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This is a chapter from the book HYPOADRENOCORTICISM, copyrighted by the Adrenal Metabolic Research Society of the Hypoglycemia Foundation, Inc., 153 Pawling Avenue, Troy, New York, USA 12180. Upon the deaths of Dr. Tintera, M.D. in 1969, and later his wife, the Tintera's heirs passed all the collected papers of the Hypoglycemia Foundation, Inc. to the Hypoglycemia Association, Inc. (HAI) This has been reproduced here with the permission of HAI, Inc.

Reprinted from NEW YORK STATE JOURNAL OF MEDICINE, Vol. 55, No. 13, July 1, 1955, Copyright 1955 by the Medical Society of the State of New York and reprinted by permission of the copyright owner.

The Hypoadrenocortical State and Its Management

John W. Tintera, M.D., Yonkers, New York

(From the Endocrine Clinic, St. John's Riverside Hospital)



In a select recorded group of 200 subjects studied over the past fifteen years, the varied symptoms exhibited, suggested some phase of adrenocortical dysfunction: either lack of adequate adrenal cortical hormone production or an imbalance among these hormones. Essentially, all of the symptoms seemed to have some bearing on the integrity of the adrenal cortex and responded, in effect, to the same mode of therapy. This report will use the conveniently designated topic of hypoadrenocorticism, and elaborations around it will be on the practical plane.

Etiology and Pathogenesis

Simply stated: hypoadrenocorticism is Addison's disease. The usually encountered case dealt with herein is actually "subclinical Addison's disease." By thus defining it, a former hypothesis - that the adrenal cortex functioned according to the classic "all or none" law - is repudiated as being contrary to both clinical and experimental evidence.

Hypoadrenocorticism may be congenital or acquired, complete or partial. The two former subdivisions frequently fail of recognition. An etiologic classification, therefore, also derives from practical considerations:

1. Constitutional or primary hypoadrenocorticism

2. Congenital hypoadrenocorticism

3. Secondary hypoadrenocorticism

CONSTITUTIONAL OR PRIMARY HYPOADRENOCORTICISM - The constitutional type may be a Mendelian trait. Because it is most common, it typifies subjects discussed in this paper. The cognitive, characteristic asthenic habitus, peculiar idiosyncrasies and sensitivities, longevity, etc., may be traced in the family history, maternal, paternal, or both.

CONGENITAL HYPOADRENOCORTICISM - This type is encountered in the infant whose mother is deficient in adrenal cortical secretion. During pregnancy the adrenal of the growing fetus and placenta apparently supplement the mother with the necessary adrenal hormones. It may be presumed that the fetal adrenals can be thus depleted. Infants manifesting such adrenal insufficiency often die neonatally: "pyloric stenosis" has been so ascribed. Others may manifest hypoadrenocorticism only as they grow older with the deficient gland inadequate to ordinary stress (See Note)

(Note) Natelson, et. al. [1] studied the "immature infant" and observed that "adrenal immaturity" is a common finding in the premature infant. They use the term to denote a condition resulting in the inability of the infant to hold water, sodium ion, and chloride ion with no unequivocal histological or pathologic evidence to show the adrenal involvement. It has also been found that the thymus gland does not regress in children with immature adrenals. Since hypersecretion from a stimulated adrenal during the alarm reaction does cause thymic involution,[2] it is logical to treat status thymicolymphaticus with adrenal cortical extracts.

SECONDARY HYPOADRENOCORTICISM (Hypopituitarism and Acquired Hypoadrenocorticism). - Hypofunction of the anterior hypophysis produces a variety of clinical pictures, depending on the amounts of specific tropic hormones produced, and so we may find hypoadrenocorticism as the result of such a condition flowered by symptoms of other glandular malfunctions.

Aside from cases resulting from hypopituitarism and steroid therapy, individuals subjected to great stresses, such as those referred to by Selye [3] in his "general adaption syndrome" (G.A.S), may develop hypoadrenocorticism. In these instances the glands work beyond their capacity, passing through the alarm reaction, the stage of resistance, and finally reaching the stage of exhaustion.

Symptomatology and Diagnosis

The chief or presenting complaints, associated symptomatology, related systemic disorders, and physical and laboratory findings are given in Table I. The order of percentage frequency by which they are tabulated is based on convenience for presentation (a few of the percentage assignments are based on a smaller sampling since these, emerging only as the series progressed, were not sought for and elicited except in more recently studied patients). However arbitrary this tabulation, its perusal reveals one significant fact. The chief complaints listed for patients with hypoadrenocorticism are often similar to those found in persons who are in the hypoglycemic state. Patients finally adjudged to be hypoadrenocortic invariably report feelings of weakness, fatigue, and faintness, all of which could result from periods of low blood sugar level, usually extant. These periods of hypoglycemia are exacerbated by and follow bouts of emotional upsets after the initial hypoglycemia. In a series of business executives, Portis [4] has shown that hypoglycemia is definitely related to emotional stress. He suggested that the emotional centers which are exposed excessively to these stress transmit impulses which cause overactivity of the parasympathetic system. This heightened vagal response stimulates the islet cells of the pancreas. Hyperinsulinism, which produces a low blood sugar level, develops from the stimulation of the islet cells.

TABLE I. - Symptomatology in 200 Cases

Chief Complaints*

Systemic Symptoms

Associated or Possible Resulting Conditions

Findings on Physical Examination

Laboratory Findings

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* Theses are hypoglycemic in nature and tend to follow physical, mental, or emotional stress.

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Whether the low blood sugar in the patient with hypoadrenocorticism is a result of similar autonomic manifestations remains undetermined. It may well be the case, however, since this type of patient is emotionally labile and responds vigorously to crucial stressful situations. Many of our patients show a glucose tolerance curve which forms practically a straight line at a low level. However, if the adrenals have been subjected to increased stress through indiscretions, e.g., high carbohydrate intake or abuses through alcohol or other toxic agents, changes occur in the liver so that a condition of fatty infiltration or degeneration ensues. With this situation a sudden rise in the blood sugar level as high as 300 or 400 mg. per 100cc of blood may occur, followed by a sudden drop to hypoglycemic levels. It is this sudden drop which usually precipitates symptoms.*

*Striker [5] has demonstrated that a patient maintaining a blood sugar of over 400 mg. had definite hypoglycemic reactions, pointing out that it is the suddenness of the fall in blood sugar which produces general reactions and not the level from which or to which it may have fallen.

Diagnosis should be possible from the history and symptomatology, together with the glucose tolerance curve and complete blood count. Inability to concentrate, loss of memory, mental depression, insomnia, periods of irritability, and a tendency to negativism and other personality aberrations are to be regarded as significant. Of pathognomonic significance, these patients are usually of the constitutionally inferior asthenic type, often falling in the allergic diathesis group, usually revealing a positive Rogoff Sign, relative lymphocytosis, and a typical low glucose tolerance curve. However, these findings may be masked, for example, in the patient who has a superimposed gonadal deficiency, with its typical obesity, or an altered glucose tolerance curve in an advanced case with hepatic damage. In addition, a history of great longevity without senility of the forebears is obtained.

Since the gastrointestinal system is particularly sensitive to emotional stress, many symptoms involving the digestive tract are reported. Chief among these is a dull ache or dragging or gnawing sensation in the epigastrium. With upset of carbohydrate metabolism pain or distress may occur in the epigastrium referred from the liver. In addition, these patients often have alternate periods of diarrhea and constipation. Their stools are frequently in the form of sclybala, and chronic mucuous colitis or chronic ulcerative colitis may develop. Bercovitz [6], in his treatment of ulcerative colitis with adrenal cortical extract, states that, "It is quite obvious from even a casual observation of these patients that they are deficient in their adrenal cortical output."

GENITOURINARY COMPLAINTS - The menarche has its onset somewhat later than average, and although it occurs regularly, there is an atypical flow lasting about seven days with profuse bleeding. In 33 percent of the cases the peculiar aspect of this type of flow was that it ceased on about the fourth day almost completely or with just slight staining, started up again profusely on the fifth or sixth day, and then slowed up or stopped on the seventh. Eighty-five per cent of the women had premenstrual tensions with such manifestations as nervousness and emotional instability, headaches, and the accentuation of carbohydrate craving and, particularly in the alcohol group, an almost uncontrollable desire to start drinking again. Dysmenorrhea is a frequent complaint because of infantile uteri, markedly retroflexed or retroverted. These small uteri may the cause of the repeated spontaneous abortions recorded in this series. It is possible that the abortions result from the fact that although the fetus grows at a normal rate, this rate is disproportionate to the rate of development of the uterus.*

*Pertinent to the assignment of abortion tendency in this category of patient is the fact that most effective treatment has been found to be estrogenic hormones and adrenal cortical extract administered during the first eight months of gestation.

Most of the men were found to have normal sexual development. The secondary sex characteristics, aside from the hair distribution, were normal. In Timme's syndrome, in addition to an adrenal insufficiency, there is a persistence of the thymus together with a gonadal deficiency, accounting for the low blood pressure, hypoplasia of the heart and vessels, and the characteristic scrotal fold surrounding the base of the underdeveloped penis in preadolescent boys. At times in this latter condition there is an abnormal bony structure simulating that seen in Paget's disease. In chronic alcoholism many cases of gonadal atrophy and gynecomastia were observed resulting in sterility or loss of libido.

PERSONALITY MANIFESTATIONS - Hypoadrenocortical patients are usually very meticulous in all of their work. They are perfectionists who often drive themselves to exhaustion since they do not know the meaning of the word "relaxation." Their greatest period of activity occur after meals. Sluggishness, lack of concentration, etc., occur just prior to lunch when the blood sugar is at a low ebb. There is a feeling of well-being after eating, but symptoms again become severe at about 3:00 or 3:30 in the afternoon. This depression can be alleviated in approximately twenty minutes by eating a bar of candy, but unfortunately, an even greater period of depression is experienced an hour or two afterward. Of much greater value would be the ingestion of a glass of milk or some fruit at this time. These patients feel best after their principal meal in the evening, and this feeling of well-being lasts for several hours. Mor profound personality involvements are seen in some patients with actual schizoid tendencies, particularly in the younger individuals, and gratifying results were obtained with the treatment to be outlined later. These severe personality defects had been previously classified as schizophrenia, manic depression, and postpartum psychosis.

As previously noted, hypoadrenocorticism is often seen in children either or both of whose parents has an adrenal insufficiency. The most outstanding change in such a child is the development of an abnormal craving for carbohydrates. This desire for candy and sweets may be so intense as to be the basis of so-called "behavior problems." In addition, many children complain of suffering from "growing pains." These may conceivably be early manifestations of the rheumatoid type of arthritis which is seen in adults with hypoadrenocorticism.

It is important to emphasize the fact that individuals of all ages suffering from hypoadrenocorticism can undergo severe personality and emotional changes but which, fortunately, in most instances are reversible.

In studying juvenile delinquents it is well to evaluate the glandular setup of the individuals before passing judgment on their antisocial acts. Included in this series were children considered as serious behavior problems but who responded dramatically to proper regulation of diet with a minimal amount of hormone therapy. Many children were reported to have a high I.Q. but still failed in their scholastic studies, particularly mathematics, which requires concentration, and who after therapy became outstanding honor students. Abnormal sexual behaviors, as exhibitionism and homosexuality, responded favorably if accompanied by adequate psychotherapy.

Alcoholism as a Manifestation of Hypoadrenocorticism

Two distinct groups of alcoholic patients have been observed. The first group comprised individuals who were typical of hypoadrenocorticism, e.g., asthenic in habitus, little or no chest hair, hypotensive, and not infrequently gynecomastic. These patients had varying degrees of hypoadrenocorticism manifested by hypoglycemia, low titer of 17-ketosteriods, etc. Such patients were found to have a constitutionally low tolerance to alcohol and were considered as likely to become alcoholics at an early age. The second group had non pre-existing hypoadrenocorticism but, though alcoholic indulgence, caused damage to the adrenal cortex and to the other glands involved in the metabolism of carbohydrates. These alcoholic patients nearly always exhibited hypoglycemia during their dry periods. [7][10]

We believe that when the blood sugar falls to a certain low level, a craving for alcohol results. Actually, this is a craving for sugar, but these patients inherently know they will respond quicker to the intake of alcohol. Continued drinking produces three changes: (1) eventual decrease of the blood sugar, (2) depletion of the liver glycogen stores, and (3) fatty infiltration of the liver. [11] In this state the liver is unable to detoxify the estrogens, and sex changes found in chronic alcoholism result, e.g., gynecomastia, loss of body hair, and gonadal atrophy.

Physical Findings

APPEARANCE - The appearance of hypoadrenocortical patients is very characteristic. They are usually tall, fair, and asthenic and have a full head of very fine and abundant hair. The hair distribution on the body, however, is rather sparse. In males, the hair on the lower lateral two thirds of the legs is usually absent with little or none on the chest, and there is often delay in the start of shaving. The palms of the hands show a marked reddening of the thenar and hypothenar eminences, and in some patients even the tips of the fingers become very brilliant red. The nails are brittle, which may be accentuated if the patient has been subjected to prolonged periods of stress. The skin is thin and dry, but there may be increased sweating of the palms and axillae. There is frequently an easy bruisability as a result of increased vascular fragility. Constitutional therapy as described later has been most effective in clearing such conditions as infantile eczema and, in later life, the neurodermatitides, circumscribed or disseminated, as well as other allergic symptoms of these patients who fall into the allergic diathesis group. These include asthma, allergic rhinitis, hay fever, urticaria, psoriasis, and ichthyosis.

BLOOD PRESSURE - A hypotension is usually found in association with a droplet shaped heart. Postural hypotension is usual in that the blood pressure may be 105/60 on standing and may be elevated to 120 or 130/70 or 80 on reclining. This is considered to be the reason why many patients find it difficult to fall asleep and reading in a semireclining position for fifteen to twenty minutes for fifteen to twenty minutes is very conducive toward sleep.

POSITIVE ROGOFF'S SIGN - When pressure is applied over the adrenal area (junction of lower rib erector spinae muscles), a very definite tenderness, with some patients experiencing excruciating pain, may be elicited.

SWELLING OF THE EXTREMITIES - This symptom is found in alcoholics, arthritics, and many other cases of hypoadrenocorticism. It is probably a result of changes in the sodium-potassium relationship. It responds readily to therapy and occasionally to the simple expedient of providing additional salt to the diet. In our patients we have observed ankle edema resulting from poor peripheral circulation, particularly with a sudden change in temperature or atmospheric pressure. Some may have a marked puffiness of the lower lids upon awakening which does not subside for several hours or until the circulation has improved by activity. Several cases of nephrosis in children with marked generalized edema and ascites, included in our series, have responded to the general treatment as outlined for hypoadrenocorticism.

PIGMENTATION - Generally, hyperpigmentation of the skin or palmar creases is not a consistent finding. In several cases, including two children with nephrotic syndrome, an almost black discoloration of the entire skin faded within two weeks of therapy. Other cases had vitiligo without demonstrating the severe symptoms of Addison's disease.

Laboratory Findings

LOW BLOOD SUGAR - Much information can be obtained from the glucose tolerance test. It is helpful in evaluating the condition of the liver (reaching hyperglycemic levels), pancreas (hypoglycemia), adrenal cortex, and pituitary (low flat curve).

LOW BASAL METABOLISM - Some texts have referred to this condition as being an atypical hypothyroidism because of the regular incidence of a low basal metabolic rate. In almost all these cases a basal metabolic rate of -11 to -15 is found. A low basal metabolic rate is not necessarily an indication for thyroid medication, especially since these patients have been found to be extremely sensitive to thyroid extract, a fact which can be explained by the physiologic relationship between the thyroid and the adrenals.[12]

LOW TITER OF 17-KETOSTERIODS - Another indication of adrenal involvement is the low titer of 17-ketosteriods. The normal range is 12 to 15 mg in men and 8-10 mg. in women, whereas in these patients we may find 3 to 12 mg. in men and 2 to 8 mg per twenty-four hours in women. However, much higher levels are possible if the determination is made at a time of stress or strain.

BLOOD COUNT - A relative lymphocytosis (35 to 55 per cent), an eosinophilia (1 to 9 per cent), and a moderated neutropenia have been recorded in our series.

OTHER TESTS - These include the Robinson-Kepler-Power water test and its modifications by Soffer and Gabrilove and, more recently, by Oleesky[13], the Thorn eosinophil test; the salt deprivation test; the prolonged fast; the intravenous glucose tolerance test; and the insulin sensitivity test. These usually give corroborative information but are not to be considered as diagnostic; and moreover, the latter four may entail some danger to the patient. Equivocal values have been obtained in determination of the serum sodium, potassium, and chlorides as well as urinary 17-hydrocorticoids, However, electrocardiographic observations in hypoadrenocorticism and particularly in acute or chronic alcoholism reveal a lowering or inversion of the T waves indicating hyperkalemia which disappears after a few days treatment with adrenal cortical extract.

Grouping of Adrenal Steroids

Every symptom of hypoadrenocorticism may be accounted for by a particular group of hormones produced by the adrenal cortex, of which about 28 have been isolated. These hormones may be divided into three groups:

1. Glucosteroids: These steroids function principally in the control of carbohydrate (and protein) metabolism. Failure to utilize sugar properly is the chief cause of symptoms in this syndrome.

2. Mineralosteroids: The water-salt balance of the body is dependent upon these steroids; the imbalance resulting from the excessive excretion of urinary sodium and cellular retention of potassium accounts for the lack of perspiration, craving for salt, and characteristic electrocardiographic findings.

3. Sexogens or 17-ketosteriods: These include the estrogens, androgens, and progesterone-like compounds, any one or combination of which may alter the sex characteristics of the individual.

Treatment of Hypoadrenocorticism

Because the symptoms of hypoadrenocorticism are often so similar to those found in patients with purely psychosomatic disorders, differentiation between those on a psychic basis and those resulting from an adrenal insufficiency is necessary. A complete history, thorough physical examination, and indicated laboratory tests are usually sufficient. In this category of patients treatment should be started only after a diagnosis has been reached through an evaluation of the facts and results obtained from them. In certain urgent categories the therapeutic test must antecede final diagnostic evaluation.

It has been observed that patients respond more rapidly to treatment if they are given a complete but simple explanation of the nature of their illness. Patients with hypoadrenocorticism are subject to various stresses and must be told how they are harmfully affected by such things as dietary indiscretions, fatigue, worry, etc. They will adjust their activities and keep to the prescribed diet more willingly if they understand how emotions can produce symptoms and how excessive carbohydrate intake produces their feelings of fatigue and weakness following a short period of well-being. Once the nature of their condition has been discussed, the three aspects of treatment may then be instituted.

ADJUSTMENT OF ACTIVITY - Many of these patients have worked out routines for themselves which may help in controlling their symptoms. They soon realize that they can prevent hypoglycemic reactions by eating between meals, taking snacks before retiring, eating less at mealtime, etc. A number of them have learned to avoid eating candy because the transitory respite is offset by the ensuing aggravation of symptoms. The most difficult part of their readjustment is to learn how to avoid fatigue. They must be taught how to take environmental and emotional stresses in stride. Many learn to reduce their activities; others, through discussions of a psychotherapeutic nature, soon change their attitudes and ideas. This aspect of treatment is most important and probably most difficult to achieve quickly and successfully.

DRUG THERAPY - [[Note, Note: Adrenal Cortical Extract (ACE) is no longer available in the United States]] The primary aim is to put the adrenal cortex at rest temporarily in order to allow the cells to return to a functioning state so that subsequently they may respond normally to stress. Sufficient amounts of adrenal cortical extract are given so that the target organs depending on these hormones are adequately supplied to return to normal function. Depending upon the severity of the condition 10 cc. of adrenal cortical extract are administered intravenously at varying intervals ranging form every four hours initially to as long as once a week. Eventually the patient may be expected to progress satisfactorily without the injections, providing there is no undue abuse of any one or combination of the factors discussed, i.e., diet, emotional and physical exertion. As the signs of adrenal cortical insufficiency diminish, the dosage of adrenal cortical extract is gradually reduced. Drug therapy application utilizes not only adrenal cortical extract but also autonomic blocking agents as well. Their respective operations are elaborated:

Adrenal Cortical Extract - This tends to adjust carbohydrate metabolism by supplying glucosteroids, to correct water-salt imbalance through its mineralosteroid activity, and to mediate secondary sex characteristics which are controlled by the precursors of the 17-ketosteroids. Once the symptoms of adrenal insufficiency are alleviated, the adrenal cortical extract is curtailed, being reinstituted if indicated at the time of periodic checkups.

Agents Influencing the Autonomic Nervous System - The autonomic nervous system undoubtedly plays a major part in converting emotional stimuli into symptoms. In order to minimize the role of emotions in the production of functional symptoms in patients with adrenal insufficiency, it has been found advisable to prescribe a combination of 1-hyoscyamine, ergotamine tartrate, and phenobarbital (Bellergal). Large doses of this preparation are not required because of a probable synergistic action with adrenal cortical extract. Patients are generally started on three tablets a day, one on arising, one at about two o'clock in the afternoon before the expected fall in blood sugar, and then one between dinner and retiring. After approximately one to two months the Bellergal is reduced to two tablets a day and then to one tablet daily. This dosage has been continued for as long as six years. This autonomic preparation helps reduce the intensity of the emotional stimuli, thus acting to prevent the development of functional disturbances.

DIET - We cannot overemphasize the importance of a proper diet. These patients will usually adhere to the prescribed diet, once they realize from our discussion that dietary indiscretions will cause an exacerbation of their symptoms. The diet essentially consists of the strict elimination of rapidly absorbed carbohydrates in order to obviate the sudden rise in blood sugar with its subsequent fall. Between meals, feedings of milk or fruit are advised to prevent any slackening off of blood sugar levels, which are prone to occur two to three hours after eating. Salt is allowed in unrestricted amounts because of the tendency to sodium depletion. During hot weather we advise supplementary salt in the form of tablets to replace the loss caused by perspiration. The following is a list of foods permitted and to be avoided:

Antihypoglycemia Diet

Foods Allowed

All meats, fish, and shell fish

Dairy products (eggs, milk, butter, and cheese. Also recommended - 1 pint to 1 quart of acidophilus milk daily)

Milk between meals; milk, cheese, and/or butter and saltines before retiring

All vegetables and fruits not listed below

Salted nuts (excellent between meals)

Peanut butter

Protein bread

Sanka, weak tea, and sugar-free soda

Soybeans and soybean products

Sucaryl as a substitute for sugar

Foods to Avoid

Potatoes, corn, macaroni, spaghetti, rice

Pie, cake, pastries, sugar, candies

Dates and raisins

Cola and other sweet soft drinks

Coffee and strong tea

All hot and cold cereals (except occasionally oatmeal)

Comment

The thesis that hypoadrenocorticism is a syndrome entity has been made. Its symptoms typify those found in adrenal cortical disease. The usual case presents those of a subclinical degree. While many of the latter point to emotional instability, they are primarily functional in nature and actually can be considered as being directly attributable to a hypofunction of the adrenal cortex. Adrenal cortical hormones have been shown to play vital roles in maintaining homeostasis in many abnormal conditions involving stress, and therefore, the adrenal cortex appears to control this homeostatic mechanism of the body.

The use of the whole adrenal cortical extract in the treatment of adrenal disease, neglected since the development of adrenocorticotropic hormone and cortisone, is herein re-emphasized. It must be pointed out that these latter agents produce dramatic and permanent results only in such acute conditions as, for example, delirium tremens, certain ophthalmologic diseases, and other emergency crises, but the results are only temporary in chronic conditions, specifically the collagen diseases.

Unfortunately, adrenal cortical extract therapy has been employed empirically regardless of clinical observations and with apparent lack of rationale. However, with adequate dosage many conditions under the heading of "hypoadrenocorticism" have responded favorably. But, it has been argued, the amount of beneficial glucocorticoids (cortisone) in 10 cc of adrenal cortical extract is minimal and of about the order of 1 mg. of cortisone-like activity. Why then should such good therapeutic results be obtained with it?

As yet, no reliable laboratory test have been devised to determine adrenal cortical activity, particularly when the gland has not been damaged by infections or toxic agents. Clinically we have shown that the activity of adrenal cortical extract is far above that which is expected from its ascribed cortisone content. From our own clinical observations we fee that there is something physiologic about adrenal cortical hormones, whereas the current literature is increasingly warning us that there is something very unphysiologic about cortisone.

No one has yet distinguished between the effects of adrenal cortical insufficiency and adrenal cortical imbalance. It would be perfectly possible to have sufficient amounts of "S" and "N" hormones, as Albright[14] classifies them, yet if one were present in excess of the other, the mutually antagonistic forces would be upset and would give rise to clinical signs. Cortisone, hydrocortisone, or glucocorticoid substances apparently alleviate certain disease processes, probably via biocatalytic modification of enzyme systems. That is to say, it is not cortisone specifically but glucocorticoid activity that gives beneficial results in relieving most of the symptoms of Addison's disease. Who knows whether nor not other, still unisolated corticoids will not prove to have still greater activity along these lines and that they may be suppressed or minimized by creating an artificial imbalance by the injudicious use of synthetic steroids.

Aside from the possibility of artificially creating an imbalance, we must also consider the effects of indiscriminate exclusive steroid medication on tropic influences. ACTH is now almost universally viewed as the tropic hormone for cortisone. Is it also to be considered the tropic influence for the other 27 steroids, or do these compounds appear solely as a physiologic response to the needs of the body? The evidence is more and more pointing to the fact that specific steroids may require specific tropic hormones. Selye[15] feels that somatropic hormone (STH) may be a tropic hormone for the adrenal cortex, stimulating the production of desoxycorticosterone acetate.

Is there then more than one ACTH, or does this compound serve to stimulate compound E and compound F as well as all the other compounds with similar activity? The possibility of the presence of more than one ACTH has already been proposed.[15] With this in mind, if we view the adrenal in hypoadrenocorticism as a "tired out" gland, unable to produce the correct or adequate supply of hormones, being constantly bombarded by stimulatory influences from above, we are in a better position to evaluate adrenal cortical extract versus cortisone or ACTH therapy. If we give ACTH, we are, so to speak, whipping a tired horse, getting a little extra cortisone to be sure, but at what expense? If we give cortisone, we stop the bombarding of the gland by tropic influences from above with respect to the cortisone only. What about the tropic influences for the other steroids? Now, if we give adrenal cortical extract, presumably we are supplying the adrenal steroids in the same ratio to each other that they normally bear. Increased amounts of these in the bloodstream would tend to shut off all tropic influences by the general rule of endocrinologic action. If 10 cc. of adrenal cortical extract are given intravenously, that is certainly not replacement therapy (since the daily adrenal output is many times that amount), but at the time of injection, blood circulating in the region of the pituitary contains increased amounts of the whole circulating hormones. this shuts off all pituitary tropic influences, not just ACTH for cortisone. The adrenal is not under constant bombardment until the adrenal cortical extract is metabolized in the liver or tissues. The inhibition is off the pituitary, and tropic hormones are again release if the need arises. In the meantime the tired adrenal has had a chance to rest and to build up its tone. At this time another injection of adrenal cortical extract will suffice again to allow it to regain more tone but will not entirely cause a cessation of activity, as would large doses of cortisone, for the glucocorticoid portion.

Usually desoxycorticosterone acetate is not indicated in these cases. There is most frequently a craving for salt, which is not harmful in itself if given with adrenal cortical extract but this must be regulated when the patient has received this mineralosteroid. Although desoxycorticosterone acetate may improve the absorption of carbohydrates from the intestine, it does not enhance gluconeogenesis during stress, and clinical results have not warranted its general usage in hypoadrenocorticism.

Summary

An attempt has been made to condense and describe a vast syndrome which has been recognized in a group of over 200 patients. Diagnosis is possible by means of a careful endocrine history and physical examination, rather than by elaborate laboratory tests. We have observed that hypoadrenocorticism may result in fatigue, mental confusion, various arthritic pains, gastrointestinal disorders, inability to concentrate, signs of disturbed carbohydrate metabolism, etc. These patients respond to therapy which includes an autonomic stabilizer, adrenal cortical extract injections, and an antihypoglycemic diet. The rationale for adrenal cortical extract therapy has been discussed.

References

1. Natelson, S., Crawford, W.L., and Munsey, F. A.: Correlation of Clinical and Chemical Observations in the Immature Infant, Rockford Illinois, Munson Printing Co., 1952, p. 11.

2. Hartman, F. A., and Brownell, F.A.: The Adrenal Gland, Philadelphia, Lea & Febiger, 1949, p. 421.

3. Selye, H.: J. Clin. Endocrinol. 6: 153 (Feb) 1946.

4. Portis, S.A., Zitman, I.H., and Lawrence, C. H.: J.A.M.A. 144: 1162 (Dec.2) 1950.

5. Striker, C.: Illinois M.J. 102: 235 (Oct.) 1952.

6. Bercovitz, Z.T.: New York State J. Med. 53:2200 (Oct 1) 1953.

7. Tintera, J.W.: Unpublished data.

8. Tintera, J.W. and Lovell, H.W.: Geriatrics 4: 274 (Sept.-Oct.) 1949.

9. Lovell, H.W., and Tintera, J.W.: ibid. 6:1 (Jan-Feb.) 1951.

10. Idem: M. Times 80: 191 (Apr) 1952.

11. Webster, J.J.: Ann Int. Med. 38: 854 (Oct) 1950.

12. McGavack, T.H.: The Thyroid. St. Louis, C.V. Mosby, 1951.

13. Oleesky, S.: Lancet 1: 769 (Apr) 1953.

14. Albright, F.: Harvey Lect. 38: 152 (1943).

15. Selye, H.: Annual Report on Stress, Montreal, Canada, Acta, 1951, p. 217.

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