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Adrenal Cortical Physiology in Health and Disease
Adrenal Cortical Physiology in Health and Disease ABBlE Il'
IN FEW areas of medicine is an understanding of physiological principles of greater practical use to the clinician than in the realm of adrenal disease. However, becautie of the geometrical progretitiion with which the pertinent literature has accumulated in recent years, the would-be reader is apt to be discouraged from attempting to keep informed of progress. This presentation does not claim, by any meanti, to provide a comprehensive review of adrenal functioll. It does aim to single out relevant basic principles, some old and some recently recognized, and to point out in what manner these may serve as a useful guide in evaluating available diagnostic and therapeutic measures. NORMAL FUNCTION OF THE ADRENAL CORTEX
The normal function of the adrenal cortex may be described in broad outline as a homeostatic one. In this it aets in a complementary fashion with the adjacent tis:·me in the medulla, the latter coming int.o play in the first moment of emergency, ,\hile the cortical hormones assume increasing importance in the long-range adjustments to change. The response to the medullary secretioml is for the most part unidirectional, whereas those of the cort.ex elicit re"ponses which may Oil one occasion be diametrically different from that Oil another-the respOI18e varying with the circumstances under which the hormone is given. It is this aspect of adrenal function which Sayersl has labeled the capacity to "normalize." The extent to which virtually every reaction in the body is influenced by the adrenal cortical secretions becomes increasingly impressive as experimental data accumulate. At the same time it is important to reemphasize that life is supportable, though granted it is precarious, in the absence of any adrenal hormone. This is possible, since the adrenal secretions act only as modifiers of existing bodily functions and do not initiate changes.
* Assistant Professor of Medicine, College of Physicians and Surgeons, Columbia Un'iversity, New York, N. Y. 811
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In certain reactions this modifying function appears relatively specific, such as the influence of at least certain of the steroids on the reabsorption of sodium. Here a direct relationship can be demonstrated between the amount of steroid given and the degree of retention of this cation. In many other reactions the role played by the adrenal hormones is less specific and has been described by Ingle 2 as a "permissive" one. Here a certain minimal level of secretion is necessary for the reaction in question to take place, but above this minimal level the extent of the reaction may vary without a change in the amount of hormone available. For example, the untreated adrenalectomized rat loses the normal ability to develop a negative nitrogen balance in response to trauma. However, Ingle has shown that if such an animal is injected with just sufficient hormone to maintain well-being under optimal conditions, it will exhibit a negative nitrogen balance following an experimental fracture and an even more strikingly negative balance after multiple fractures-all this without any increase in the maintenance dose of adrenal hormone. Adrenocorticotrophic Hormone
The secretion of the adrenal cortex is determined by the trophic hormone of the anterior pituitary gland, adrenocorticotrophic hormone (ACTH). In 1916 Smith's studies established the existence of such a hormone by showing that removal of the anterior hypophysis from a tadpole was followed by atrophy of the adrenals. The actual cell type in the pituitary which is responsible for the elaboration of this hormone is not known with certainty. Earlier studies3 • 4 implicated the basophils, but most convincing evidence at present points to the eosinophils.5. 6 ACTH has been isolated as a homogeneous protein from hog and sheep glands with a molecular weight of 20,000. Several questions about the nature of ACTH remain unanswered, such as whether there is more than one ACTH, or whether ACTH acts in any capacity apart from adrenal stimulation. There is some experimental evidence that ACTH may increase work ability in adrenalectomized animals; however, clinically its effect appears limited to its trophic action upon the adrenal. A possible exception is its role in skin pigmentation. ACTH, like intermedin, causes dilatation of the melanophores in the skin of a frog when applied topically,1' 8 as does the blood of patients with Addison's disease and certain patients with Cushing's syndrome. Although the identity of ACTH and this pigmenting substance has been questioned, the connection of the two deserves mention. Much investigative work has been aimed at clarifying the regulatory mechanisms involved in the release of ACTH. Of the several recognized, the most important is a self-regulatory one, i.e., the secretion of ACTH is dependent upon the level of cortical hormone available to the tissues. When the supply is in excess, ACTH production is suppressed; when the
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supply is inadequate, it forms a stimulus to ACTH elaboration and liberation. 9, 10 However, the rapidity with which ACTH can be released in response to an appropriate stimulus has suggested that a neural or neurohumoral factor governs its liberationY, 12 However, this is not the exclusive means by which ACTH is released, since pituitary tissue transph1nted to the anterior chamber of the eye or to the spleen, away from any possible neural connections, has been shown to liberate ACTH in response to subjecting the animal so prepared to an appropriate stimulus. l The role of the medullary secretions in stimulating the release of ACTH has been fully explored. The review of Gershberg and his coworkers13 leaves no question but that epinephrine can bring about a release of the pituitary hormone. However, the continued administration of epinephrine does not lead to adrenal cortical hyperfunction. THE ADRENAL HORMONES
Exact knowledge of the nature of the adrenal cortical secretion has only recently become available. For the past two decades an increasing number of steroids have been isolated from adrenal tissue, but it remained for studies based upon adrenal vein blood analyses and adrenal gland perfusions to provide information as to which of the many known steroids were elaborated by the gland in vivo. The initial report of Nelson, Reich and Samuels l4 has been much extended,t5, 16 and most recently, data on human adrenals has been made availableY In all specie3 stUdied, corticosterone (Compound B of Kendall) and/or hydrocortisone (Compound F of Kendall) have been found to constitute 85 per cent or more of total steroids of adrenal origin, although the proportion of each varies considerably from species to species. Two years ago Simpson, Tait and Bush 18 reported the occurrence of yet another fraction in adrenal vein blood exhibiting marked sodium-retaining properties. Recently the chemical structure of this ~mbstance has been established in Reichstein's laboratory,J9 as a steroid with an aldehyde ring, aldosterone. These three steroids--corticosterone, hydrocortisone and aldosterone -appear to account for most of the biological activity of the adrenal secretion. It is known that the total amount secreted may range widely depending upon the body's needs, but whether the proportion in which these substances are secreted is fixed or varies in response to the type of stimulus to which the organism is exposed, is not known. A recent report indicates that under prolonged ACTH administration the rabbit secretes proportionately increasing amounts of hydrocortisone and less corticosterone. 20 The chemical formulas are shown in Figure 132. The numbering of certain important carbon atoms is indicated in the formula of aldosterone. Two additional steroids, which are not present in the adrenal vein secretion in significant amounts, are included in this figure-cortisone (Compound E of Kendall) and desoxycorticosterone (DOC).
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Cortisone and desoxycorticosterone are of clinical importance because of their commercial availability, and both have been extensively used in therapy. The latter is of historical interest in that it was the first "adrenal" steroid to be synthesized, although whether it is present in adrenal tissue in significant amounts is questionable. The former has found even wider application therapeutically and is present in considerable quantities in adrenal tissue, although it does not contribute measurably to the glandular secretion into adrenal vein blood.
cx56 0~' ::.~H
11
It.
~
o· Aldostet'one
Corticosterone
Desoxycorticosterone
Hydrocorti sane
Cortisone
Fig. 132. Adrenal steroids.
Action of the Adrenal Hormone
1. Electrolyte Metabolism. In the face of a wide fluctuation in intake, the adrenal secretion serves to maintain a normal concentration in the extracellular fluids of the osmotically important cation, sodium. When the intake of this salt is curtailed, the secretion from the cortex acts to minimize depletion of this ion by facilitating its reabsorption from renal tubular fluid, decreasing the quantities excreted in sweat, saliva and even the normally very small amount present in feces. In the absence of normal adrenal cortical function there occurs a wasting of sodium from extravascular fluids primarily into urine and to a lesser extent into sweat. The resulting decrease in osmolarity is in part compensated for by a loss of fluid externally into urine and also internally into cells. The reduction in the volume of extracellular fluid is progressive, initially affecting the extravascular compartment, but, as the condition advances, involving the plasma volume as well. However, the loss of fluid rarely parallels exactly the loss of sodium, with the result that the concentration of this ion in the serum is usually reduced. As fluid is lost, evidences of hemoconcentration appear and, as this becomes more marked, circulatory function is impaired. The latter, by virtue of a decreased blood flow, affords an explanation for the rise in nonprotein nitrogen and for the increase in serum potassium, although an additional more direct action of the adrenal hormones upon this cation is possible.
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When excess amounts of adrenal hormone are secreted, somewhat the reverse of the above is seen. There may occur an abnormal retention of sodium extracellularly and intracellularly, as well as a comparable loss of potaHHium. At times this is accompanied by an elevation in the concentration of serum sodium, reduction in potat3sium along with an elevation in serum bicarbonate and associated decrease in serum chloride. The several individual steroids mentioned above vary widely in their action upon the renal excretion of sodium. Table 1 roughly compares Table 1 RELA'I'IVI'; ACTIVrl'Y OF ADR]<;NAL STI.;ROIDS RODllJM
VA:-;CULAH
MgTA HOLIRM REKI'ONSIVI';-
Aldosterone .....
........
Corticosterone ..... Hydrocorticosterone ... Desoxycorticosterone .... Cortisone .........
MgTABOLIKM
KTI(gflN
+++
++ ++++
+ + ++++ 0 +++
++++
±
DURING
NI';K"
(X 10 to 100)
+ ± ++++
Plto'!'I';CTION M]<;DIAHY
.?
++++ ± +++
these steroids aH to their ability to retain sodium and excrete potassium. It is evident that aldosterone is many times more potent in this respect than desoxycorticosterone. Compared to these two, the activity of the remaining steroids is weak indeed. Experimentally, prolonged use of desoxycorticosterone hat3 been associated with the development of hypertension in a wide variety of HpecieH, man included. A prerequisite for the appearance of thiH rise in blood preHsure is a liberal Hodium chloride intake, and it seems likely that this abnormality is related to that adrenal function which modifies the handlinl!; of Hodium. Aldot3terone has not been studied over a Hufficiently long period to say whether or not it shares this property of desoxycorticosterone. 21 Both cortisone and hydrocortisone in high dosage have also been accompanied by hypertension in certain species, and aH with desoxycorticosterone thiH effect has been seen, at least with the former, in man. However, this blood pressure effect differs from deHoxycorticosterone hypertension in that it is unrelated to sodium chloride intake. 2. Vasc1ilar Rcsponsiveness. For many years it has been recognized that the adrenal secretions play a role in the maintenance of normal circulatory function apart from their influence upon electrolyte metabolism. The untreated adrenalectomized dOl!; can be returned to relative normal from a state of profound collapse by a single intravenous injection of cortical extract without the administration of sodium or of significant amounts of intravenous fluid. Indeed, in advanced insuffici-
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ency, serum infusions without extract may be ineffective. Direct observation of the small arterioles of untreated adrenalectomized animals indicates that these vessels lose the normal ability to constrict in response to the repeated administration of epinephrine or norepinephrine, but that this ability can be restored, locally, by the topical application, or generally, by the injection of a whole adrenal extract. Similarly, adrenalectomized dogs given repeated injections of epinephrine show a rapidly diminishing ability to exhibit a normal pressor response. This, too, can be returned to normal by adrenal extracts. The opposite situation, a greater than normal response to the medullary hormones, has been reported in humans receiving large doses of cortisone or ACTH. It is not known to what extent the individual steroids comprising the adrenal secretion partake in this action upon blood vessels. Cortisone, whole adrenal extract and desoxycorticosterone have been reported to restore the responsiveness of the small blood vessels to epinephrine to normal,22 while cortisone in big doses increases the reactivity of the vascular bed above normaF3 (Fig. 2). 3. Intermediary Metabolism. The influence of the adrenal secretions upon the metabolism of protein, carbohydrates and fats is of great importance in the body economy, but because of the efficiency with which the whole operates under normal conditions it is difficult at such times to point to the sites of their action. However, in the absence of these hormones in the adrenalectomized animal, unless the environmental conditions are ideal, a multiplicity of abnormalities becomes apparent. If food is withheld, it is evident that the operated animal is unable to draw upon its body stores of protein as a source for carbohydrate, and, if the animal is fed, more of the dietary intake is stored as body protein than is normal. Conversely, in the animal injected with excess amounts of adrenal hormones there is both a decrease in the laying down of such protein and an increased mobilization of protein stores. This general effect upon protein metabolism finds specific expression in a decreased formation of granulomatous tissue, prolongation of the healing time of wounds, diminution in antibody production and interference with the deposition of the cartilaginous matrix which is an essential preliminary to normal bone formation. Accompanying protein changes there is, in the absence of the adrenals, a fall in blood sugar under conditions of starving, since inadequate amounts can be made available from protein sources. In the opposite situation there is both a greater amount of carbohydrate formed from protein and a decrease in the utilization of sugar, since the adrenal hormones in conjunction with the hormones of the anterior pituitary inhibit the initial step in glucose utilization, the conversion of glucose to glucose-6-phosphate. Elevation in the blood sugar level, diminution in the carbohydrate tolerance and even frank diabetes may ensue. The story with respect to fat metabolism is less well understood.
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Adrenalectomized animals, when partially starved, lose excessive amounts of adipose tissue, suggesting greater than normal utilization of fat.24 This excessive loss can be prevented by the steroid cortisone which favors the utilization of protein at the expense of carbohydrate and fat. Liver fat is consistently increased in animals receiving cortisone, and ketonemia and ketonuria are both suppressed, suggesting that there is a decreased oxidation of fat. Of the steroids secreted by the adrenal gland, hydrocortisone is by far the most active in influencing intermediary metabolism, corticosterone much less so, while the action of aldosterone is not yet wholly known. 21 , 25 4. Ability to Withstand Stress. It is debatable whether this should be listed as a separate function of the adrenal, since each of the three functions previously described contributes to the capacity of the normal organism to withstand a wide variety of misadventures, such as exposure to cold, starvation, forced exercise, burns and trauma. The lack of this capacity is an impressive characteristic of the adrenalectomized animal. However, the role the adrenals play in affording this protection is for the most part a "permissive" one, and as might be expected from this, the injection of additional adrenal hormone to the normal animal does not provide a greater than normal ability to withstand damaging insults. Of the known adrenal vein steroids, hydrocortisone is the most effective in affording protection to the adrenalectomized animal, cortisone far less so. Aldosterone is as active as cortisone in providing protection against cold exposure,20 the latter steroid being only ~lightly less potent than hydrocortisone in this regard. This action of aldosterone is somewhat surprising, since desoxycorticosterone, which it otherwise closely resembles, is relatively inactive in this sphere (Table 1). MEASURES OF ADRENAL FUNCTION
Corticoid and 17-Ketosteroid Excretion (ACTH Stimulation Test)
The most direct measure of adrenal function should be the determination of circulating adrenal hormone in the peripheral blood,26 but, at present, this is not yet practical clinically, and clinical tests must still rely on indirect evidences of the activity of the glands. Among the most useful of these is the measurement of the urinary excretion of the breakdown products of the adrenal hormones-the "corticoids" and the 17-ketosteroids-and particularly the determination of these substances during a period of adrenal stimulation by ACTH. "Corticoids" include a group of compounds with the sterol nucleus and a side chain, extending from the 17 carbon atom and containing a ketone and an alcohol (see Fig. 132). Such substances are almost exclusively of adrenal origin. Two chemical methods are in use for their determination: the one outlined by Daughaday and his associates27 depends upon the destruction of the side chain and measurement of the formaldehyde formed therefrom;
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the one described by Porter and Silber26 depends upon a color reaction between phenylhydrazine and glycerol, which is derived from the 17, 20 and 21 carbon atoms. Normal values vary widely depending upon the preliminary treatment of the urine, and to interpret a given figure with confidence it is necessary to know the normal range for the laboratory performing the determination. In response to many untoward events-burns, operations, etc.-a riHe in the normal excretion will occur. In long-standing chronic illnesses lower than usual amounts may be present, while in untreated Addison's disease the levels are almost always significantly below normal. In Cushing's Hyndrome the excretion is elevated, although an occasional normal value may be obtained. The 17-keto steroids, substances with the sterol nucleus but with a ketone group instead of a side chain on the 17-carbon atom, are derived in part from breakdown of adrenal hormones and in part, in men, from the testicular androgens. With a commonly employed method, the Holtorff-Koch modification of the Zimmerman reaction,2s normal valuet-! range from 10 to 20 mg. per 24 hours in males and 8 to 15 mg. in females. The excretion iH consistently leRs than normal in chronic diseaRe stateH. In hypofunction of the adrenal cortex, the output of 17-ketosteroids it-! almost uniformly markedly reduced, usually to /eRS than 7 mg. in males and 5 mg. in females. However, small but measurable quantities of 17-ketosteroids and also of "corticoids" are present consistently in patients with Addison's disease. In hyperadrenalism, Cushing's syndrome, the 17-ketosteroid excretion is variable. In patients with adrenal hyperplasia the values are normal to moderately elevated. In the group of patients with an adrenal tumor the level of excretion will depend upon the hormonal output of the tumor. If the secretion from the tumor consists of non-l7 -ketosteroid precursors yet is capable of suppressing the normal production of ACTH and thereby causing atrophy of the nontumorous adrenal tissue, the resultillg 17-ketosteroid excretion may be less than normal. If, on the other hand the tumor does secrete 17ketosteroid precursors, the urine may contain normal amounts or at times greater than normal amounts of these substances, even though the atrophic residual adrenal tissue contributes little. In the aberrant adrenal function described as the adrenogenital syndrome, the excretion of 17-ketosteroids is consistently and sometimes remarkably elevated. In response to a period of ACTII stimulation, the excretion of both "corticoicls" and 17-ketosteroids increases sharply. To obtain definitive changes it is necessary to stimulate the adrenals maximally over an adequate time interval. For this, either 25 units given intravenously in a four-hour infusion 011 two to three successive days, or 25 units intramuscularly every six hours for a similar length of time, is advocated. Normally the increase is of the order of 100 per cent or more. In response to a period of cortisone or hydrocortisone administration (100 to 200 units of the former intramuscularly for two or three days, or
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25 units of the latter intravenously for one day) there ensues a decrease in endogenous ACTH production and a temporary fall in the 17-ketosteroid excretion. Such a fall implies that the pituitary is normally sensitive to the inhibiting effects of the increase in circulating adrenal hormone and also that the adrenal gland is in turn normally sensitive to this decrease in ACTH. This test findtl its application in the states of hyperadrenalism in which an adrenal or pituitary turn or is suspected. In those patients with an independently functioning turn or of the adrenal or the pituitary the cortisone will be without effect upon the excretion of 17ketosteroids, while in those with adrenal hyperplasia, a fall will be tleen.29 Salt Withdrawal Test
The other most helpful meatlure of adrenal function is the response of the individual to a period of sodium deprivation. Many varieties of the "salt withdrawal" test exitlt. The test should be carried out under hospital observation, because the accompanying difficulties which may develop in a patient with loss of this adrenal function can be extremely hazardous. It should not be undertaken in a patient whm;e serum concentration of sodium is already below normal. In its simplest form the patient is placed on a moderately low sodium diet (1.5 grams of sodium chloride daily) until evidence of an abnormality in sodium metabolism has been obtained, or, if such does not develop, for a period of a week to ten days. During this test the patient is observed carefully for weight loss, diminution in blood pressure, dizziness, nausea or vomiting, and the test is discontinued if clinical illness appears. At termination, blood is drawn for serum sodium, potassium, hematocrit and nonprotein or urea nitrogen. In the absence of clinical abnormalities, blood is drawn for the above determinations every two or three days. If laboratory facilities permit, the determination of the daily urinary excretion of sodium or of chloride is of added usefulness. No hard and fast rules need be set down for what constitutes a positive test. A fall in serum sodium from normal to 130 mEq.jL. or less, a rise in potassium above normal, a significant rise in hematocrit or nonprotein nitrogen, continued sodium loss in the urine after 24 to 36 hours on the restricted diet-all would indicate abnormal function with respect to sodium and constitute a positive test. Upon obtaining such evidence the test should be terminated. Since renal as well as adrenal mechanisms are involved in the reabsorption of sodium, a positive "salt withdrawal test" may be obtained in individuals with renal disease of sufficient severity to compromise the base saving mechanisms of the kidney even though the adrenal cortices are functioning normally. Other Tests
Other tests of adrenal function exist but have less specificity than those described above. One of these is the water-loading test, originally de-
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scribed by Robinson, Power and Kepler. In its simplest form a measured amount of water, 20 cc. per kilogram or 1000 to 1500 cc., is given the patient to drink within 30 minutes. The water is administered in the fasting state. Subsequently urine is collected at hourly intervals. A normal individual will excrete 70 to 90 per cent of this "water load" within the ensuing four-hour period. In patients with decreased adrenal cortical function this ability is frequently impaired and usually less than 50 per cent is excreted in the four-hour interval. However, a similar delay in excretion may be seen in patients without adrenal disease. Stahl and Stephan30 report such a delay in alcoholics and in malnourished individuals. Hence a diagnosis of adrenal insufficiency cannot be made on the basis of this test alone, although it remains a helpful confirmatory procedure. Accompanying the administration of ACTH there may be a sharp fall in circulating eosinophils and a simple test of adrenal function has been devised based on this. However, it has heen recognized that this test is not wholly reliable, since there exist factors other than the adrenal hormones which influence eosinophil leveh->. lIence, at times normal responses may be seen in the presence of frank adrenal insufficiency, and certain patients without adrenal disease may fail to respond normally. This is particularly true if the control levels are either very low or very high. At present, this test may be considered a confirmatory hut by no means a definitive measure of adrenal function. ADDISON'S DISEASE
Diagnosis
The majority of the symptoms presented by the patient with Addison's history of weight loss, progressive weakness, decrease in blood pressure and gastrointestinal disturbances (anorexia, nausea and vomiting)~can be ascribed to a loss of the ability to conserve sodium, while the occasional hypoglycemic episode and the severe prostration in response to even minor intercurrent illnesses reflect a lack of those steroids influencing carbohydrate metabolism and vascular integrity. The appearance of, or increase in, skin and buccal pigmentation which is highly specific has been attributed to excess amounts of ACTH. Although this hypothesis has been questioned, it is compatible with the observed clinical fact that increased pigmentation is uniformly observed in patients with primary adrenal disease while it is absent in patients with adrenal cortical failure secondary to pituitary hypofunction. It is also compatible with the fact that pigmentation frequently decreases in patients maintained on cortisone, a steroid which suppresses ACTH production. It goes without saying that the finding of the classical symptoms and signs along with laboratory evidence of a diminished serum concentration of sodium and a decreased 24-hour excretion of 17-ketosteroids disease~a
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and corticoids with or without the confirmatory findings of an elevated serum potassium, hemoconcentration and a low fasting blood sugar are sufficient to establish the presence of adrenal cortical insufficiency without further diagnostic procedures. It is only for the patient in whom the history and findings are equivocal that the provocative tests of adrenal function are reserved. For these the patient should be hospitalized, and of these, as described above, the most definitive are the ACTH stimulation test and the sodium withdrawal test. Each have their unique usefulness, and although it is most common for an individual with adrenal insufficiency to show abnormal responses to both, a rare patient may respond normally to ACTH but exhibit an inability to maintain normal sodium balance. A word of caution is necessary about the diagnosis and/or treatment of /la little adrenal insufficiency." Unless definite abnormalities are demonstrated as outlined above, the patient cannot be said to have clinically evident hypofunction, nor is treatment for hypofunction justified. All too frequently the patient with a presenting complaint of weakness, is placed on a regimen of adrenal replacement therapy without adequate investigation, and the improvement which may follow, though due to suggestion rather than any intrinsic quality in the steroid given, is erroneously labeled /la diagnosis by therapeutic trial." Addison's Disease with Tuberculosis
In all patients with adrenal insufficiency a series of diagnostic procedures to establish the presence or absence of a tuberculous infection is in order. Although the frequency of tuberculosis of the adrenals as the cause of Addison's disease is less at present than textbooks of former decades would indicate, tuberculosis remains an important cause of the disease. X-rays of the chest and adrenal area may reveal calcification and, also in the former, evidence of active parenchymal disease. Careful examination of the urine and collection of 24-hour specimens for guinea pig inoculation will help determine possible renal involvement. Should evidence of active tuberculosis be uncovered, therapy for this obviously forms an integral part of the patient's total management. Because of the ever-constant possibility of tuberculosis in the patient with Addison's disease, it is wise to consider how the presence of tuberculosis can modify plans for therapy. Cortisone and presumably hydrocortisone, in large doses, unquestionably accentuate the spread of tuberculosis by suppressing those reactions which tend to localize the infection. It is true that in the maintenance therapy of adrenal insufficiency the physician does not aim to give massive doses but to provide only sufficient amounts to replace deficient adrenal secretions. However, what the physiological dosage is, cannot be known with certainty and the possibility of overdosage is constantly present. From this point of view, maintenance therapy carries less risk to the Addisonian patient with
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tuberculosis if it can be achieved without cortisone, using only added sodium chloride, or sodium chloride plus d()soxyeorticosterone acetate (DCA). However, equally important to the patient with tuberculosis is the maintenance of general health and oJtimal weight. In a significant percentage of the patients with Addison's disease this cannot be achieved with desoxycorticosterone and salt alone, but requires the addition of cortisone. In Addisonian patients with tuberculm;is who fall in thi:-; latter category, the addition of cortisone in small doses carries less risk than withholding this steroid, and should be given with the hope that the improvement in general health following its use will provide, nonspecifically, greater resistance to the infection. The management of the patient with adrenal cortical insufficiency divides itself into day-to-day maintenance and the problem of acutn intercurrent illnesses and crises. Maintenance Therapy
From what is known of the physiology of the adrenal, the most complete replacement therapy would be provided by a whole adrenal extract. However, several reasons exist why this is not practical. It necessitates parenteral therapy because, although whole extracts are effective orally under experimental conditions in animals, no commercial extract is at present available of sufficient potency to support maintenance orally. Furthermore, the cost of the amounts needed for maintenance by parenteral injection is such as to make this form of therapy prohibitive. In the absence of available whole extracts, maintenance must depend upon additional sodium chloride and one or more adrenal steroids. Of those that the adrenal is known to secrete, corticosterone is not available commercially, and aldosterone is not as yet available. If aldosterone proves effective orally it may well, when available, replace the steroid desoxycorticosterone which has been widely used over the past] 5 years in the correction of sodium imbalance. Desoxycorticosterone acetatp has the disadvantage that it must be given parenterally or sublingually. Hydrocortisone is available as the acetate and is effective orally; ho\\,ever, since its actions so closely resemble those of cortisone which has been available for a longer period, the latter has been more widely used in therapy. For completeness, mention should be made of a family of compounds-three steroids resembling hydrocortisone hut with a chloride, a bromide or a fluoride ion in the 9a position. To date, clinical experience has been fragmentary, but all three of these compounds have marked sodium-retaining activity as well as marked influence on carbohydrate and protein metabolism. All are active orally. If further experience fulfills the promise of initial studies, one of these tmbstances may well afford the ideal replacement therapy for the Addisonian patient. In the Addisonian patient without evident tuberculosis, cortisone plus
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a supplement of sodium chloride provides the simplest form of maintenance therapy. Daily doses of cortisone from 6 to 25 mg. by mouth, while surprisingly small in comparison to those required to produce a hyperadrenal effect in normals, are sufficient to bring about increases in appetite, impressive weight gain, and even, on occasion, evidence of excess dosage such as acne or the appearance of facial hair in women. In a third or more of patients placed on such a regimen, it becomes necessary to fortify the weakly active sodium-retaining effects of cortisone with desoxycorticosterone acetate in addition to a sodium chloride supplement. Desoxycorticosterone has the disadvantage that it is not effective orally. It may be given intramuscularly or subcutaneously in oil, absorbed sublingually or introduced subcutaneously, either in pellet form or by depot injection as the trimethyl acetate. Daily dosage ranges from O.f) to 5 mg. The sublingual route requires relatively higher dosage because of less effective absorption, while the dosages needed in depot therapy are somewhat lower. Because of the necessity of continued therapy, patients should be advised of the importance of faithfully adhering to their program, and because of the inability to withstand stress, patients are urged to inform their physician promptly of any intercurrent illness. If such an illness is a minor one, protection may be provided by doubling or tripling the daily cortisone dosage, or, if cortisone is not part of the maintenance regimen, by adding this steroid in doses of 25 to 50 mg. per day. In addition, to ensure a constant intake of sodium if intake is curtailed, an increase in the daily supplement of sodium chloride or in the dose of desoxycorticosterone acetate is in order. However, if the patient is significantly febrile (> 101°) or unable to eat, hospitalization is in order. Under such circumstances, treatment would be that outlined for crisis. Crisis Therapy
In crisis reflecting the failure of several phases of adrenal fUllction, the patient is classically febrile with cold, cyanotic extremities, a soft feeble pulse and lowered blood pressure. The mental state may range from lucidity to deep coma. There may be no chemical abnormalities, but more commonly, as described above, the serum sodium is reduced with reduction in the carbon dioxide combining power or serum chlorides, or both. The serum potassium is less frequently abnormal, but may be elevated. Usually there is some evidence of hemoconcentration in the urea nitrogen, hematocrit, hemoglobin, erythrocytes or proteins. Occasionally, severe hypoglycemia is present. In the treatment of crisis, cortisone and hydrocortisone are of particular importance because of the known protection which these steroids provide against damaging insults, by virtue of their effect upon vascular permeability and by their action in intermediary metabolism. In times of acute stress, quantities of these steroids, far in excess of maintenance
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dosages, are needed. What the optimal amounts are is not known with certainty, and probably varies from patient to patient. Dosages in the range of 200 mg. of cortisone acetate orally or intramuscularly per day, or 50 mg. of hydrocortisone intravenously, have been found effective. Desoxycorticosterone acetate is indicated if there has been significant sodium loss, in doses of 5 mg. or so, intramuscularly. Larger doses of this latter steroid are of no benefit since it offers little protection against stresses, and indeed such doses may cause unwelcome excess fluid retention. In addition to cortisone, hydrocortisone, and/or desoxycorticosterone, salt-containing fluids are needed to support the circulation and restore hydration. However, with adequate steroid replacement the total volume of fluid need not be large (averaging 1500 to 2500 cc.), and excessive amounts carry the same hazard as excess desoxycorticosterone. Glucose should be given if the blood sugar is significantly reduced. If shock is profound, norepinephrine by intravenous drip is of benefit but only in conjunction with hydrocortisone or cortisone. Apart from such treatment for the "crisis," therapy is, of course, in order for the precipitating illness, whatever it be. Even in the absence of obvious infection, if the patient is markedly febrile, a wide-spectrum antibiotic should be given. As the therapeutic effect of the steroids given intravenously or by mouth is rapid, improvement is usually seen within 12 hours, and by 24 hours barring a severe accompanying illness, the patient is usually able to take fluids and feels remarkably better. As improvement becomes evident, the nepd for large doses of steroid diminishes. Cortisone acetate may now be gradually reduced, and by the end of about a week the hormone can usually be decreased to maintenance levels or cancelled. Similarly the desoxycorticosterone and added sodium chloride are decreased. Preparation for, and treatment during major operations is similar to that outlined above, with the added provision that the large doses of intramuscular cortisone acetate are started 24 to 36 hours preoperatively in order to allow time for their full effect to be manifest by the day of operation, and are continued several days postoperatively. HYPERADRENALISM
Cushing's Syndrollle
'With the current knowledge of adrenal function, it becomes clear that Cushing's syndrome is no more or less than hyperadrenalism,3] and with this in mind many of the seemingly unrelated abnormalities in this bizarre condition assume an understandable pattern. In many respects these are the opposite of those encountered in Addison's disease. The hypertension, which occurs in over 80 per cent of such patients, has its experimental counterpart in the elevated blood pressures which accom-
Adrenal Cortical Physiology in Health and Disease
825
pally large doseH of adrenal HteroidH. The equally common decreaHe in carbohydrate tolerance (94 per cent) is comprehensible from the known effect of the adrenal hormones in intermediary metabolism. The increased sUHceptibility to infection (42 per cent) and the delay in wound healing seen in a distressingly high number of such patients reflects changes in protein metabolism, as does the osteoporosis which occurs in two out of three. The disturbances in electrolytes, seen in the minority, follow the pattern exhibited by experimental animals given desoxycorticosterone. The increased excretion of corticoids is certainly an expected finding. Although the picture in general outline is compatible with excess adrenal activity, there remain certain aspects of the syndrome for which current knowledge of adrenal function provides no ready explanation, Huch as the obesity with its peculiar distribution and the high incidence of mental aberration. From what has been said above, concerning the excretion of 17keto steroids in this syndrome, a low value provides suggestive evidence of an adrenal tumor. Likewise the response of the 17-ketosteroid output to the administration of cortisone may help in determining whether or not an independently functioning adrenal or pituitary tumor is present. However, neither the 17-ketoHteroid levels under control conditions or after cortisone nor perirenal air insumation can be depended upon to indicate with certainty the presence or absence of an adrenal tumor, and exploration of the adrenal area remains the only means of settling the question definitively. Treatment. Since Cushing'H Hyndrome is clinical hyperadrenalism, it is obviouH that therapy should be aimed at reducing the hyperfunction of the adrenals. The means selected to achieve this will depend upon the abnormality or abnormalities present in the individual patient. In few other diseases need therapy be so "tailor made" to the individual patient, since in few diseases can such a variety of pathological lesions be associated with the same clinical picture. Before embarking on treatment it is wise to consider the possible varieties of pathologic change which have been found in a series of patients with this disease. a1 The adrenal was the Heat of a tumor in approximately one-third of patients, and the tumor was twice as often malignant as benign. In the absence of a tumor the adrenals exhibited bilateral hyperplasia, although in a rare patient the glands were grossly normal. Pituitary neoplasia occurred in approximately one-half of the patients; of these tumors, three-fifths were basophilic, the remainder composed of any of the cell types in the anterior lobe. In the light of this information, therapy is directed initially at exclusion of a neoplasm. If no obvious pituitary tumor exists, operation to exclude or to remove an adrenal tumor is indicated. If none is found, therapy may take one of two courses: (1) pituitary irradiation, which leads
826
A bb'ie I ngalls K nowlton
to lasting benefit in approximately one-fourth to one-third of the patients so treated ;:11, :12 or (2) i:iUbtotal adrenalectomy. Benefit, when it occurs, is evident two to four months after the course of therapy is completed. In operative procedures the availability of the adrenal steroids active in protection against stress has made possible more effective management of the patient after removal of an adrenal tumor or after subtotal adrenalectomy. Untreated, such a patient may develop acute adrenal insufficiency postoperatively, from which the mortality is extremely high. With treatment as outlined for an Addisonian crisis, the appearance of postoperative hypoadrenalism can be averted. In the patient with adrenal hyperplasia, treatment is not needed after the first adrenalectomy, as the remaining gland will support normal function. After removal or i:iUbtotal removal of the second gland, therapy as outlined is continued in gradually decreasing amounts over tml days to two weeks, until it can either be withdrawn entirely or, should symptoms of insufficiency become evident, it can be level cd off at a maintenance dosage level. In the patient with an adrenal tumor, the administration of ACTH postoperatively is indicated in addition to the preceding therapy. This serves to stimulate the remaining normal and usually atrophic adrenal tissue, and hence to shorten the period of postoperative hyposecretion. This treatment with ACTH should be continued until after the termination of desoxycorticosterone and cortisone therapy. Adrenogenital Syndrome
From what is currently understood of adrenal physiology it is clear that the adrenogenital syndrome should be considered not as hyperadrenal function, but as aberrant adrenal fUllction. In the synthesis and degradation of such steroids as corticosterone and hydrocortisone, it is chemically possible that intermediary productH of androgenic character exist, and indeed such substances are present in adrenal tissue. In the patient with an adrenal tumor, the neoplastic cells might well produce abnormal amounts of these intermediary products. In patients with hyperplasia it has been postulated by J ailer 33 that a partial block exists in the ability of the adrenal to form hydrocortisone from 17-hydroxyprogesterone and 21-desoxyhydrocortisone, that the androgenic steroids are breakdown products of these two steroids. Such a block would result in the secretion of less than normal amounts of hydrocortisone which, in turn, would lead to an increase in ACTH, since the abnormal intermediaries do not suppress the pituitary gland. The increased amounts of ACTH furnish an explanation for the ob::;erved adrenal hyperplasia and the excretion of great quantities of androgenic steroids. Interestingly enough, the secretion of normal adrenal steroids ii:l maintained, perhaps by virtue of the hyperplasia. Hence, other aspects of adrenal cortical activity remain normal. Exceptions to this are found in the rare infant with the !}drenogenital syndrome who has. in addition, disturbance in
Adrenal Cortical Physiology in Health and Disease
827
electrolyte metaboliHm Himilar to that in the Addi:·;onian patient, and in the equally rare patient in whom true virilization is found accompanying features of the Cushing's syndrome. However, the great majority of patients with the adrenogenital syndrome have no disturbance in electrolyte metabolism nor are there abnormalities in carbohydrate and protein metabolism apart from the changes resulting from the high level of androgens-increased strength and muscle mass, increased growth in children but with early closure of epiphysis. It is logical that the clinical picture will vary considerably with the age at which the abnormal cortical function develops. If this occurs in utero, it will modify the development of the genital organs of a female infant, HO as to result in pseudohermaphroditism, the external organs approaching the male configuration although ovaries are present. If the infant is male, no abnormality may be evident at birth. If the condition makes its appearance during childhood both boys and girls will show marked acceleration in growth and marked muscular development. Precocious puberty is evident in males, while masculinization occurs in females with the development of base voice and abnormal growt,h of the clitoriH, although the genital organs will be clearly female Hince their development antedated onset of the disease. Where onset occurs in adult life in females there occurs true virilization, hirsutism, amenorrhea, acne, clitoral enlargement and voice changes. No counterpart of the syndrome has been recognized in adult males. Treatment. Knowledge of adrenal physiology has been of real benefit diagnostically in this group of patients and has provided as well a rational form of medical therapy. Mention has been made above of the diagnostic use of cortisone in differentiating the patient with hyperplasia from the patient with an adrenal tumor. The continued use of cortisone in the patient with hyperplasia has provided a real advance in therapy. Doses of 100 mg. three times weekly in adults, with correspondingly Hmaller dm,es in children, have been accompanied by a striking improvement with marked diminution ill t,he extent of the virilization, with the development, of breasts and onset of menses. For this, cortisone given parenterally is preferable to the oral preparations because of the longer duration of its effectiveness. In the management of the patient with adrenogenital syndrome during the operative removal of an adrenal tumor, knowing that the remaining "normal" adrenal tissue is not suppressed makes it unnecessary to carry out the preoperative and postoperative program as outlined for the patient with Cushing's disease. SUMMARY
In Hummary, this brief review of adrenal function has emphasized how helpful an underHtanding of a few basic aspects of adrenal physiology can be to the clinician in establishing the diagnosis and planning the management of patients with adrenal dysfunction.
828
Abb1:e Ingalls Knowlton REFERENCES
1. Sayers, George: The Adrenal Cortex and Homeostasis. Physiol. Rev. 30: 24[, 1950. 2. Ingle, D. J.: The Role of the Adrenal Cortex in Homeostasis. J. Endocrinol. 8: 23, 1952. 3. Crooke, A. C.: A Change in the Basophil Cells of the Pituitary Gland Common to Conditions Which Exhibit the Syndrome Attributed to Basophilic Adenoma. J. Path. & Bact. 41: 339,1935. 4. Laqueur, G. L. The Hyman Hypophysis in Diseases of the Adrenal Cortex. Stanford Med. Bull. 9: 75, 1951. 5. lTerlant, M.: La corticotrophine est bien elaboree par cellules acidophiles de l'hypophyse. Ann. d'endocrinol. 14: 64, 1953. 6. Ladman, A. J. and Barrnett, R. J.: Histochemical Demonstration of ProteinBound Sulfhydryl and Disulfide Groups in Cells of the Anterior Pituitary. Endocrinology 54: 355, 1954. 7. SuI man, F. G.: Chromatophoretic Effect of Adrenoeorticotrophic HormorlP. Nature 169: 588, 1952. 8. Johnsson, S. and Hiigberg, B.: Observations on the Connexion Between Intermedin and Adrenocorticotrophic Hormone. Nature 169: 286, 1952. 9. Ingle, D. J.: The EffeetH of Administering Large Amounts of Cortin on the Adrenal Cortices of Normal and Hypophysectomized Rats. Am ..1. Physiol. 124: 369, 1938. 10. Sayer, G. and Cheng, C.: Adrenalectomy and Pituitary Adrenoeortieotrophie Hormone Content. 1'roc. Soc. Exper. BioI. & Med. 70: 61, 1949. 11. Hume, D. M. and Wittenstein, G. J.: The Relationship of the Hypothalamus to Pituitary-Adrenocortical Function. 1'roc. First ACTH Conf., B1akiston Co., Philadelphia, 1950, pp. 134-136. 12. Harris, G. W.: The Hypothalamus and Regulation of ACTH Secretion. Adrenal Cortex. Tr. Third Conf. Josiah Macy Jr. Foundation, Progress Associate, Inc., Caldwell, N. J., 1952, p. 54. 13. Gershberg, H., Fry, E. G., Brobeck, J. R. and Long, C. N. H.: The Role of Epinephrine in the Secretion of the Adrenal Cortex. Yale J. BioI. & Med. 23: 32, 1950. 14. Nelson, D. H., Reich, H. and Samuels, L. T.: Isolation of Steroid Hormone from Adrenal Vein Blood of Dogs. Science 111: 578, 1950. 15. Hechter, O. and others: Nature and Biogenesis of Adrenal Secretory Product. Recent Prog. Hormone Research 6: 215, 1951. 16. Rush, 1. E.: Species Differences and Other Factors Infiuencing Adrenocortical Secretion. Ciba Foundation Colloquia on Endocrinology. 7. Synthesis and Metabolism of Adrenocortical Steroids. Boston, Little, Brown & Co., 19.53, p.21O. 17. Romanoff, E. B., Hudson, P. and Pincus, G.: Isolation of Hydrocortisone and Corticosterone from Human Adrenal Vein Blood . .T. Clin. Endoerinol. 18: 1546, 1953. 18. Simpson, S. A., Tait, J. F. and Bush, I. E.: Secretion of a Salt-Retaining Hormone by the Mammalian Adrenal Cortex. Lancet 263: 226, 1952. 19. Simpson, S. A. and others: Konstitution des Aldosterons des neuen mineralcortieoids. Experientia 10: 132, 1954. 20. Kass, E. n., Hechter, 0., Macchi, I. A. and Mou, T. W.: Changes in Patterns of Secretion of Corticosteroids in Rabbits after Prolonged Treatment with ACTH. Proc. Soc. Exper. BioI. & Med. 85: 583, 1954. 2l. Mach, R. S. and others: Action elinique et metabolique de I' Aldosterone (Electrocortine). J. Suisse de med. 84: 407, 1954. 22. Fl'itz, I. and Levine, R.: Action of the Adrenal Cortical Steroids and l'Ii orepillephrine on Vascular Responses of Stress in Adrenolectomized Rats. Am. J. Physiol., 165: 456, 1951. 23. Zweifach, B. W., Shorr, E. and Black, M. M.: The Infiuenee of the Adrenal Cortex on Behavior of Terminal Vascular Bed. New York Aead. Sc. Ann. 56: 626, 1953.
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24. Stoerk, H. C. and Porter, C. C.: Prevention of Lo"s of Fat by Cortisone. l'ro(!. Soc. Expel'. BioI. & Med. 74: 65, 1950. 2.~. Gaunt, R. and others: Biological Studies with Electrocortin (Aldo3tel'Olw). Endocrinology 55: 236, 1954. 26. Silber, R. H. and Porter, C. C.: J. BioI. Chem. In press. 27. Daughaday, W. H., Jaffe, H. and Williams, R. H.: Chemical Assay for "Cortin." Determination of Formaldehyde Liberated on Oxidation with Periouic Acicl, J. Clin. Endocrinol. 8: 166, 1948. 28. Holtorff, A. F. and Koch, F. C.: The Colorimetric Estimation of 17-Ketosteroids and Their Application to Urine Extracts. J. BioI. Chem. 135: 377,1940. 29. Jailer, J. W., Gold, J. J. and Wallace, E. Z.: Evaluation of the "Cortisone Test" as a Diagnostic Aid in Differentiating Adrenal Hyperplasia from Adrcmal Neoplasia. Am. J. Med. 16: 340, 1954. 30. Stahl, J. and Stephan, F.: Quelque aspects du role de la corticosurrenale dans I' equilibre hydromineral. Arch. d. sc. physiol. 8: 175, 1!l54. 31. Plotz, C. M., Knowlton, A. I. anu Ragan, C.: The Natural History of Cushing's Syndrome. Am ..T. Med. 5: 597, 1952. 32. Sosman, M. C. Cushing's Disease-Pituitary Basophilism. Caldwell Leeture, 1937. Am. J. Roentgenol. 62: 1, 194!l. 33. Jailer, J. W.: In press. (i22 West 168th Street New York 32, N. Y.
IN FEW areas of medicine is an understanding of physiological principles of greater practical use to the clinician than in the realm of adrenal disease. However, becautie of the geometrical progretitiion with which the pertinent literature has accumulated in recent years, the would-be reader is apt to be discouraged from attempting to keep informed of progress. This presentation does not claim, by any meanti, to provide a comprehensive review of adrenal functioll. It does aim to single out relevant basic principles, some old and some recently recognized, and to point out in what manner these may serve as a useful guide in evaluating available diagnostic and therapeutic measures. NORMAL FUNCTION OF THE ADRENAL CORTEX
The normal function of the adrenal cortex may be described in broad outline as a homeostatic one. In this it aets in a complementary fashion with the adjacent tis:·me in the medulla, the latter coming int.o play in the first moment of emergency, ,\hile the cortical hormones assume increasing importance in the long-range adjustments to change. The response to the medullary secretioml is for the most part unidirectional, whereas those of the cort.ex elicit re"ponses which may Oil one occasion be diametrically different from that Oil another-the respOI18e varying with the circumstances under which the hormone is given. It is this aspect of adrenal function which Sayersl has labeled the capacity to "normalize." The extent to which virtually every reaction in the body is influenced by the adrenal cortical secretions becomes increasingly impressive as experimental data accumulate. At the same time it is important to reemphasize that life is supportable, though granted it is precarious, in the absence of any adrenal hormone. This is possible, since the adrenal secretions act only as modifiers of existing bodily functions and do not initiate changes.
* Assistant Professor of Medicine, College of Physicians and Surgeons, Columbia Un'iversity, New York, N. Y. 811
812
Abbt'c Ingalls Knowlton
In certain reactions this modifying function appears relatively specific, such as the influence of at least certain of the steroids on the reabsorption of sodium. Here a direct relationship can be demonstrated between the amount of steroid given and the degree of retention of this cation. In many other reactions the role played by the adrenal hormones is less specific and has been described by Ingle 2 as a "permissive" one. Here a certain minimal level of secretion is necessary for the reaction in question to take place, but above this minimal level the extent of the reaction may vary without a change in the amount of hormone available. For example, the untreated adrenalectomized rat loses the normal ability to develop a negative nitrogen balance in response to trauma. However, Ingle has shown that if such an animal is injected with just sufficient hormone to maintain well-being under optimal conditions, it will exhibit a negative nitrogen balance following an experimental fracture and an even more strikingly negative balance after multiple fractures-all this without any increase in the maintenance dose of adrenal hormone. Adrenocorticotrophic Hormone
The secretion of the adrenal cortex is determined by the trophic hormone of the anterior pituitary gland, adrenocorticotrophic hormone (ACTH). In 1916 Smith's studies established the existence of such a hormone by showing that removal of the anterior hypophysis from a tadpole was followed by atrophy of the adrenals. The actual cell type in the pituitary which is responsible for the elaboration of this hormone is not known with certainty. Earlier studies3 • 4 implicated the basophils, but most convincing evidence at present points to the eosinophils.5. 6 ACTH has been isolated as a homogeneous protein from hog and sheep glands with a molecular weight of 20,000. Several questions about the nature of ACTH remain unanswered, such as whether there is more than one ACTH, or whether ACTH acts in any capacity apart from adrenal stimulation. There is some experimental evidence that ACTH may increase work ability in adrenalectomized animals; however, clinically its effect appears limited to its trophic action upon the adrenal. A possible exception is its role in skin pigmentation. ACTH, like intermedin, causes dilatation of the melanophores in the skin of a frog when applied topically,1' 8 as does the blood of patients with Addison's disease and certain patients with Cushing's syndrome. Although the identity of ACTH and this pigmenting substance has been questioned, the connection of the two deserves mention. Much investigative work has been aimed at clarifying the regulatory mechanisms involved in the release of ACTH. Of the several recognized, the most important is a self-regulatory one, i.e., the secretion of ACTH is dependent upon the level of cortical hormone available to the tissues. When the supply is in excess, ACTH production is suppressed; when the
Adrenal Cortical Physiology in Health and Disease
818
supply is inadequate, it forms a stimulus to ACTH elaboration and liberation. 9, 10 However, the rapidity with which ACTH can be released in response to an appropriate stimulus has suggested that a neural or neurohumoral factor governs its liberationY, 12 However, this is not the exclusive means by which ACTH is released, since pituitary tissue transph1nted to the anterior chamber of the eye or to the spleen, away from any possible neural connections, has been shown to liberate ACTH in response to subjecting the animal so prepared to an appropriate stimulus. l The role of the medullary secretions in stimulating the release of ACTH has been fully explored. The review of Gershberg and his coworkers13 leaves no question but that epinephrine can bring about a release of the pituitary hormone. However, the continued administration of epinephrine does not lead to adrenal cortical hyperfunction. THE ADRENAL HORMONES
Exact knowledge of the nature of the adrenal cortical secretion has only recently become available. For the past two decades an increasing number of steroids have been isolated from adrenal tissue, but it remained for studies based upon adrenal vein blood analyses and adrenal gland perfusions to provide information as to which of the many known steroids were elaborated by the gland in vivo. The initial report of Nelson, Reich and Samuels l4 has been much extended,t5, 16 and most recently, data on human adrenals has been made availableY In all specie3 stUdied, corticosterone (Compound B of Kendall) and/or hydrocortisone (Compound F of Kendall) have been found to constitute 85 per cent or more of total steroids of adrenal origin, although the proportion of each varies considerably from species to species. Two years ago Simpson, Tait and Bush 18 reported the occurrence of yet another fraction in adrenal vein blood exhibiting marked sodium-retaining properties. Recently the chemical structure of this ~mbstance has been established in Reichstein's laboratory,J9 as a steroid with an aldehyde ring, aldosterone. These three steroids--corticosterone, hydrocortisone and aldosterone -appear to account for most of the biological activity of the adrenal secretion. It is known that the total amount secreted may range widely depending upon the body's needs, but whether the proportion in which these substances are secreted is fixed or varies in response to the type of stimulus to which the organism is exposed, is not known. A recent report indicates that under prolonged ACTH administration the rabbit secretes proportionately increasing amounts of hydrocortisone and less corticosterone. 20 The chemical formulas are shown in Figure 132. The numbering of certain important carbon atoms is indicated in the formula of aldosterone. Two additional steroids, which are not present in the adrenal vein secretion in significant amounts, are included in this figure-cortisone (Compound E of Kendall) and desoxycorticosterone (DOC).
A bbl:e I ngalls Knowlton
814
Cortisone and desoxycorticosterone are of clinical importance because of their commercial availability, and both have been extensively used in therapy. The latter is of historical interest in that it was the first "adrenal" steroid to be synthesized, although whether it is present in adrenal tissue in significant amounts is questionable. The former has found even wider application therapeutically and is present in considerable quantities in adrenal tissue, although it does not contribute measurably to the glandular secretion into adrenal vein blood.
cx56 0~' ::.~H
11
It.
~
o· Aldostet'one
Corticosterone
Desoxycorticosterone
Hydrocorti sane
Cortisone
Fig. 132. Adrenal steroids.
Action of the Adrenal Hormone
1. Electrolyte Metabolism. In the face of a wide fluctuation in intake, the adrenal secretion serves to maintain a normal concentration in the extracellular fluids of the osmotically important cation, sodium. When the intake of this salt is curtailed, the secretion from the cortex acts to minimize depletion of this ion by facilitating its reabsorption from renal tubular fluid, decreasing the quantities excreted in sweat, saliva and even the normally very small amount present in feces. In the absence of normal adrenal cortical function there occurs a wasting of sodium from extravascular fluids primarily into urine and to a lesser extent into sweat. The resulting decrease in osmolarity is in part compensated for by a loss of fluid externally into urine and also internally into cells. The reduction in the volume of extracellular fluid is progressive, initially affecting the extravascular compartment, but, as the condition advances, involving the plasma volume as well. However, the loss of fluid rarely parallels exactly the loss of sodium, with the result that the concentration of this ion in the serum is usually reduced. As fluid is lost, evidences of hemoconcentration appear and, as this becomes more marked, circulatory function is impaired. The latter, by virtue of a decreased blood flow, affords an explanation for the rise in nonprotein nitrogen and for the increase in serum potassium, although an additional more direct action of the adrenal hormones upon this cation is possible.
Adrenal Cortical Physiology '£n Health and Disease
815
When excess amounts of adrenal hormone are secreted, somewhat the reverse of the above is seen. There may occur an abnormal retention of sodium extracellularly and intracellularly, as well as a comparable loss of potaHHium. At times this is accompanied by an elevation in the concentration of serum sodium, reduction in potat3sium along with an elevation in serum bicarbonate and associated decrease in serum chloride. The several individual steroids mentioned above vary widely in their action upon the renal excretion of sodium. Table 1 roughly compares Table 1 RELA'I'IVI'; ACTIVrl'Y OF ADR]<;NAL STI.;ROIDS RODllJM
VA:-;CULAH
MgTA HOLIRM REKI'ONSIVI';-
Aldosterone .....
........
Corticosterone ..... Hydrocorticosterone ... Desoxycorticosterone .... Cortisone .........
MgTABOLIKM
KTI(gflN
+++
++ ++++
+ + ++++ 0 +++
++++
±
DURING
NI';K"
(X 10 to 100)
+ ± ++++
Plto'!'I';CTION M]<;DIAHY
.?
++++ ± +++
these steroids aH to their ability to retain sodium and excrete potassium. It is evident that aldosterone is many times more potent in this respect than desoxycorticosterone. Compared to these two, the activity of the remaining steroids is weak indeed. Experimentally, prolonged use of desoxycorticosterone hat3 been associated with the development of hypertension in a wide variety of HpecieH, man included. A prerequisite for the appearance of thiH rise in blood preHsure is a liberal Hodium chloride intake, and it seems likely that this abnormality is related to that adrenal function which modifies the handlinl!; of Hodium. Aldot3terone has not been studied over a Hufficiently long period to say whether or not it shares this property of desoxycorticosterone. 21 Both cortisone and hydrocortisone in high dosage have also been accompanied by hypertension in certain species, and aH with desoxycorticosterone thiH effect has been seen, at least with the former, in man. However, this blood pressure effect differs from deHoxycorticosterone hypertension in that it is unrelated to sodium chloride intake. 2. Vasc1ilar Rcsponsiveness. For many years it has been recognized that the adrenal secretions play a role in the maintenance of normal circulatory function apart from their influence upon electrolyte metabolism. The untreated adrenalectomized dOl!; can be returned to relative normal from a state of profound collapse by a single intravenous injection of cortical extract without the administration of sodium or of significant amounts of intravenous fluid. Indeed, in advanced insuffici-
816
Abbie Ingalls Knowlton
ency, serum infusions without extract may be ineffective. Direct observation of the small arterioles of untreated adrenalectomized animals indicates that these vessels lose the normal ability to constrict in response to the repeated administration of epinephrine or norepinephrine, but that this ability can be restored, locally, by the topical application, or generally, by the injection of a whole adrenal extract. Similarly, adrenalectomized dogs given repeated injections of epinephrine show a rapidly diminishing ability to exhibit a normal pressor response. This, too, can be returned to normal by adrenal extracts. The opposite situation, a greater than normal response to the medullary hormones, has been reported in humans receiving large doses of cortisone or ACTH. It is not known to what extent the individual steroids comprising the adrenal secretion partake in this action upon blood vessels. Cortisone, whole adrenal extract and desoxycorticosterone have been reported to restore the responsiveness of the small blood vessels to epinephrine to normal,22 while cortisone in big doses increases the reactivity of the vascular bed above normaF3 (Fig. 2). 3. Intermediary Metabolism. The influence of the adrenal secretions upon the metabolism of protein, carbohydrates and fats is of great importance in the body economy, but because of the efficiency with which the whole operates under normal conditions it is difficult at such times to point to the sites of their action. However, in the absence of these hormones in the adrenalectomized animal, unless the environmental conditions are ideal, a multiplicity of abnormalities becomes apparent. If food is withheld, it is evident that the operated animal is unable to draw upon its body stores of protein as a source for carbohydrate, and, if the animal is fed, more of the dietary intake is stored as body protein than is normal. Conversely, in the animal injected with excess amounts of adrenal hormones there is both a decrease in the laying down of such protein and an increased mobilization of protein stores. This general effect upon protein metabolism finds specific expression in a decreased formation of granulomatous tissue, prolongation of the healing time of wounds, diminution in antibody production and interference with the deposition of the cartilaginous matrix which is an essential preliminary to normal bone formation. Accompanying protein changes there is, in the absence of the adrenals, a fall in blood sugar under conditions of starving, since inadequate amounts can be made available from protein sources. In the opposite situation there is both a greater amount of carbohydrate formed from protein and a decrease in the utilization of sugar, since the adrenal hormones in conjunction with the hormones of the anterior pituitary inhibit the initial step in glucose utilization, the conversion of glucose to glucose-6-phosphate. Elevation in the blood sugar level, diminution in the carbohydrate tolerance and even frank diabetes may ensue. The story with respect to fat metabolism is less well understood.
Adrenal Cortical Physiology in Health and Disease
817
Adrenalectomized animals, when partially starved, lose excessive amounts of adipose tissue, suggesting greater than normal utilization of fat.24 This excessive loss can be prevented by the steroid cortisone which favors the utilization of protein at the expense of carbohydrate and fat. Liver fat is consistently increased in animals receiving cortisone, and ketonemia and ketonuria are both suppressed, suggesting that there is a decreased oxidation of fat. Of the steroids secreted by the adrenal gland, hydrocortisone is by far the most active in influencing intermediary metabolism, corticosterone much less so, while the action of aldosterone is not yet wholly known. 21 , 25 4. Ability to Withstand Stress. It is debatable whether this should be listed as a separate function of the adrenal, since each of the three functions previously described contributes to the capacity of the normal organism to withstand a wide variety of misadventures, such as exposure to cold, starvation, forced exercise, burns and trauma. The lack of this capacity is an impressive characteristic of the adrenalectomized animal. However, the role the adrenals play in affording this protection is for the most part a "permissive" one, and as might be expected from this, the injection of additional adrenal hormone to the normal animal does not provide a greater than normal ability to withstand damaging insults. Of the known adrenal vein steroids, hydrocortisone is the most effective in affording protection to the adrenalectomized animal, cortisone far less so. Aldosterone is as active as cortisone in providing protection against cold exposure,20 the latter steroid being only ~lightly less potent than hydrocortisone in this regard. This action of aldosterone is somewhat surprising, since desoxycorticosterone, which it otherwise closely resembles, is relatively inactive in this sphere (Table 1). MEASURES OF ADRENAL FUNCTION
Corticoid and 17-Ketosteroid Excretion (ACTH Stimulation Test)
The most direct measure of adrenal function should be the determination of circulating adrenal hormone in the peripheral blood,26 but, at present, this is not yet practical clinically, and clinical tests must still rely on indirect evidences of the activity of the glands. Among the most useful of these is the measurement of the urinary excretion of the breakdown products of the adrenal hormones-the "corticoids" and the 17-ketosteroids-and particularly the determination of these substances during a period of adrenal stimulation by ACTH. "Corticoids" include a group of compounds with the sterol nucleus and a side chain, extending from the 17 carbon atom and containing a ketone and an alcohol (see Fig. 132). Such substances are almost exclusively of adrenal origin. Two chemical methods are in use for their determination: the one outlined by Daughaday and his associates27 depends upon the destruction of the side chain and measurement of the formaldehyde formed therefrom;
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the one described by Porter and Silber26 depends upon a color reaction between phenylhydrazine and glycerol, which is derived from the 17, 20 and 21 carbon atoms. Normal values vary widely depending upon the preliminary treatment of the urine, and to interpret a given figure with confidence it is necessary to know the normal range for the laboratory performing the determination. In response to many untoward events-burns, operations, etc.-a riHe in the normal excretion will occur. In long-standing chronic illnesses lower than usual amounts may be present, while in untreated Addison's disease the levels are almost always significantly below normal. In Cushing's Hyndrome the excretion is elevated, although an occasional normal value may be obtained. The 17-keto steroids, substances with the sterol nucleus but with a ketone group instead of a side chain on the 17-carbon atom, are derived in part from breakdown of adrenal hormones and in part, in men, from the testicular androgens. With a commonly employed method, the Holtorff-Koch modification of the Zimmerman reaction,2s normal valuet-! range from 10 to 20 mg. per 24 hours in males and 8 to 15 mg. in females. The excretion iH consistently leRs than normal in chronic diseaRe stateH. In hypofunction of the adrenal cortex, the output of 17-ketosteroids it-! almost uniformly markedly reduced, usually to /eRS than 7 mg. in males and 5 mg. in females. However, small but measurable quantities of 17-ketosteroids and also of "corticoids" are present consistently in patients with Addison's disease. In hyperadrenalism, Cushing's syndrome, the 17-ketosteroid excretion is variable. In patients with adrenal hyperplasia the values are normal to moderately elevated. In the group of patients with an adrenal tumor the level of excretion will depend upon the hormonal output of the tumor. If the secretion from the tumor consists of non-l7 -ketosteroid precursors yet is capable of suppressing the normal production of ACTH and thereby causing atrophy of the nontumorous adrenal tissue, the resultillg 17-ketosteroid excretion may be less than normal. If, on the other hand the tumor does secrete 17ketosteroid precursors, the urine may contain normal amounts or at times greater than normal amounts of these substances, even though the atrophic residual adrenal tissue contributes little. In the aberrant adrenal function described as the adrenogenital syndrome, the excretion of 17-ketosteroids is consistently and sometimes remarkably elevated. In response to a period of ACTII stimulation, the excretion of both "corticoicls" and 17-ketosteroids increases sharply. To obtain definitive changes it is necessary to stimulate the adrenals maximally over an adequate time interval. For this, either 25 units given intravenously in a four-hour infusion 011 two to three successive days, or 25 units intramuscularly every six hours for a similar length of time, is advocated. Normally the increase is of the order of 100 per cent or more. In response to a period of cortisone or hydrocortisone administration (100 to 200 units of the former intramuscularly for two or three days, or
Adrenal Cortical Physiology 'in Health and Disease
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25 units of the latter intravenously for one day) there ensues a decrease in endogenous ACTH production and a temporary fall in the 17-ketosteroid excretion. Such a fall implies that the pituitary is normally sensitive to the inhibiting effects of the increase in circulating adrenal hormone and also that the adrenal gland is in turn normally sensitive to this decrease in ACTH. This test findtl its application in the states of hyperadrenalism in which an adrenal or pituitary turn or is suspected. In those patients with an independently functioning turn or of the adrenal or the pituitary the cortisone will be without effect upon the excretion of 17ketosteroids, while in those with adrenal hyperplasia, a fall will be tleen.29 Salt Withdrawal Test
The other most helpful meatlure of adrenal function is the response of the individual to a period of sodium deprivation. Many varieties of the "salt withdrawal" test exitlt. The test should be carried out under hospital observation, because the accompanying difficulties which may develop in a patient with loss of this adrenal function can be extremely hazardous. It should not be undertaken in a patient whm;e serum concentration of sodium is already below normal. In its simplest form the patient is placed on a moderately low sodium diet (1.5 grams of sodium chloride daily) until evidence of an abnormality in sodium metabolism has been obtained, or, if such does not develop, for a period of a week to ten days. During this test the patient is observed carefully for weight loss, diminution in blood pressure, dizziness, nausea or vomiting, and the test is discontinued if clinical illness appears. At termination, blood is drawn for serum sodium, potassium, hematocrit and nonprotein or urea nitrogen. In the absence of clinical abnormalities, blood is drawn for the above determinations every two or three days. If laboratory facilities permit, the determination of the daily urinary excretion of sodium or of chloride is of added usefulness. No hard and fast rules need be set down for what constitutes a positive test. A fall in serum sodium from normal to 130 mEq.jL. or less, a rise in potassium above normal, a significant rise in hematocrit or nonprotein nitrogen, continued sodium loss in the urine after 24 to 36 hours on the restricted diet-all would indicate abnormal function with respect to sodium and constitute a positive test. Upon obtaining such evidence the test should be terminated. Since renal as well as adrenal mechanisms are involved in the reabsorption of sodium, a positive "salt withdrawal test" may be obtained in individuals with renal disease of sufficient severity to compromise the base saving mechanisms of the kidney even though the adrenal cortices are functioning normally. Other Tests
Other tests of adrenal function exist but have less specificity than those described above. One of these is the water-loading test, originally de-
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scribed by Robinson, Power and Kepler. In its simplest form a measured amount of water, 20 cc. per kilogram or 1000 to 1500 cc., is given the patient to drink within 30 minutes. The water is administered in the fasting state. Subsequently urine is collected at hourly intervals. A normal individual will excrete 70 to 90 per cent of this "water load" within the ensuing four-hour period. In patients with decreased adrenal cortical function this ability is frequently impaired and usually less than 50 per cent is excreted in the four-hour interval. However, a similar delay in excretion may be seen in patients without adrenal disease. Stahl and Stephan30 report such a delay in alcoholics and in malnourished individuals. Hence a diagnosis of adrenal insufficiency cannot be made on the basis of this test alone, although it remains a helpful confirmatory procedure. Accompanying the administration of ACTH there may be a sharp fall in circulating eosinophils and a simple test of adrenal function has been devised based on this. However, it has heen recognized that this test is not wholly reliable, since there exist factors other than the adrenal hormones which influence eosinophil leveh->. lIence, at times normal responses may be seen in the presence of frank adrenal insufficiency, and certain patients without adrenal disease may fail to respond normally. This is particularly true if the control levels are either very low or very high. At present, this test may be considered a confirmatory hut by no means a definitive measure of adrenal function. ADDISON'S DISEASE
Diagnosis
The majority of the symptoms presented by the patient with Addison's history of weight loss, progressive weakness, decrease in blood pressure and gastrointestinal disturbances (anorexia, nausea and vomiting)~can be ascribed to a loss of the ability to conserve sodium, while the occasional hypoglycemic episode and the severe prostration in response to even minor intercurrent illnesses reflect a lack of those steroids influencing carbohydrate metabolism and vascular integrity. The appearance of, or increase in, skin and buccal pigmentation which is highly specific has been attributed to excess amounts of ACTH. Although this hypothesis has been questioned, it is compatible with the observed clinical fact that increased pigmentation is uniformly observed in patients with primary adrenal disease while it is absent in patients with adrenal cortical failure secondary to pituitary hypofunction. It is also compatible with the fact that pigmentation frequently decreases in patients maintained on cortisone, a steroid which suppresses ACTH production. It goes without saying that the finding of the classical symptoms and signs along with laboratory evidence of a diminished serum concentration of sodium and a decreased 24-hour excretion of 17-ketosteroids disease~a
Adrenal Cortical Physiology in Health and Dt'sease
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and corticoids with or without the confirmatory findings of an elevated serum potassium, hemoconcentration and a low fasting blood sugar are sufficient to establish the presence of adrenal cortical insufficiency without further diagnostic procedures. It is only for the patient in whom the history and findings are equivocal that the provocative tests of adrenal function are reserved. For these the patient should be hospitalized, and of these, as described above, the most definitive are the ACTH stimulation test and the sodium withdrawal test. Each have their unique usefulness, and although it is most common for an individual with adrenal insufficiency to show abnormal responses to both, a rare patient may respond normally to ACTH but exhibit an inability to maintain normal sodium balance. A word of caution is necessary about the diagnosis and/or treatment of /la little adrenal insufficiency." Unless definite abnormalities are demonstrated as outlined above, the patient cannot be said to have clinically evident hypofunction, nor is treatment for hypofunction justified. All too frequently the patient with a presenting complaint of weakness, is placed on a regimen of adrenal replacement therapy without adequate investigation, and the improvement which may follow, though due to suggestion rather than any intrinsic quality in the steroid given, is erroneously labeled /la diagnosis by therapeutic trial." Addison's Disease with Tuberculosis
In all patients with adrenal insufficiency a series of diagnostic procedures to establish the presence or absence of a tuberculous infection is in order. Although the frequency of tuberculosis of the adrenals as the cause of Addison's disease is less at present than textbooks of former decades would indicate, tuberculosis remains an important cause of the disease. X-rays of the chest and adrenal area may reveal calcification and, also in the former, evidence of active parenchymal disease. Careful examination of the urine and collection of 24-hour specimens for guinea pig inoculation will help determine possible renal involvement. Should evidence of active tuberculosis be uncovered, therapy for this obviously forms an integral part of the patient's total management. Because of the ever-constant possibility of tuberculosis in the patient with Addison's disease, it is wise to consider how the presence of tuberculosis can modify plans for therapy. Cortisone and presumably hydrocortisone, in large doses, unquestionably accentuate the spread of tuberculosis by suppressing those reactions which tend to localize the infection. It is true that in the maintenance therapy of adrenal insufficiency the physician does not aim to give massive doses but to provide only sufficient amounts to replace deficient adrenal secretions. However, what the physiological dosage is, cannot be known with certainty and the possibility of overdosage is constantly present. From this point of view, maintenance therapy carries less risk to the Addisonian patient with
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tuberculosis if it can be achieved without cortisone, using only added sodium chloride, or sodium chloride plus d()soxyeorticosterone acetate (DCA). However, equally important to the patient with tuberculosis is the maintenance of general health and oJtimal weight. In a significant percentage of the patients with Addison's disease this cannot be achieved with desoxycorticosterone and salt alone, but requires the addition of cortisone. In Addisonian patients with tuberculm;is who fall in thi:-; latter category, the addition of cortisone in small doses carries less risk than withholding this steroid, and should be given with the hope that the improvement in general health following its use will provide, nonspecifically, greater resistance to the infection. The management of the patient with adrenal cortical insufficiency divides itself into day-to-day maintenance and the problem of acutn intercurrent illnesses and crises. Maintenance Therapy
From what is known of the physiology of the adrenal, the most complete replacement therapy would be provided by a whole adrenal extract. However, several reasons exist why this is not practical. It necessitates parenteral therapy because, although whole extracts are effective orally under experimental conditions in animals, no commercial extract is at present available of sufficient potency to support maintenance orally. Furthermore, the cost of the amounts needed for maintenance by parenteral injection is such as to make this form of therapy prohibitive. In the absence of available whole extracts, maintenance must depend upon additional sodium chloride and one or more adrenal steroids. Of those that the adrenal is known to secrete, corticosterone is not available commercially, and aldosterone is not as yet available. If aldosterone proves effective orally it may well, when available, replace the steroid desoxycorticosterone which has been widely used over the past] 5 years in the correction of sodium imbalance. Desoxycorticosterone acetatp has the disadvantage that it must be given parenterally or sublingually. Hydrocortisone is available as the acetate and is effective orally; ho\\,ever, since its actions so closely resemble those of cortisone which has been available for a longer period, the latter has been more widely used in therapy. For completeness, mention should be made of a family of compounds-three steroids resembling hydrocortisone hut with a chloride, a bromide or a fluoride ion in the 9a position. To date, clinical experience has been fragmentary, but all three of these compounds have marked sodium-retaining activity as well as marked influence on carbohydrate and protein metabolism. All are active orally. If further experience fulfills the promise of initial studies, one of these tmbstances may well afford the ideal replacement therapy for the Addisonian patient. In the Addisonian patient without evident tuberculosis, cortisone plus
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823
a supplement of sodium chloride provides the simplest form of maintenance therapy. Daily doses of cortisone from 6 to 25 mg. by mouth, while surprisingly small in comparison to those required to produce a hyperadrenal effect in normals, are sufficient to bring about increases in appetite, impressive weight gain, and even, on occasion, evidence of excess dosage such as acne or the appearance of facial hair in women. In a third or more of patients placed on such a regimen, it becomes necessary to fortify the weakly active sodium-retaining effects of cortisone with desoxycorticosterone acetate in addition to a sodium chloride supplement. Desoxycorticosterone has the disadvantage that it is not effective orally. It may be given intramuscularly or subcutaneously in oil, absorbed sublingually or introduced subcutaneously, either in pellet form or by depot injection as the trimethyl acetate. Daily dosage ranges from O.f) to 5 mg. The sublingual route requires relatively higher dosage because of less effective absorption, while the dosages needed in depot therapy are somewhat lower. Because of the necessity of continued therapy, patients should be advised of the importance of faithfully adhering to their program, and because of the inability to withstand stress, patients are urged to inform their physician promptly of any intercurrent illness. If such an illness is a minor one, protection may be provided by doubling or tripling the daily cortisone dosage, or, if cortisone is not part of the maintenance regimen, by adding this steroid in doses of 25 to 50 mg. per day. In addition, to ensure a constant intake of sodium if intake is curtailed, an increase in the daily supplement of sodium chloride or in the dose of desoxycorticosterone acetate is in order. However, if the patient is significantly febrile (> 101°) or unable to eat, hospitalization is in order. Under such circumstances, treatment would be that outlined for crisis. Crisis Therapy
In crisis reflecting the failure of several phases of adrenal fUllction, the patient is classically febrile with cold, cyanotic extremities, a soft feeble pulse and lowered blood pressure. The mental state may range from lucidity to deep coma. There may be no chemical abnormalities, but more commonly, as described above, the serum sodium is reduced with reduction in the carbon dioxide combining power or serum chlorides, or both. The serum potassium is less frequently abnormal, but may be elevated. Usually there is some evidence of hemoconcentration in the urea nitrogen, hematocrit, hemoglobin, erythrocytes or proteins. Occasionally, severe hypoglycemia is present. In the treatment of crisis, cortisone and hydrocortisone are of particular importance because of the known protection which these steroids provide against damaging insults, by virtue of their effect upon vascular permeability and by their action in intermediary metabolism. In times of acute stress, quantities of these steroids, far in excess of maintenance
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Abbie Ingalls Knowlton
dosages, are needed. What the optimal amounts are is not known with certainty, and probably varies from patient to patient. Dosages in the range of 200 mg. of cortisone acetate orally or intramuscularly per day, or 50 mg. of hydrocortisone intravenously, have been found effective. Desoxycorticosterone acetate is indicated if there has been significant sodium loss, in doses of 5 mg. or so, intramuscularly. Larger doses of this latter steroid are of no benefit since it offers little protection against stresses, and indeed such doses may cause unwelcome excess fluid retention. In addition to cortisone, hydrocortisone, and/or desoxycorticosterone, salt-containing fluids are needed to support the circulation and restore hydration. However, with adequate steroid replacement the total volume of fluid need not be large (averaging 1500 to 2500 cc.), and excessive amounts carry the same hazard as excess desoxycorticosterone. Glucose should be given if the blood sugar is significantly reduced. If shock is profound, norepinephrine by intravenous drip is of benefit but only in conjunction with hydrocortisone or cortisone. Apart from such treatment for the "crisis," therapy is, of course, in order for the precipitating illness, whatever it be. Even in the absence of obvious infection, if the patient is markedly febrile, a wide-spectrum antibiotic should be given. As the therapeutic effect of the steroids given intravenously or by mouth is rapid, improvement is usually seen within 12 hours, and by 24 hours barring a severe accompanying illness, the patient is usually able to take fluids and feels remarkably better. As improvement becomes evident, the nepd for large doses of steroid diminishes. Cortisone acetate may now be gradually reduced, and by the end of about a week the hormone can usually be decreased to maintenance levels or cancelled. Similarly the desoxycorticosterone and added sodium chloride are decreased. Preparation for, and treatment during major operations is similar to that outlined above, with the added provision that the large doses of intramuscular cortisone acetate are started 24 to 36 hours preoperatively in order to allow time for their full effect to be manifest by the day of operation, and are continued several days postoperatively. HYPERADRENALISM
Cushing's Syndrollle
'With the current knowledge of adrenal function, it becomes clear that Cushing's syndrome is no more or less than hyperadrenalism,3] and with this in mind many of the seemingly unrelated abnormalities in this bizarre condition assume an understandable pattern. In many respects these are the opposite of those encountered in Addison's disease. The hypertension, which occurs in over 80 per cent of such patients, has its experimental counterpart in the elevated blood pressures which accom-
Adrenal Cortical Physiology in Health and Disease
825
pally large doseH of adrenal HteroidH. The equally common decreaHe in carbohydrate tolerance (94 per cent) is comprehensible from the known effect of the adrenal hormones in intermediary metabolism. The increased sUHceptibility to infection (42 per cent) and the delay in wound healing seen in a distressingly high number of such patients reflects changes in protein metabolism, as does the osteoporosis which occurs in two out of three. The disturbances in electrolytes, seen in the minority, follow the pattern exhibited by experimental animals given desoxycorticosterone. The increased excretion of corticoids is certainly an expected finding. Although the picture in general outline is compatible with excess adrenal activity, there remain certain aspects of the syndrome for which current knowledge of adrenal function provides no ready explanation, Huch as the obesity with its peculiar distribution and the high incidence of mental aberration. From what has been said above, concerning the excretion of 17keto steroids in this syndrome, a low value provides suggestive evidence of an adrenal tumor. Likewise the response of the 17-ketosteroid output to the administration of cortisone may help in determining whether or not an independently functioning adrenal or pituitary tumor is present. However, neither the 17-ketoHteroid levels under control conditions or after cortisone nor perirenal air insumation can be depended upon to indicate with certainty the presence or absence of an adrenal tumor, and exploration of the adrenal area remains the only means of settling the question definitively. Treatment. Since Cushing'H Hyndrome is clinical hyperadrenalism, it is obviouH that therapy should be aimed at reducing the hyperfunction of the adrenals. The means selected to achieve this will depend upon the abnormality or abnormalities present in the individual patient. In few other diseases need therapy be so "tailor made" to the individual patient, since in few diseases can such a variety of pathological lesions be associated with the same clinical picture. Before embarking on treatment it is wise to consider the possible varieties of pathologic change which have been found in a series of patients with this disease. a1 The adrenal was the Heat of a tumor in approximately one-third of patients, and the tumor was twice as often malignant as benign. In the absence of a tumor the adrenals exhibited bilateral hyperplasia, although in a rare patient the glands were grossly normal. Pituitary neoplasia occurred in approximately one-half of the patients; of these tumors, three-fifths were basophilic, the remainder composed of any of the cell types in the anterior lobe. In the light of this information, therapy is directed initially at exclusion of a neoplasm. If no obvious pituitary tumor exists, operation to exclude or to remove an adrenal tumor is indicated. If none is found, therapy may take one of two courses: (1) pituitary irradiation, which leads
826
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to lasting benefit in approximately one-fourth to one-third of the patients so treated ;:11, :12 or (2) i:iUbtotal adrenalectomy. Benefit, when it occurs, is evident two to four months after the course of therapy is completed. In operative procedures the availability of the adrenal steroids active in protection against stress has made possible more effective management of the patient after removal of an adrenal tumor or after subtotal adrenalectomy. Untreated, such a patient may develop acute adrenal insufficiency postoperatively, from which the mortality is extremely high. With treatment as outlined for an Addisonian crisis, the appearance of postoperative hypoadrenalism can be averted. In the patient with adrenal hyperplasia, treatment is not needed after the first adrenalectomy, as the remaining gland will support normal function. After removal or i:iUbtotal removal of the second gland, therapy as outlined is continued in gradually decreasing amounts over tml days to two weeks, until it can either be withdrawn entirely or, should symptoms of insufficiency become evident, it can be level cd off at a maintenance dosage level. In the patient with an adrenal tumor, the administration of ACTH postoperatively is indicated in addition to the preceding therapy. This serves to stimulate the remaining normal and usually atrophic adrenal tissue, and hence to shorten the period of postoperative hyposecretion. This treatment with ACTH should be continued until after the termination of desoxycorticosterone and cortisone therapy. Adrenogenital Syndrome
From what is currently understood of adrenal physiology it is clear that the adrenogenital syndrome should be considered not as hyperadrenal function, but as aberrant adrenal fUllction. In the synthesis and degradation of such steroids as corticosterone and hydrocortisone, it is chemically possible that intermediary productH of androgenic character exist, and indeed such substances are present in adrenal tissue. In the patient with an adrenal tumor, the neoplastic cells might well produce abnormal amounts of these intermediary products. In patients with hyperplasia it has been postulated by J ailer 33 that a partial block exists in the ability of the adrenal to form hydrocortisone from 17-hydroxyprogesterone and 21-desoxyhydrocortisone, that the androgenic steroids are breakdown products of these two steroids. Such a block would result in the secretion of less than normal amounts of hydrocortisone which, in turn, would lead to an increase in ACTH, since the abnormal intermediaries do not suppress the pituitary gland. The increased amounts of ACTH furnish an explanation for the ob::;erved adrenal hyperplasia and the excretion of great quantities of androgenic steroids. Interestingly enough, the secretion of normal adrenal steroids ii:l maintained, perhaps by virtue of the hyperplasia. Hence, other aspects of adrenal cortical activity remain normal. Exceptions to this are found in the rare infant with the !}drenogenital syndrome who has. in addition, disturbance in
Adrenal Cortical Physiology in Health and Disease
827
electrolyte metaboliHm Himilar to that in the Addi:·;onian patient, and in the equally rare patient in whom true virilization is found accompanying features of the Cushing's syndrome. However, the great majority of patients with the adrenogenital syndrome have no disturbance in electrolyte metabolism nor are there abnormalities in carbohydrate and protein metabolism apart from the changes resulting from the high level of androgens-increased strength and muscle mass, increased growth in children but with early closure of epiphysis. It is logical that the clinical picture will vary considerably with the age at which the abnormal cortical function develops. If this occurs in utero, it will modify the development of the genital organs of a female infant, HO as to result in pseudohermaphroditism, the external organs approaching the male configuration although ovaries are present. If the infant is male, no abnormality may be evident at birth. If the condition makes its appearance during childhood both boys and girls will show marked acceleration in growth and marked muscular development. Precocious puberty is evident in males, while masculinization occurs in females with the development of base voice and abnormal growt,h of the clitoriH, although the genital organs will be clearly female Hince their development antedated onset of the disease. Where onset occurs in adult life in females there occurs true virilization, hirsutism, amenorrhea, acne, clitoral enlargement and voice changes. No counterpart of the syndrome has been recognized in adult males. Treatment. Knowledge of adrenal physiology has been of real benefit diagnostically in this group of patients and has provided as well a rational form of medical therapy. Mention has been made above of the diagnostic use of cortisone in differentiating the patient with hyperplasia from the patient with an adrenal tumor. The continued use of cortisone in the patient with hyperplasia has provided a real advance in therapy. Doses of 100 mg. three times weekly in adults, with correspondingly Hmaller dm,es in children, have been accompanied by a striking improvement with marked diminution ill t,he extent of the virilization, with the development, of breasts and onset of menses. For this, cortisone given parenterally is preferable to the oral preparations because of the longer duration of its effectiveness. In the management of the patient with adrenogenital syndrome during the operative removal of an adrenal tumor, knowing that the remaining "normal" adrenal tissue is not suppressed makes it unnecessary to carry out the preoperative and postoperative program as outlined for the patient with Cushing's disease. SUMMARY
In Hummary, this brief review of adrenal function has emphasized how helpful an underHtanding of a few basic aspects of adrenal physiology can be to the clinician in establishing the diagnosis and planning the management of patients with adrenal dysfunction.
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1. Sayers, George: The Adrenal Cortex and Homeostasis. Physiol. Rev. 30: 24[, 1950. 2. Ingle, D. J.: The Role of the Adrenal Cortex in Homeostasis. J. Endocrinol. 8: 23, 1952. 3. Crooke, A. C.: A Change in the Basophil Cells of the Pituitary Gland Common to Conditions Which Exhibit the Syndrome Attributed to Basophilic Adenoma. J. Path. & Bact. 41: 339,1935. 4. Laqueur, G. L. The Hyman Hypophysis in Diseases of the Adrenal Cortex. Stanford Med. Bull. 9: 75, 1951. 5. lTerlant, M.: La corticotrophine est bien elaboree par cellules acidophiles de l'hypophyse. Ann. d'endocrinol. 14: 64, 1953. 6. Ladman, A. J. and Barrnett, R. J.: Histochemical Demonstration of ProteinBound Sulfhydryl and Disulfide Groups in Cells of the Anterior Pituitary. Endocrinology 54: 355, 1954. 7. SuI man, F. G.: Chromatophoretic Effect of Adrenoeorticotrophic HormorlP. Nature 169: 588, 1952. 8. Johnsson, S. and Hiigberg, B.: Observations on the Connexion Between Intermedin and Adrenocorticotrophic Hormone. Nature 169: 286, 1952. 9. Ingle, D. J.: The EffeetH of Administering Large Amounts of Cortin on the Adrenal Cortices of Normal and Hypophysectomized Rats. Am ..1. Physiol. 124: 369, 1938. 10. Sayer, G. and Cheng, C.: Adrenalectomy and Pituitary Adrenoeortieotrophie Hormone Content. 1'roc. Soc. Exper. BioI. & Med. 70: 61, 1949. 11. Hume, D. M. and Wittenstein, G. J.: The Relationship of the Hypothalamus to Pituitary-Adrenocortical Function. 1'roc. First ACTH Conf., B1akiston Co., Philadelphia, 1950, pp. 134-136. 12. Harris, G. W.: The Hypothalamus and Regulation of ACTH Secretion. Adrenal Cortex. Tr. Third Conf. Josiah Macy Jr. Foundation, Progress Associate, Inc., Caldwell, N. J., 1952, p. 54. 13. Gershberg, H., Fry, E. G., Brobeck, J. R. and Long, C. N. H.: The Role of Epinephrine in the Secretion of the Adrenal Cortex. Yale J. BioI. & Med. 23: 32, 1950. 14. Nelson, D. H., Reich, H. and Samuels, L. T.: Isolation of Steroid Hormone from Adrenal Vein Blood of Dogs. Science 111: 578, 1950. 15. Hechter, O. and others: Nature and Biogenesis of Adrenal Secretory Product. Recent Prog. Hormone Research 6: 215, 1951. 16. Rush, 1. E.: Species Differences and Other Factors Infiuencing Adrenocortical Secretion. Ciba Foundation Colloquia on Endocrinology. 7. Synthesis and Metabolism of Adrenocortical Steroids. Boston, Little, Brown & Co., 19.53, p.21O. 17. Romanoff, E. B., Hudson, P. and Pincus, G.: Isolation of Hydrocortisone and Corticosterone from Human Adrenal Vein Blood . .T. Clin. Endoerinol. 18: 1546, 1953. 18. Simpson, S. A., Tait, J. F. and Bush, I. E.: Secretion of a Salt-Retaining Hormone by the Mammalian Adrenal Cortex. Lancet 263: 226, 1952. 19. Simpson, S. A. and others: Konstitution des Aldosterons des neuen mineralcortieoids. Experientia 10: 132, 1954. 20. Kass, E. n., Hechter, 0., Macchi, I. A. and Mou, T. W.: Changes in Patterns of Secretion of Corticosteroids in Rabbits after Prolonged Treatment with ACTH. Proc. Soc. Exper. BioI. & Med. 85: 583, 1954. 2l. Mach, R. S. and others: Action elinique et metabolique de I' Aldosterone (Electrocortine). J. Suisse de med. 84: 407, 1954. 22. Fl'itz, I. and Levine, R.: Action of the Adrenal Cortical Steroids and l'Ii orepillephrine on Vascular Responses of Stress in Adrenolectomized Rats. Am. J. Physiol., 165: 456, 1951. 23. Zweifach, B. W., Shorr, E. and Black, M. M.: The Infiuenee of the Adrenal Cortex on Behavior of Terminal Vascular Bed. New York Aead. Sc. Ann. 56: 626, 1953.
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24. Stoerk, H. C. and Porter, C. C.: Prevention of Lo"s of Fat by Cortisone. l'ro(!. Soc. Expel'. BioI. & Med. 74: 65, 1950. 2.~. Gaunt, R. and others: Biological Studies with Electrocortin (Aldo3tel'Olw). Endocrinology 55: 236, 1954. 26. Silber, R. H. and Porter, C. C.: J. BioI. Chem. In press. 27. Daughaday, W. H., Jaffe, H. and Williams, R. H.: Chemical Assay for "Cortin." Determination of Formaldehyde Liberated on Oxidation with Periouic Acicl, J. Clin. Endocrinol. 8: 166, 1948. 28. Holtorff, A. F. and Koch, F. C.: The Colorimetric Estimation of 17-Ketosteroids and Their Application to Urine Extracts. J. BioI. Chem. 135: 377,1940. 29. Jailer, J. W., Gold, J. J. and Wallace, E. Z.: Evaluation of the "Cortisone Test" as a Diagnostic Aid in Differentiating Adrenal Hyperplasia from Adrcmal Neoplasia. Am. J. Med. 16: 340, 1954. 30. Stahl, J. and Stephan, F.: Quelque aspects du role de la corticosurrenale dans I' equilibre hydromineral. Arch. d. sc. physiol. 8: 175, 1!l54. 31. Plotz, C. M., Knowlton, A. I. anu Ragan, C.: The Natural History of Cushing's Syndrome. Am ..T. Med. 5: 597, 1952. 32. Sosman, M. C. Cushing's Disease-Pituitary Basophilism. Caldwell Leeture, 1937. Am. J. Roentgenol. 62: 1, 194!l. 33. Jailer, J. W.: In press. (i22 West 168th Street New York 32, N. Y.