum calcium, although there are exceptions to this rule. Occasionally a patient with extreme lowering of the calcium value will suddenly develop tetanic convulsions without showing either a Chvostek or a Trousseau- sign and without complaining of any numbness. However, hypoparathyroidism is almost always detected before it progresses to the state _of tetanic convulsions and no patient should die at the present time from parathyroid tetany. In general, it may be said that the development of convulsions in this disease indicates poor management. The signs and symptoms of tetany usually do not develop until the concentration of calcium in the serum drops to about 7.5 mg. per 100 cc., although the actual level varies somewhat from patient to patient. In most patients with complete hypoparathyroidism the concentration of calcium drops to between 4 and. 5 mg. per 100cc. It should be emphasized that the determination of the serum calcium is not very valuable unless it is accompanied by the determination of the
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concentration of the serum protein. About one half of the calcium in the serum is bound by protein and it is the ionized or diffusible calcium that is of primary importance-in tFtany. For this reason, the concentration of calcium in serum may be low without any symptoms of hypoparathyroidism being present. This phenomenon is seen in patients with nephrosis. COMPLICATIONS.-The most serious complication of untreated hypoparathyroidism is the development of bilateral cataracts. These do not seem to appear except in the more marked forms of the disease, and they do not appear at all if adequate treatment is given. It is, therefore, very important in treating patients with tetany to be sure that the treatment is adequate to maintain the calcium in the serum within normal limits and that the eyes are examined periodically to make sure that cataracts are not developing. Some spasm of th'e vocal cords may be present in patients with parathyroid tetany. This is particularly evident in patients who have paralysis of at least one vocal cord. The same operative procedure that results in injury to the parathyroid glands may also result in injury to one of the recurrent laryngeal nerves. Consequently the association of parathyroid tetany and unilateral vocal cord paralysis is a common one. The symptoms produced by the paralysis are aggravated by the spasm resulting from parathyroid tetany. TREATMENT.-In treating the chronic form of the disease, parathyroid extract is not used and it is rarely used at the present time in the acute stage immediately following operation. The following procedures have proved most useful for prolonged management: (1) Administration of from 45 to 90 grains of calcium lactate or calcium chloride per day. This is administered in three equal doses. The first one is given with breakfast, the second about the middle of the afternoon and the third at bedtime. (2) Administration of some material that promotes the absorption of calcium from the gastro-intestinal tract. The best material for this purpose is dihydrotachysterol, which ,is given in doses of 1 cc. two to four times per week. Large doses of vitamin D 2 such as 50,000 U.S.P. units daily are also of value but perhaps .not quite as effective as dihydrotachysterol. The object 'of treatment is to maintain the level of serum calcium within normal limits (9 to 11 mg. per 100 cc.). As a rule, when the patient feels well, the concentration of calcium is normal but this is not necessarily the case. The disease cannot be managed sa~isfactorily without laboratory facilities for determining the concentration of serum calcium. This is a comparatively difficult determination technically and the results obtained in many laboratories are often fictitious. Hyperparathyroidism.-Hyperparathyroidism is a rare disease, althopgh a considerable number of cases have been reported in some
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special clinics; It is usually present for years before it is recognized and is often detected only after serious damage is done to the body. In most instances it is not discovered until there have developed ruul-, tiple bone cysts (osteitis fibrosa cystica), spontaneous fractures, collapse of the vertebrae, renal calculi or giant cell tumors. The damage done by collapse of the spine cannot be repaired and chronic nephritis may develop in the more chronic cases of renal calculi. DIAGNOSIs.-Hyperparathyroidism should always be thought of in patients with unexplained muscle weakness, hypotonia, lack of appetite, nausea, constipation" pain in the bones and polyuria. The most important diagnostic sign is the presence of a high concentration of calcium in the serum. The concentration of phosphorus is low and that of the phosphatase is high. The excretion of calcium and phosphorus in the urine is high but normal in the stools. The diagnosis usually cannot be definitely established by laboratory procedures unless the concentration of calcium in the serum is 12 mg. per 100 cc. or more. Careful roentgen ray examination of the skeleton is important, although thinning of the bone and the development of multiple bone cysts may be prevented by the drinking of large quantities of milk. It is wise to make serum calcium determinations in all patients with renal calculi, particularly in those with recurrent stones. Nodules may often be palpated in the region of the thyroid, although they are usually not as large as thyroid adenomas. However, they may sometimes be very large and they vary greatly in position. All of the parathyroid tumor is sometimes in the mediastinum, just as in the case of some thyroid tumors. TREATMENT.-Treatment consists in the removal of an adequate' amou~t of parathyroid tissue. Certain practical difficulties are encoun~ tered in this procedure. The number of parathyroid glands varies from one to fourteen and it is not always easy to find the offending gland or glands. An effort should always be made to determine where the parathyroid tumor is and to confirm the diagnosis by frozen section at operation and then .to perform a subtotal parathyroidectomy. The development of parathyroid tetany after operation is common but this condition may be only temporary. Following op'eration, the concentrations of calcium and phosphorus in the serum usually return to normal fairly promptly, but the concentration of phosphatase becomes normal more slowly. In order to replace the calciu'm and phosphorus which have been lost from the skeleton, it is desirable to administer large quantities of these materials, as well as an adequate amount of vitamin' D, for many months. The objects of treatment are to prevent permanent damage to the skeleton and to prevent the development of renal calculi and chronic nephritis.
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WILLARD O. THOMPSON ANTERIOR PITUITARY
The most important of the chronic diseases of the anterior lobe of the pituitary are dystrophia adiposogenitalis (Frohlich's syndrome), Simmonds' disease, chromophobe adenoma, dwarfism, acromegaly and pituitary basophilism (Cushing's syndrome). Dystrophia Adiposogenitalis.-The term "dystrophia adiposogenitalis" is a general one which applies to the disease in both children and adults, whereas the disease in children is known as the Frohlich syndrome. This condition is characterized in the male by obesity, hypogonadism and genu valgum. The shoulders are narrow, the breasts full, the abdomen large with a characteristic transverse fold just above the pubic area, the hips are broad and the forearms and lower extremities are often not much increased in size in contrast to the great excess of weight in the middle portion of the body. In only a few of the patients is cryptorchidism present. In the female the breasts may be poorly developed, one may be larger than the other or they may be normal in size but contain an excessive amount of fat tissue. Tbe disease is sometimes but not very often associated with dwarfism, particularly if a pituitary tumor is present. In most instances the sella turcica is normal in size. In some patients of this type, a complete transformation will occur at the time of puberty without treatment. In others, the condition persists throughout life. The diagnostic criteria are inadequate at present. TREATMENT.-It is probably wise to carry out treatment in all individuals in whom the hypogonadism is marked. It should be started between the tenth and twelfth years and continued until epiphyseal union is completed. In the male, the treatment consists of the adminis. tration of from 500 to 1000 international units of chorionic gonadotropin three times weekly. Sometimes with the administration of this material alone, complete transformation of the body contour occurs and no other form of therapy is necessary. In others, it may be necessary to supplement this form of therapy with a weight-redu~ing diet; and if the basal metabolism is lo,v, with the administration of desiccated thyroid. In tbe female, the administration of chorionic gonadotropin does not appear to be as effective as in the male and in the more marked forms of the disease it may be ~ecessary to use female sex hormone to influence skeletal molding and induce sexual maturity. When the disease is not detected until later in life, a considerable amount of improvement may be produced in men by the administration of chorionic gonadotropin and a weight-reducing diet as above noted. However, the skeletal contour cannot be affected. In women, gonadotropic substances are not notably effective and as a rule some form of estrogenic material must be used. Simml>'nds' Disease.-Simmonds' disease or pituitary cachexia is a rare disorder· in .which there is a complete loss of all functions of the
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anterior lobe of the pituitary, commonly following an infection. It is characterized by extreme weakness, loss of weight, lowering of the basal metabolism, lowering of the concentration of sugar in the blood (which may be so extreme that hyglycemic convulsions occur), loss of memory, anemia and hypogonadism with loss of sex function. The disease is often confused with anorexia nervosa and most patients that have been reported to have Simmonds' disease have pro~ably actually suffered from anorexia nervosa. Patients with Simmonds' disease appear seriously ill whereas those with anorexia nervosa appear comparatively well in spite of the extrem,e loss of weight. Some improvement may be produced in Simmonds' disease by the correction of the hypogonadism with suitable gonadotropic material or sex hormone, by correcting the hypothyroidism and by administering a high caloric diet. Chromophobe Adenoma.-The chromophobe cells 'are inert and chromophobe adenomas are therefore commonly associated with underfunction of the pituitary, particularly when they are large enough to compress or replace the normal tissue. They vary greatly in size and the sympto~s associated with them usually persist' until adequate treatment is carried out. DIAGNOSIS.-The symptom conlplex depends upon the degree of loss of pituitary function and upon the presence or absence of pressure on the structures above the sella turcica, notably the optic chiasm and the hypothalamic area of the brain. Signs and Symptoms Related to Underfunction of the Anterior Lobe of the Pitztitary.-l. Hypothyroidism (secondary). The basal metabolism may drop to as low a level as in patients with complete absence of thyroid function, namely minus 40 to minus 50 per cent, but the clinical picture is different from that seen in myxedema. The rough, dry, scaly skin and the typical myxedematous facies are absent. The skin is usually smooth and soft and the hair is of fine texture. 2. Hypogonadism (secondary), with atrophy of the genitalia, azoospermia and amenorrhea. 3. Change in sugar metabolism with flattening of the sugar tolerance curve and a reduction of the fasting blood sugar. 4. Obesity is commonly but not necessarily associated with the condition. When present it may be related to a disturbance in the base of the brain. Effects of Pressure on the Optic Chiasm.-The most common effect of pressure on the optic chiasm is a bitemporal hemianopia which at first involves the upper quadrants and later becomes complete. Finally the whole optic nerve degenerates a~d blindness ensues. The tumor may, of course, grow laterally and compress only one optic nerve, producing a contralateral homonymous hemianopia. When the tumor breaks through the dural diaphragm, it may encroach on the floor of
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the third ventricle, producing various symptoms. In some instances it may extend far enough to block the third ventricle, therefore producing an internal hydrocephalus. In rare instances it may compress the third, fourth and sixth nerves, producing an extra-ocular palsy or it may invade the temporal lobe, producing uncinate seizures. TREATMENT.-The symptoms associated with chromophobe adenoma of the pituitary usually persist throughout life unless specific treatment is given. In some patients definite improvement may follow removal of part or all of the adenoma, or release of the cystic fluid which it may contain. Such improvement is probably related to .removal of pressure from the normal pituitary cells. Surgical intervention is indicated only when the tumor extends through the roof of the sella turcica and invades the structures lying just above it, particularly the optic' chiasm. Roentgen ray therapy is of little value in this condition. ' It is necessary to treat the hypopituitarism regardless of whether or not surgical measures are indicated. This is best done by treating the glandular hypofunctions that are secondary to the hypopituitarism, inasmuch as there is no pituitary extract that is very effective clinically. Great improvement may follow the treatment of the hypothyroidism with desiccated thyroid and the treatment of the hypogonadism with stimulation or substitution therapy. As obesity is commonly an associated condition, administration of a suitable weight-reducing diet may constitute an important part-of the treatment. Dwarfism.-Pituitary dwarfism may persist indefinitely because there is no preparation of the growth factor of the pituitary that has much effect in man. It may be associated with a chromophobe adenoma, or no tumor may be present at all. '-rhe deficiency of growth factor must develop during the active growth period in order for dwarfism to result. All degrees of the condition may be noted, depending upon the severity of the pituitary deficiency and the age at which it begins. It is commonly associated with a deficiency of other functions of the pituitary, notably the thyrotropic and gonadotropic functions, but this is not necessarily the case. Growth factor is produced by the eosinophilic cells and the gonadotropic factor by the basophilic cells. It is therefore possible to have a pituitary dwarf with normal development of the genitalia and normal sex function, just as it is possible to have the reverse condition, namely eunuchoidism secondary to a deficient production of gonadottopic factor in an individual who is normal in height and whose pituitary therefore produces an adequate amount of pituitary growth factor. TREATMENT.-Although preparations ,of the growth factor are not particularly effective clinically, a considerable amount of skeletal growth may be induced in the male pituitary dwarf by stimulating the testes,to produce mal~ sex hormone, with chorionic gonadotropin or by' th~ administration of male sex hormone itself. In order for this
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nlaterial to produce its maximum effect, treatment must be started not' later than the age of ten to twelve years. The amount of skeletal growth that can be induced in this manner is linlited, and if the dwarfIsm is extrenle the skeleton will never achieve normal height regardless of the age at which treatment is started. Acromegaly.-Acromegaly is a disease of long duration. There are instances on record in which it has lasted for fifty years. It is usually caused by an eosinophilic aden9ma of the pituitary, although it may be the result of hyperplasia of the eosinophil cells without the presence of an adenoma. The disease is rather frequently associated with overproduction of the thyrotropic factor and overproduction of the diabetogenic factor, so that syndromes resembling exophthalnlic goiter and diabetes nlellitus respectively are produced. The high basal metabolism in this condition shows some reduction during the administration of iodine and the diabetes is controlled with insulin, just as it is in patients who do not have acromegaly. DIAGNOSIS.-There is little difficulty in making a diagnosis when ·the disease is well advanced. There is overgrowth of all the tissues in the body, resulting in characteristic changes in the facies, hands and feet. It is not often that the diagnosis is made in the early stages. TREATMENT.-The size of the sella turcica varies greatly but the adenoma is rarely large enough to demand surgical intervention, the only indication for which is pressure on the optic chiasm or on the Hoor of the third ventricle. In rare instances all the characteristic manifestations of invasion of the hypothalamic area may ensue. Unless surgery is indicated, roentgen ray therapy is the treatment of choice. This form of therapy is unsatisfactory and it is very difficult to tell when the disease is quiescent and when it is progressive. Skeletal changes may increase in spite of the presence of a normal level of basal metabolism and the absence of diabetes. In SOUle patients, severe headache is.a very pronlinent feature and it 11lay be very refractory to treatment. Chronic hypertrophic arthritis and renal calculi are not uncomnlon cornplications of acronlegaly. Pituitary Basophilism (Cushing's Syndrome) .-A few years ago Cushing described a disease characterized by the following nlanifestations: obesity, hypertension, glycosuria, purplish striae in the abdonlen, thighs and chest,. hypogonadism (with anlenorrhea in the female), hypertrichosis, weakness and increased excretion of nitrogen in the urine. The condition is commonly fatal, although the patients may live for several years. According to Cushing's interpretation, the disease is the result of a basophilic adenoma of the pituitary, which may be microscopic in size. Other investigators have claimed it to be the result of an adenoma of the adrenal cortex, which is found in a fairly large percentage of the patients. TREATMENT.-Some improvenlent has been reported in isolated in-
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stances following irradiation of 'the pituitary and following removal of basophilic adenomas of the pituitary and adenomas of the adrenals. Improvement has also been reported following the administration of male sex hormone, which causes storage of protein. THE POSTERIOR PITUITARY
Diabetes Insipidus.-Diabetes ins~pidus is a rare disease but is occasionally encountered by the general practitioner. There are many reasons for believing that it is the result of a lesion in the base of the brain above ~he pituitary and not directly the result of a lesion in the posterior lobe itself. Diabetes insipidus is characterized by excessive polydipsia and polyuria, with the passage of as much as from 12 to 14 liters. of urine per day. The urine is of necessity of low specific gravity and water is eliminated from the body almost as fast as it is absorbed. The hormone of the posterior pituitary has some direct action on the kidney which results in the retention of water. In rare instances the disease may be associated with hypofunction of the anterior lobe, with or without a pituitary tumor, although diabetes insipidus is not a common accompaniment of disturbances of the anterior lobe. The symptoms of the disease depend upon what involvement, if any, there is of the anterior lobe and of the hypothalamic area. The patients may be thin or obese. TREATMENT.-The disease is best treated by the insufflation of desiccated posterior pituitary powder into the nasal cavities. This procedure must be carried out six or eight times during the day in order to promote fairly continuous absorption. Two principles have been isolated from the posterior lobe, one having pressor and water-tetaining properties (pitressin) and the other having oxytocic properties and causing the contraction of smooth muscle .(pitocin). In actual practice, pitressin is rarely used in the treatment of diabetes insipidus. THE ADRENALS
Addison's Disease.-The most important chronic disorder of the adrenals is Addison's disease, which invariably persists once it develops. It is caused by tuberculosis of the adrenals in about half of the patients and by atrophy in most of the rem~inder, resulting in destruction of the adrenal cortex. Without treatment, the disease 'is characterized by remissions and relapses and a gradual downhill course. The patient finally dies in a relapse or crisis from six months to fourteen years after the onset. DIAGNOsIs.-Among the more important manifestations of the disease are the following: (1) brownish pigmentation of the skin and buccal mucosa; (2) weakness; (3Y loss of weight; (4) hypotension; (5) anorexia, nausea and vomiting; (6) reduction in the concentration of
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sodium, chloride, carbon dioxide and sugar in the serum; (7) increase in the concentration of potassium and nonprotein nitrogen in the serum, and (8) increased excretion of sodium and chloride in the urine. In a crisis all of the signs and symptoms of the disease are exaggerated but the most outstanding manifestations are nausea, vomiting and hypotension. Nausea is always to be regarded in the most serious manner and means that adequate treatment must be instituted at once. TREATMENT.-A crisis is treated as follows: 1. Administration of from 10 to 40 cc. of adrenal cortex extract intravenously every hour. 2. Intravenous administration of 5 per cent dextrose in Ringer's solution at the rate of 1 liter in eight hours. If desoxycorticosterone acetate has been used in treatment, the daily dose is continued throughout the crisis and supplemented with the forms of therapy just described. As nausea subsides the patient is given food and fluid by mouth and the dose of cortical extract is gradually reduced. The patient is finally put on a maintenance program, which may consist of anyone of the following procedures: 1. Subcutaneous administration of from 10 to 40 cc. of adrenal cortex extract daily in divided doses. 2. Subcutaneous administration of smaller amounts of adrenal cortex extract supplemented by sodium salts. 3. Subcutaneous implantation of pellets of desoxycorticosterone acetate (the initial implantation usually does not need to exceed 450 mg.). 4. Daily intramuscular injection of desoxycorticosterone acetate in a dose of from 5 to 20 mg. 5. A combination of smaller doses of desoxycorticosterone acetate and sodium salts. The best results are obtained with large doses of adrenal cortex extract without supplementary salt therapy, but this form of treatment is very expensive. In a few patients the response to desoxycorticosterone acetate is unsatisfactory. Among the complications of its use may be mentioned generalized edema and hypertension, focal necrosis of the heart muscle, sudden death from myocardial failure and flaccid paralysis of the extremities. A few patients cannot tolerate this material and must therefore receive adrenal cortex extract. When it is effective, the most economical and time-saving method of administration of desoxycorticosterone acetate is in the form of pellets placed in the subcutaneous area. One implantation lasts from six to nine months. Desoxycorticosterone acetate affects the metabolism of sodium and potassium but does not have any effect on sugar metabolism. Corticosterone does affect both functions, while compound E affects primarily the sugar metabolism~
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Patients with Addison's disease are particularly susceptible to the development of upper respiratory infections, and every infection is to be regarded seriously because it appears to increase the demands placed upon the adrenal glands. With adequate treatment, it would appear possible to keep these patients alive for many years. THE OVARIES
The problem of most importance is that of hypofunction. For an intelligent understanding of deficient function of the ovaries and testes certain general principles must be borne in mind. An intimate relationship exists between the anterior lobe of the pituitary and the gonads. Gonadotropic materials are produced in the pituitary which influence ovarian and testicular function. A follicle-stimulating principle stimulates the growth of the graafian follicles in the ovary and influences the function of the seminiferous tubules in the testis. A luteinizing principle causes luteinization of the developing follicles in the ovary and stinlulates the interstitial cells in the testis. Hypogonadism may be primary or secondary, depending upon whether or not the defect is present in the gonads or elsewhere, notably in the anterior lobe of the pituitary. In a similar manner, hypogonadism may be treated either by stimulating the gonads with suitable gonadotropic material or by substituting for it with the appropriate sex hormone. The type of treatment used depends upon the type of hypogonadism present and upon the activity of the therapeutic agents available. Most cases of hypogonadism appear to be secondary in type. Three varieties of gonadotropic material are available for stimulation therapy: 1. Pituitary gonadotropin prepared from the pituitary itself 2. Equine gonadotropin prepared from the serum of the pregnant mare 3. Chorionic gonadotropin prepared from the urine of pregnant women (arises from the chorionic villi of the placenta). Pituitary and equine gonadotropin are theoretically desirable as stimu-:lating agents because they contain both follicle-stimulating and luteinizing material. In actual practice they are not especially effective. Chorionic. gonadotropin is luteinizing in nature and is very effective in stimulating the interstitial cells of the testis, and therefore, in the treatment of secondary hypogonadism in the male. It is not especially effective in the female, and in the male it has the disadvantage that it does not stimulate spermatogenesis. The status of stimulation therapy in the female is not satisfactory, and in many instances in which this form of treatment is indicated, substitution therapy must be used because effective stimulating agents are not available. Very active preparations of the male and female sex hormones are obtainable in the form oftestosterone propionate and various esters of estradiol, respectively.
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Secondary Hypoovarianism.-Stimulation therapy is theoretically indicated in all cases of hypoovarianism which are secondary to hypopituitaris1n. This abnormality is seen most commonly in women who have scanty or delayed menstruation, or both. The intermenstrual periods are usually prolonged and menstruation may be completely absent. Obesity is usually but not necessarily present. The external genitalia and the uterus may be poorly developed or they may be normal in size. The breasts are commonly within normal limits but the areolae and nipples are pale and poorly developed or atrophic. Axillary and pubic hair may be scanty. TREATMENT.-It is always wise first to try stimulation therapy with pituitary and equine gonadotropin and then resort to substitution therapy with female sex hormone if the former are ineffective. If substitution therapy is !Ised, it is wise to combine it with progesterone in such a way as to reproduce the hormonal changes that occur during the normal menstrual cycle. This may be done in many instances by administering 1.66 mg. of estradiol benzoate intramuscularly twice a week for three weeks, although the effective dose varies in different patients. One day after the last dose, the daily administration of 10 mg. of progesterone is begun and continued for three days. Menstruation will usually set in .within two to five days after the last dose of progesterone. The course of treatment may then be repeated. In a few patients, scanty and delayed menstruation is caused by hypothyroidism and may be corrected by the administration of desiccated thyroid alone. Occasionally, in patients with amenorrhea who are very obese, menstruation will appear at regular iritervals following great loss of weight. Primary Hypoovarianism.-Substitution therapy is indicated in primary deficiencies of the ovary, notably in the menopause and in some cases of sexual immaturity. When the ovaries fail to function during the period of puberty, a syndrome develops that resembles the eunuchoid state in the male. Secondary sex characteristics do not appear, the breasts remain undeveloped, the external and internal genitalia remain infantile, little if any axillary and pubic hair appears, menstruation does not set in and skeletal disproportions are evident, the trunk being short and the extremities long although the total height of the body may be within normal limits. TREATMENT.--Following the administration of suitable doses of female sex hormone (from 1.66 mg. to 5 mg. of estradiol benzoate or dipropionate once or twice a week) to 'such a woman, development of the secondary sex characteristics is noted, with enlargement of the breasts, growth of the labia minora and uterus, gain in weight of from 15 to 20 pounds, increase in strength and development of a normal emotional status. Similar changes are induced by stilbestrol. Uterine bleeding appears at irregular intervals but may be made to appear
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regularly by combining the administration of estrogenic material with progesterone in the proper manner. The Menopause.-The menopause is one of the major glandular problems that confront women. The symptoms vary greatly in intensity and duration, although it is not uncommon for them to last for several years. They are completely controlled by the administration of some suitable form of female sex born1one such as estradiol benzoate or dipropionate. The effective dose varies from 1.66 mg. to 5 mg. every seven to fourteen days, by intramuscular injection. The synthetic estrogen, stilbestrol, is highly effective and possesses the advantages of cheapness and of being active when administered orally. It is important to administer the minmum amount that will control symptoms. The effective dose varies from 0.33 to 1.5 mg. daily in most patients. One of the serious complications of estrogenic therapy is the production in some women of abnormal and excessive· bleeding. This is most likely to occur in patients with fibroids, particularly when large amounts of estrogenic material are used. Women with fibroids must be treated with the greatest caution, and it is important in all instances not to overtreat the patient. In the treatment of ovarian deficiencies of all types, it is essential that the patient be examined frequently and that the endocrinologist work in close cooperation with the gynecologist. THE TESTES
The most important chronic endocrine disorders of the testes are the primary and secondary types of male hypogonadism, the secondary type being the more common. Examples of tliis are the Frohlich syndrome and chromophobe adenoma of the pituitary described above and also some cases of undescended testes in which the primary defect appears to lie in the anterior lobe of the pituitary. Chorionic gonadotropin is effective in the treatment of these conditions and is commonly employed in a dose of from 500 to 1000 international units three times per week. Eunuchoidism.-Eunuchoidism may be primary or secondary and is usually associated with bilateral cryptorchidism, although very small atrophic testes may be present in the scrotum. The condition is characterized by poor development of secondary sex characteristics and by certain skeletal disproportions, notably a short trunk and long extremities~ Eunuchoidism may vary in degree, depending upon the amount of function of the testicular· tissue. Eunuchism represents complete loss of testicular function from inflammation, trauma or total ablation of the testes. TREATMENT.-In some cases of eunuchoidism, stimulation therapy may be effective, although in the majority, treatment with male sex hormone is indicated in a dose of from 25 to 50 mg. administered intra-
CHRONIC ENDOCRINE DISORDERS
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muscularly three times a week. Striking changes occur with this material. In sexually immature men all the secondary sex characteristics will develop, including growth of the genitalia, prostate and body hair, lowering of the pitch of the voice and development of the musculature. All of the symptoms of eunuchoidism are completely alleviated by this form of therapy. The skeletal disproportions cannot be corrected after the age of puberty. Male Climacteric.-In a few men a condition known as the male climacteric occurs after the age of forty-five years. It is very much less common than the menopause in the female, 'although the symptoms are similar. It is relieved promptly by the administration of male sex hormone. Great care must be exercised in arriving at the diagnosis in order not to overlook any serious organic disease. BIBLIOGRAPHY L Thompson, W.O.: Endocrinology. Chapter IX in "Specialties in Medical Practice" edited by E.V. Allen. New York, Thomas Nelson & Sons, 1940.
O. THOMPSON, M.D., F.A.C.P.*
MOST endocrine disorders are chronic in the sense that they commonly persist until specific treatment is carried out and those involving hypofunction of glands of internal secretion usually recur when specific treatment is omitted. It will, therefore, be impossible in the space allotted to cover in detail the whole field of chronic disorders of the endocrine glands. Emphasis will be placed on those disturbances with which the practicing physician is most often confronted. THE THYROID
Hypothyroidism.-Once a deficiency of the thyroid develops, it usually persists throughout life and its manifestations will usually reappear gradually when the administration of desiccated' thyroid is discontinued. The signs and symptoms that develop on omission of treatment are always similar in the same patient except in the case of cretinism. In this condition the administration of thyroid may produce such great changes in the patient that some manifestations of thyroid deficiency which follow the· omission of treatment may vary at different ages in the same patient. DIAGNOsIs.-Cretinism and myxedema are not commonly encountered by the average physician, with the result that the diagnosis is often not made until the disease has been present for a considerable length of time. Perhaps the single most important consideration in cretinism is the problem of early diagnosis. The brain doubles in size during the first year of life,. and complete absenc.~ of thyroid function for only a few months of this period means that the function of the brain will never be completely normal. It is, therefore, extremely important to think of the possibility of cretinism in any infant who is very sluggish, eats poorly, cries very little and does not grow at an adequate rate. It is not possible in most instances to corroborate the diagnosis in infancy and childhood with basal metabolism determinations. Facilities are available in only a few places for carrying out this test in young children and the standards are not as well worked out as in older people. The dose of desiccated thyroid must therefore be determined empirically and varies from JAo grain U.S.P. material daily at the age of six months to one grain daily at the age of fourteen years. From the Department of Medicine, University of Illinois College of Medicine, and the Presbyterian Hospital, Chicago. *' Professor of Medicine (Rush), University of Illinois College of Medicine; Associate Attending Physician, Presbyterian Hospital, Chicago. 467
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To the trained observer the diagnosis of full blown myxedema is not difficult. To the average physician, however, it presents some difficulty because of its rarity. It is still confused with chronic nephritis, particularly the nephrotic variety, with anemias of various sorts and with Simmonds' disease (pituitary cachexia). It is sometimes confused with chronic nephritis because some older patients with myxedema may have hypertension, transient albuminuria .and secondary anemia. The characteristic myxedematous facies is absent in chronic nephritis as well as the dryness of the skin, thickness of the tongue and slow, thick characteristic speech. Some patients with myxedema develop edema of dependent portions of the body and in some it may be extreme and result in marked ascites, thereby causing the disease to be confused with nephrosis in which the basal metabolism is also often very low. However, the concentration of serum protein is normal in'myxedema, and there is no reversal of the albumin-globulin ratio as in nephrosis. Some degree of secondary anemia is commonly present in patients with myxedema, and occasionally myxedema and pernicious anemia coexist in the same patient. The anemia per se, however, does not produce the clinical appearance of myxedema. It is usually necessary to give specific treatment for both anemia and myxedema in order to correct them. Occasionally patients with myxedema are thought to have a brain tumor because of the presence of ataxia and a high concentration of protein in the cerebrospinal fluid. The cerebrospinal fluid does not show other abnormalities. During the administration of thyroid the concentration of protein in the fluid promptly drops to within normal limits. TREATMENT.-Myxedema develops insidiously over a period of many years. Two serious errors may be made in treatment: (1) The' initial dose of desiccated thyroid may be too large so that unpleasant and sometimes harmful effects are produced. There is great 'danger in older people of inducing a coronary thrombosis by the initial administration of too large doses. (2) Failure to continue treatment. The treatment of primary hypothyroidism may be outlined as folJows:! 1. Administer the minimum amount of desiccated thyroid necessary to maintain a normal level of metabolism. The average dose required for maintenance in adult thyroidless individuals is from 1% to 2 grains of U.S.P. thyroid daily (0.18 to 0.23 per cent iodine). The dosage for cretins is noted above. 2. Begin with a small dose (1 grain daily in adults) and increas.e gradually after several weeks until the correct amount is being administered. 3. Changes in the dose should be made slowly because of slow adjustmeilt. At least two months is required for complete adjustment to any dose.
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4. Avoid large initial doses in all patients, particularly in those with arteriosclerosis and coronary disease. In such patients the initial dose should not exceed ~ grain daily, and it may be necessary to adjust the metabolism at a slightly subnormal level because of the inability of the heart to meet the demands placed upon it by a normal level. 5. Thyroxin has no advantage over desiccated thyroid in the treatment of myxedema except in rare instances. Any attempt to correct the disease quickly by the initial administration of thyroxin intravenously not only may make the patient very uncomfortable because of muscle tenderness but may be very harmful. If' an initial dose of desiccated thyroid is too large, muscle tenderness may be so great that the patient is unable to sleep. From the standpoint of hypometabolism, the problem that confronts the physician most is the matter of diagnosis and treatment in patients who have a moderate depression of the basal metabolism (from minus 15 to minus 25 per cent) but who do not appear to be myxedematous. In some of these patients there is present a mild hypothyroidism that is primary in type; in others there is a mild hypothyroidism that is secondary to a deficiency of the anterior lobe of the pituitary. In others the cause of the low metabolism cannot be determined at the present time. In many of them it is possible to determine the presence or absence of hypothyroidism only by a· therapeutic test with thyroid. If the patient is improved when given the minimum amount of desiccated thyroid that is necessary to. raise the basal metabolism to normal, it may be assumed that some hypothyroidism is present and the administration of desiccated thyroid necessary. However, if the patient does not improve, its administration is futile and may even make the patient worse. ,~' '1' :
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not entirely clear. In some instances inadequate removal of the thyroid plays a role, but in others rapid regeneration of thyroid tissue occurs in spite of adequate subtotal thyroidectomy. In some patients, records show that the disease is not completely abolished by three or four subtotal thyroidectomies. In such patients it would appear that the cause of the disease is acting with great intensity and is not eliminated by the thyroidectomy. It should be pointed out that postoperative thyrotoxicosis usually represents a persistence of the disease and only occasionally a recurrence. This means, of course, that once the basal metabolism drops to within normal limits following the thyroidectomy and remains there for as long as one month when the patient is not receiving iodine, it is unlikely that the patient will ever be thyrotoxic again. In rare instances a recurrence may be observed months or years after the operation. Thyrotoxicosis following subtotal thyroidectomy behaves in the same manner as the untreated disease and is characterized in some patients by remissions and relapses. The management of the condition differs only slightly from that of the untreated disease. TREATMENT.-In most instances it is desirable to perform a subtotal thyroidectomy after adequate preparation of the patient. In a few others it may be possible to maintain the basal metabolism within normal limits by the administration of iodine until the disease disappears. It should be pointed out that the danger of complications, notably recurrent laryngeal nerve paralysis and parathyroid tetany, is much greater with the second and third than with the first thyroidectomy. In some instances in which one vocal cord is paralyzed and most of the palpable thyroid tissue is present on the opposite side, it may be desirable to use roentgen-ray therapy instead of resorting to further surgery. In general, however, the treatment of toxic goiter by irradiation of the gland is a very unsatisfactory procedure. Of great interest are recent experiments on the control of toxic goiter by nonsurgical methods, particularly by the use of radioactive iodine and by the administration of thiourea and tbiouracil. Sometimes during the prolonged administration of the thyrotropic factor of the pituitary, the basal metabolism will drop to within normal limits after an initial rise. There are many reasons for believing that the treatment of toxic goiter will eventually be accomplished by medical and not surgical procedures. However, these recent observations are still in the experimental stage and the best routine method of managing ~he disease still remains the performance" of a subtotal thyroidectomy after adequate preoperative preparation of the patient. THE PARATHYROIDS
Hypofunction and hyperfunction of the parathyroid glands are not very common and when they develop are usually cared for in special
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clinics. However, both conditions may be encountered by any practicing physician. He must, therefore, be somewhat familiar with their signs and symptoms. Hypoparathyroidism (Tetany).-Hypofunction of the parathyroids in most instances follows the removal of the parathyroid glands at the time of a thyroidectomy. It occasionally follows the removal of too much parathyroid tissue during a parathyroidectomy for hyperparathyroidism. In rare instances, a spontaneous form of the disease is seen which corresponds to spontaneous myxedema. The disease may vary greatly in severity, depending upon the extent of hypofunction. Acute and chronic forms are observed. Acute manifestations of the disease are noted when the function of the parathyroids is suddenly withdrawn, as following a parathyroidectomy. As time goes on, one of two things may happen. Some regeneration of parathyroid tissue may occur so that the hypofunction may be partially or completely relieved. It is more common for some degree of hypofunction to persist. The body gradually adapts itself to the loss of parathyroid function so that the symptoms of the disease in its chronic form are not so severe as in the acute form. DIAGNOSIS.-The most important clinical signs of tetany are numbness and tingling of the extremities, which mayor may not be accompanied by pain; the signs of Chvostek and Trousseau; lowering of the concentration of calcium in the serum; and increase in the concentration of phosphorus while the phosphatase remains normal. The excretion of both calcium and phosphorus is low in the urine and normal in the stools. Erb's phenomenon, which is caused by increased nervous excitability, can be elicited only by special equipment which is rarely used in the practice of the average physician. In general, the intensity of signs and symptoms is proportional to the degree of lowering of the concentration of the serum calcium, although there are exceptions to this rule. Occasionally a patient with extreme lowering of the calcium value will suddenly develop tetanic convulsions without showing either a Chvostek or a Trousseau- sign and without complaining of any numbness. However, hypoparathyroidism is almost always detected before it progresses to the state _of tetanic convulsions and no patient should die at the present time from parathyroid tetany. In general, it may be said that the development of convulsions in this disease indicates poor management. The signs and symptoms of tetany usually do not develop until the concentration of calcium in the serum drops to about 7.5 mg. per 100 cc., although the actual level varies somewhat from patient to patient. In most patients with complete hypoparathyroidism the concentration of calcium drops to between 4 and. 5 mg. per 100cc. It should be emphasized that the determination of the serum calcium is not very valuable unless it is accompanied by the determination of the
472
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concentration of the serum protein. About one half of the calcium in the serum is bound by protein and it is the ionized or diffusible calcium that is of primary importance-in tFtany. For this reason, the concentration of calcium in serum may be low without any symptoms of hypoparathyroidism being present. This phenomenon is seen in patients with nephrosis. COMPLICATIONS.-The most serious complication of untreated hypoparathyroidism is the development of bilateral cataracts. These do not seem to appear except in the more marked forms of the disease, and they do not appear at all if adequate treatment is given. It is, therefore, very important in treating patients with tetany to be sure that the treatment is adequate to maintain the calcium in the serum within normal limits and that the eyes are examined periodically to make sure that cataracts are not developing. Some spasm of th'e vocal cords may be present in patients with parathyroid tetany. This is particularly evident in patients who have paralysis of at least one vocal cord. The same operative procedure that results in injury to the parathyroid glands may also result in injury to one of the recurrent laryngeal nerves. Consequently the association of parathyroid tetany and unilateral vocal cord paralysis is a common one. The symptoms produced by the paralysis are aggravated by the spasm resulting from parathyroid tetany. TREATMENT.-In treating the chronic form of the disease, parathyroid extract is not used and it is rarely used at the present time in the acute stage immediately following operation. The following procedures have proved most useful for prolonged management: (1) Administration of from 45 to 90 grains of calcium lactate or calcium chloride per day. This is administered in three equal doses. The first one is given with breakfast, the second about the middle of the afternoon and the third at bedtime. (2) Administration of some material that promotes the absorption of calcium from the gastro-intestinal tract. The best material for this purpose is dihydrotachysterol, which ,is given in doses of 1 cc. two to four times per week. Large doses of vitamin D 2 such as 50,000 U.S.P. units daily are also of value but perhaps .not quite as effective as dihydrotachysterol. The object 'of treatment is to maintain the level of serum calcium within normal limits (9 to 11 mg. per 100 cc.). As a rule, when the patient feels well, the concentration of calcium is normal but this is not necessarily the case. The disease cannot be managed sa~isfactorily without laboratory facilities for determining the concentration of serum calcium. This is a comparatively difficult determination technically and the results obtained in many laboratories are often fictitious. Hyperparathyroidism.-Hyperparathyroidism is a rare disease, althopgh a considerable number of cases have been reported in some
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special clinics; It is usually present for years before it is recognized and is often detected only after serious damage is done to the body. In most instances it is not discovered until there have developed ruul-, tiple bone cysts (osteitis fibrosa cystica), spontaneous fractures, collapse of the vertebrae, renal calculi or giant cell tumors. The damage done by collapse of the spine cannot be repaired and chronic nephritis may develop in the more chronic cases of renal calculi. DIAGNOSIs.-Hyperparathyroidism should always be thought of in patients with unexplained muscle weakness, hypotonia, lack of appetite, nausea, constipation" pain in the bones and polyuria. The most important diagnostic sign is the presence of a high concentration of calcium in the serum. The concentration of phosphorus is low and that of the phosphatase is high. The excretion of calcium and phosphorus in the urine is high but normal in the stools. The diagnosis usually cannot be definitely established by laboratory procedures unless the concentration of calcium in the serum is 12 mg. per 100 cc. or more. Careful roentgen ray examination of the skeleton is important, although thinning of the bone and the development of multiple bone cysts may be prevented by the drinking of large quantities of milk. It is wise to make serum calcium determinations in all patients with renal calculi, particularly in those with recurrent stones. Nodules may often be palpated in the region of the thyroid, although they are usually not as large as thyroid adenomas. However, they may sometimes be very large and they vary greatly in position. All of the parathyroid tumor is sometimes in the mediastinum, just as in the case of some thyroid tumors. TREATMENT.-Treatment consists in the removal of an adequate' amou~t of parathyroid tissue. Certain practical difficulties are encoun~ tered in this procedure. The number of parathyroid glands varies from one to fourteen and it is not always easy to find the offending gland or glands. An effort should always be made to determine where the parathyroid tumor is and to confirm the diagnosis by frozen section at operation and then .to perform a subtotal parathyroidectomy. The development of parathyroid tetany after operation is common but this condition may be only temporary. Following op'eration, the concentrations of calcium and phosphorus in the serum usually return to normal fairly promptly, but the concentration of phosphatase becomes normal more slowly. In order to replace the calciu'm and phosphorus which have been lost from the skeleton, it is desirable to administer large quantities of these materials, as well as an adequate amount of vitamin' D, for many months. The objects of treatment are to prevent permanent damage to the skeleton and to prevent the development of renal calculi and chronic nephritis.
474
WILLARD O. THOMPSON ANTERIOR PITUITARY
The most important of the chronic diseases of the anterior lobe of the pituitary are dystrophia adiposogenitalis (Frohlich's syndrome), Simmonds' disease, chromophobe adenoma, dwarfism, acromegaly and pituitary basophilism (Cushing's syndrome). Dystrophia Adiposogenitalis.-The term "dystrophia adiposogenitalis" is a general one which applies to the disease in both children and adults, whereas the disease in children is known as the Frohlich syndrome. This condition is characterized in the male by obesity, hypogonadism and genu valgum. The shoulders are narrow, the breasts full, the abdomen large with a characteristic transverse fold just above the pubic area, the hips are broad and the forearms and lower extremities are often not much increased in size in contrast to the great excess of weight in the middle portion of the body. In only a few of the patients is cryptorchidism present. In the female the breasts may be poorly developed, one may be larger than the other or they may be normal in size but contain an excessive amount of fat tissue. Tbe disease is sometimes but not very often associated with dwarfism, particularly if a pituitary tumor is present. In most instances the sella turcica is normal in size. In some patients of this type, a complete transformation will occur at the time of puberty without treatment. In others, the condition persists throughout life. The diagnostic criteria are inadequate at present. TREATMENT.-It is probably wise to carry out treatment in all individuals in whom the hypogonadism is marked. It should be started between the tenth and twelfth years and continued until epiphyseal union is completed. In the male, the treatment consists of the adminis. tration of from 500 to 1000 international units of chorionic gonadotropin three times weekly. Sometimes with the administration of this material alone, complete transformation of the body contour occurs and no other form of therapy is necessary. In others, it may be necessary to supplement this form of therapy with a weight-redu~ing diet; and if the basal metabolism is lo,v, with the administration of desiccated thyroid. In tbe female, the administration of chorionic gonadotropin does not appear to be as effective as in the male and in the more marked forms of the disease it may be ~ecessary to use female sex hormone to influence skeletal molding and induce sexual maturity. When the disease is not detected until later in life, a considerable amount of improvement may be produced in men by the administration of chorionic gonadotropin and a weight-reducing diet as above noted. However, the skeletal contour cannot be affected. In women, gonadotropic substances are not notably effective and as a rule some form of estrogenic material must be used. Simml>'nds' Disease.-Simmonds' disease or pituitary cachexia is a rare disorder· in .which there is a complete loss of all functions of the
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anterior lobe of the pituitary, commonly following an infection. It is characterized by extreme weakness, loss of weight, lowering of the basal metabolism, lowering of the concentration of sugar in the blood (which may be so extreme that hyglycemic convulsions occur), loss of memory, anemia and hypogonadism with loss of sex function. The disease is often confused with anorexia nervosa and most patients that have been reported to have Simmonds' disease have pro~ably actually suffered from anorexia nervosa. Patients with Simmonds' disease appear seriously ill whereas those with anorexia nervosa appear comparatively well in spite of the extrem,e loss of weight. Some improvement may be produced in Simmonds' disease by the correction of the hypogonadism with suitable gonadotropic material or sex hormone, by correcting the hypothyroidism and by administering a high caloric diet. Chromophobe Adenoma.-The chromophobe cells 'are inert and chromophobe adenomas are therefore commonly associated with underfunction of the pituitary, particularly when they are large enough to compress or replace the normal tissue. They vary greatly in size and the sympto~s associated with them usually persist' until adequate treatment is carried out. DIAGNOSIS.-The symptom conlplex depends upon the degree of loss of pituitary function and upon the presence or absence of pressure on the structures above the sella turcica, notably the optic chiasm and the hypothalamic area of the brain. Signs and Symptoms Related to Underfunction of the Anterior Lobe of the Pitztitary.-l. Hypothyroidism (secondary). The basal metabolism may drop to as low a level as in patients with complete absence of thyroid function, namely minus 40 to minus 50 per cent, but the clinical picture is different from that seen in myxedema. The rough, dry, scaly skin and the typical myxedematous facies are absent. The skin is usually smooth and soft and the hair is of fine texture. 2. Hypogonadism (secondary), with atrophy of the genitalia, azoospermia and amenorrhea. 3. Change in sugar metabolism with flattening of the sugar tolerance curve and a reduction of the fasting blood sugar. 4. Obesity is commonly but not necessarily associated with the condition. When present it may be related to a disturbance in the base of the brain. Effects of Pressure on the Optic Chiasm.-The most common effect of pressure on the optic chiasm is a bitemporal hemianopia which at first involves the upper quadrants and later becomes complete. Finally the whole optic nerve degenerates a~d blindness ensues. The tumor may, of course, grow laterally and compress only one optic nerve, producing a contralateral homonymous hemianopia. When the tumor breaks through the dural diaphragm, it may encroach on the floor of
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the third ventricle, producing various symptoms. In some instances it may extend far enough to block the third ventricle, therefore producing an internal hydrocephalus. In rare instances it may compress the third, fourth and sixth nerves, producing an extra-ocular palsy or it may invade the temporal lobe, producing uncinate seizures. TREATMENT.-The symptoms associated with chromophobe adenoma of the pituitary usually persist throughout life unless specific treatment is given. In some patients definite improvement may follow removal of part or all of the adenoma, or release of the cystic fluid which it may contain. Such improvement is probably related to .removal of pressure from the normal pituitary cells. Surgical intervention is indicated only when the tumor extends through the roof of the sella turcica and invades the structures lying just above it, particularly the optic' chiasm. Roentgen ray therapy is of little value in this condition. ' It is necessary to treat the hypopituitarism regardless of whether or not surgical measures are indicated. This is best done by treating the glandular hypofunctions that are secondary to the hypopituitarism, inasmuch as there is no pituitary extract that is very effective clinically. Great improvement may follow the treatment of the hypothyroidism with desiccated thyroid and the treatment of the hypogonadism with stimulation or substitution therapy. As obesity is commonly an associated condition, administration of a suitable weight-reducing diet may constitute an important part-of the treatment. Dwarfism.-Pituitary dwarfism may persist indefinitely because there is no preparation of the growth factor of the pituitary that has much effect in man. It may be associated with a chromophobe adenoma, or no tumor may be present at all. '-rhe deficiency of growth factor must develop during the active growth period in order for dwarfism to result. All degrees of the condition may be noted, depending upon the severity of the pituitary deficiency and the age at which it begins. It is commonly associated with a deficiency of other functions of the pituitary, notably the thyrotropic and gonadotropic functions, but this is not necessarily the case. Growth factor is produced by the eosinophilic cells and the gonadotropic factor by the basophilic cells. It is therefore possible to have a pituitary dwarf with normal development of the genitalia and normal sex function, just as it is possible to have the reverse condition, namely eunuchoidism secondary to a deficient production of gonadottopic factor in an individual who is normal in height and whose pituitary therefore produces an adequate amount of pituitary growth factor. TREATMENT.-Although preparations ,of the growth factor are not particularly effective clinically, a considerable amount of skeletal growth may be induced in the male pituitary dwarf by stimulating the testes,to produce mal~ sex hormone, with chorionic gonadotropin or by' th~ administration of male sex hormone itself. In order for this
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477
nlaterial to produce its maximum effect, treatment must be started not' later than the age of ten to twelve years. The amount of skeletal growth that can be induced in this manner is linlited, and if the dwarfIsm is extrenle the skeleton will never achieve normal height regardless of the age at which treatment is started. Acromegaly.-Acromegaly is a disease of long duration. There are instances on record in which it has lasted for fifty years. It is usually caused by an eosinophilic aden9ma of the pituitary, although it may be the result of hyperplasia of the eosinophil cells without the presence of an adenoma. The disease is rather frequently associated with overproduction of the thyrotropic factor and overproduction of the diabetogenic factor, so that syndromes resembling exophthalnlic goiter and diabetes nlellitus respectively are produced. The high basal metabolism in this condition shows some reduction during the administration of iodine and the diabetes is controlled with insulin, just as it is in patients who do not have acromegaly. DIAGNOSIS.-There is little difficulty in making a diagnosis when ·the disease is well advanced. There is overgrowth of all the tissues in the body, resulting in characteristic changes in the facies, hands and feet. It is not often that the diagnosis is made in the early stages. TREATMENT.-The size of the sella turcica varies greatly but the adenoma is rarely large enough to demand surgical intervention, the only indication for which is pressure on the optic chiasm or on the Hoor of the third ventricle. In rare instances all the characteristic manifestations of invasion of the hypothalamic area may ensue. Unless surgery is indicated, roentgen ray therapy is the treatment of choice. This form of therapy is unsatisfactory and it is very difficult to tell when the disease is quiescent and when it is progressive. Skeletal changes may increase in spite of the presence of a normal level of basal metabolism and the absence of diabetes. In SOUle patients, severe headache is.a very pronlinent feature and it 11lay be very refractory to treatment. Chronic hypertrophic arthritis and renal calculi are not uncomnlon cornplications of acronlegaly. Pituitary Basophilism (Cushing's Syndrome) .-A few years ago Cushing described a disease characterized by the following nlanifestations: obesity, hypertension, glycosuria, purplish striae in the abdonlen, thighs and chest,. hypogonadism (with anlenorrhea in the female), hypertrichosis, weakness and increased excretion of nitrogen in the urine. The condition is commonly fatal, although the patients may live for several years. According to Cushing's interpretation, the disease is the result of a basophilic adenoma of the pituitary, which may be microscopic in size. Other investigators have claimed it to be the result of an adenoma of the adrenal cortex, which is found in a fairly large percentage of the patients. TREATMENT.-Some improvenlent has been reported in isolated in-
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stances following irradiation of 'the pituitary and following removal of basophilic adenomas of the pituitary and adenomas of the adrenals. Improvement has also been reported following the administration of male sex hormone, which causes storage of protein. THE POSTERIOR PITUITARY
Diabetes Insipidus.-Diabetes ins~pidus is a rare disease but is occasionally encountered by the general practitioner. There are many reasons for believing that it is the result of a lesion in the base of the brain above ~he pituitary and not directly the result of a lesion in the posterior lobe itself. Diabetes insipidus is characterized by excessive polydipsia and polyuria, with the passage of as much as from 12 to 14 liters. of urine per day. The urine is of necessity of low specific gravity and water is eliminated from the body almost as fast as it is absorbed. The hormone of the posterior pituitary has some direct action on the kidney which results in the retention of water. In rare instances the disease may be associated with hypofunction of the anterior lobe, with or without a pituitary tumor, although diabetes insipidus is not a common accompaniment of disturbances of the anterior lobe. The symptoms of the disease depend upon what involvement, if any, there is of the anterior lobe and of the hypothalamic area. The patients may be thin or obese. TREATMENT.-The disease is best treated by the insufflation of desiccated posterior pituitary powder into the nasal cavities. This procedure must be carried out six or eight times during the day in order to promote fairly continuous absorption. Two principles have been isolated from the posterior lobe, one having pressor and water-tetaining properties (pitressin) and the other having oxytocic properties and causing the contraction of smooth muscle .(pitocin). In actual practice, pitressin is rarely used in the treatment of diabetes insipidus. THE ADRENALS
Addison's Disease.-The most important chronic disorder of the adrenals is Addison's disease, which invariably persists once it develops. It is caused by tuberculosis of the adrenals in about half of the patients and by atrophy in most of the rem~inder, resulting in destruction of the adrenal cortex. Without treatment, the disease 'is characterized by remissions and relapses and a gradual downhill course. The patient finally dies in a relapse or crisis from six months to fourteen years after the onset. DIAGNOsIs.-Among the more important manifestations of the disease are the following: (1) brownish pigmentation of the skin and buccal mucosa; (2) weakness; (3Y loss of weight; (4) hypotension; (5) anorexia, nausea and vomiting; (6) reduction in the concentration of
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sodium, chloride, carbon dioxide and sugar in the serum; (7) increase in the concentration of potassium and nonprotein nitrogen in the serum, and (8) increased excretion of sodium and chloride in the urine. In a crisis all of the signs and symptoms of the disease are exaggerated but the most outstanding manifestations are nausea, vomiting and hypotension. Nausea is always to be regarded in the most serious manner and means that adequate treatment must be instituted at once. TREATMENT.-A crisis is treated as follows: 1. Administration of from 10 to 40 cc. of adrenal cortex extract intravenously every hour. 2. Intravenous administration of 5 per cent dextrose in Ringer's solution at the rate of 1 liter in eight hours. If desoxycorticosterone acetate has been used in treatment, the daily dose is continued throughout the crisis and supplemented with the forms of therapy just described. As nausea subsides the patient is given food and fluid by mouth and the dose of cortical extract is gradually reduced. The patient is finally put on a maintenance program, which may consist of anyone of the following procedures: 1. Subcutaneous administration of from 10 to 40 cc. of adrenal cortex extract daily in divided doses. 2. Subcutaneous administration of smaller amounts of adrenal cortex extract supplemented by sodium salts. 3. Subcutaneous implantation of pellets of desoxycorticosterone acetate (the initial implantation usually does not need to exceed 450 mg.). 4. Daily intramuscular injection of desoxycorticosterone acetate in a dose of from 5 to 20 mg. 5. A combination of smaller doses of desoxycorticosterone acetate and sodium salts. The best results are obtained with large doses of adrenal cortex extract without supplementary salt therapy, but this form of treatment is very expensive. In a few patients the response to desoxycorticosterone acetate is unsatisfactory. Among the complications of its use may be mentioned generalized edema and hypertension, focal necrosis of the heart muscle, sudden death from myocardial failure and flaccid paralysis of the extremities. A few patients cannot tolerate this material and must therefore receive adrenal cortex extract. When it is effective, the most economical and time-saving method of administration of desoxycorticosterone acetate is in the form of pellets placed in the subcutaneous area. One implantation lasts from six to nine months. Desoxycorticosterone acetate affects the metabolism of sodium and potassium but does not have any effect on sugar metabolism. Corticosterone does affect both functions, while compound E affects primarily the sugar metabolism~
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Patients with Addison's disease are particularly susceptible to the development of upper respiratory infections, and every infection is to be regarded seriously because it appears to increase the demands placed upon the adrenal glands. With adequate treatment, it would appear possible to keep these patients alive for many years. THE OVARIES
The problem of most importance is that of hypofunction. For an intelligent understanding of deficient function of the ovaries and testes certain general principles must be borne in mind. An intimate relationship exists between the anterior lobe of the pituitary and the gonads. Gonadotropic materials are produced in the pituitary which influence ovarian and testicular function. A follicle-stimulating principle stimulates the growth of the graafian follicles in the ovary and influences the function of the seminiferous tubules in the testis. A luteinizing principle causes luteinization of the developing follicles in the ovary and stinlulates the interstitial cells in the testis. Hypogonadism may be primary or secondary, depending upon whether or not the defect is present in the gonads or elsewhere, notably in the anterior lobe of the pituitary. In a similar manner, hypogonadism may be treated either by stimulating the gonads with suitable gonadotropic material or by substituting for it with the appropriate sex hormone. The type of treatment used depends upon the type of hypogonadism present and upon the activity of the therapeutic agents available. Most cases of hypogonadism appear to be secondary in type. Three varieties of gonadotropic material are available for stimulation therapy: 1. Pituitary gonadotropin prepared from the pituitary itself 2. Equine gonadotropin prepared from the serum of the pregnant mare 3. Chorionic gonadotropin prepared from the urine of pregnant women (arises from the chorionic villi of the placenta). Pituitary and equine gonadotropin are theoretically desirable as stimu-:lating agents because they contain both follicle-stimulating and luteinizing material. In actual practice they are not especially effective. Chorionic. gonadotropin is luteinizing in nature and is very effective in stimulating the interstitial cells of the testis, and therefore, in the treatment of secondary hypogonadism in the male. It is not especially effective in the female, and in the male it has the disadvantage that it does not stimulate spermatogenesis. The status of stimulation therapy in the female is not satisfactory, and in many instances in which this form of treatment is indicated, substitution therapy must be used because effective stimulating agents are not available. Very active preparations of the male and female sex hormones are obtainable in the form oftestosterone propionate and various esters of estradiol, respectively.
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Secondary Hypoovarianism.-Stimulation therapy is theoretically indicated in all cases of hypoovarianism which are secondary to hypopituitaris1n. This abnormality is seen most commonly in women who have scanty or delayed menstruation, or both. The intermenstrual periods are usually prolonged and menstruation may be completely absent. Obesity is usually but not necessarily present. The external genitalia and the uterus may be poorly developed or they may be normal in size. The breasts are commonly within normal limits but the areolae and nipples are pale and poorly developed or atrophic. Axillary and pubic hair may be scanty. TREATMENT.-It is always wise first to try stimulation therapy with pituitary and equine gonadotropin and then resort to substitution therapy with female sex hormone if the former are ineffective. If substitution therapy is !Ised, it is wise to combine it with progesterone in such a way as to reproduce the hormonal changes that occur during the normal menstrual cycle. This may be done in many instances by administering 1.66 mg. of estradiol benzoate intramuscularly twice a week for three weeks, although the effective dose varies in different patients. One day after the last dose, the daily administration of 10 mg. of progesterone is begun and continued for three days. Menstruation will usually set in .within two to five days after the last dose of progesterone. The course of treatment may then be repeated. In a few patients, scanty and delayed menstruation is caused by hypothyroidism and may be corrected by the administration of desiccated thyroid alone. Occasionally, in patients with amenorrhea who are very obese, menstruation will appear at regular iritervals following great loss of weight. Primary Hypoovarianism.-Substitution therapy is indicated in primary deficiencies of the ovary, notably in the menopause and in some cases of sexual immaturity. When the ovaries fail to function during the period of puberty, a syndrome develops that resembles the eunuchoid state in the male. Secondary sex characteristics do not appear, the breasts remain undeveloped, the external and internal genitalia remain infantile, little if any axillary and pubic hair appears, menstruation does not set in and skeletal disproportions are evident, the trunk being short and the extremities long although the total height of the body may be within normal limits. TREATMENT.--Following the administration of suitable doses of female sex hormone (from 1.66 mg. to 5 mg. of estradiol benzoate or dipropionate once or twice a week) to 'such a woman, development of the secondary sex characteristics is noted, with enlargement of the breasts, growth of the labia minora and uterus, gain in weight of from 15 to 20 pounds, increase in strength and development of a normal emotional status. Similar changes are induced by stilbestrol. Uterine bleeding appears at irregular intervals but may be made to appear
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regularly by combining the administration of estrogenic material with progesterone in the proper manner. The Menopause.-The menopause is one of the major glandular problems that confront women. The symptoms vary greatly in intensity and duration, although it is not uncommon for them to last for several years. They are completely controlled by the administration of some suitable form of female sex born1one such as estradiol benzoate or dipropionate. The effective dose varies from 1.66 mg. to 5 mg. every seven to fourteen days, by intramuscular injection. The synthetic estrogen, stilbestrol, is highly effective and possesses the advantages of cheapness and of being active when administered orally. It is important to administer the minmum amount that will control symptoms. The effective dose varies from 0.33 to 1.5 mg. daily in most patients. One of the serious complications of estrogenic therapy is the production in some women of abnormal and excessive· bleeding. This is most likely to occur in patients with fibroids, particularly when large amounts of estrogenic material are used. Women with fibroids must be treated with the greatest caution, and it is important in all instances not to overtreat the patient. In the treatment of ovarian deficiencies of all types, it is essential that the patient be examined frequently and that the endocrinologist work in close cooperation with the gynecologist. THE TESTES
The most important chronic endocrine disorders of the testes are the primary and secondary types of male hypogonadism, the secondary type being the more common. Examples of tliis are the Frohlich syndrome and chromophobe adenoma of the pituitary described above and also some cases of undescended testes in which the primary defect appears to lie in the anterior lobe of the pituitary. Chorionic gonadotropin is effective in the treatment of these conditions and is commonly employed in a dose of from 500 to 1000 international units three times per week. Eunuchoidism.-Eunuchoidism may be primary or secondary and is usually associated with bilateral cryptorchidism, although very small atrophic testes may be present in the scrotum. The condition is characterized by poor development of secondary sex characteristics and by certain skeletal disproportions, notably a short trunk and long extremities~ Eunuchoidism may vary in degree, depending upon the amount of function of the testicular· tissue. Eunuchism represents complete loss of testicular function from inflammation, trauma or total ablation of the testes. TREATMENT.-In some cases of eunuchoidism, stimulation therapy may be effective, although in the majority, treatment with male sex hormone is indicated in a dose of from 25 to 50 mg. administered intra-
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muscularly three times a week. Striking changes occur with this material. In sexually immature men all the secondary sex characteristics will develop, including growth of the genitalia, prostate and body hair, lowering of the pitch of the voice and development of the musculature. All of the symptoms of eunuchoidism are completely alleviated by this form of therapy. The skeletal disproportions cannot be corrected after the age of puberty. Male Climacteric.-In a few men a condition known as the male climacteric occurs after the age of forty-five years. It is very much less common than the menopause in the female, 'although the symptoms are similar. It is relieved promptly by the administration of male sex hormone. Great care must be exercised in arriving at the diagnosis in order not to overlook any serious organic disease. BIBLIOGRAPHY L Thompson, W.O.: Endocrinology. Chapter IX in "Specialties in Medical Practice" edited by E.V. Allen. New York, Thomas Nelson & Sons, 1940.