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Cortisol and immunity
Medical Hypotheses Medico/ Hypotheses (1991) 34, 198- 208 0 Longman Group UK Ltd 1991
Cortisol and Immunity W. McK. JEFFERIES 2423 Newbury Drive, Cleveland, Ohio 44 7 78, USA
Abstract - The relationship between adrenocortical function and immunity is a complex one. In addition to the well-known detrimental effects of large, pharmacologic dosages of glucocorticoids upon the immune process, there is impressive evidence that physiologic amounts of cortisol, the chief glucocorticoid normally produced by the human adrenal cortex, is necessary for the development and maintenance of normal immunity. This evidence is reviewed, and the importance of differentiating between physiologic and pharmacologic dosages and effects is discussed. The popular use of synthetic derivatives of cortisol, which differ greatly from the natural hormone in strength, and the dynamic nature of the normal adrenocortical response, which varies with the degree of stress being experienced, have contributed to the confusion. Further studies of the nature of the beneficial effect of cortisol, and possibly of other normal adrenocortical hormones, upon immunity in humans are needed, especially in view of recent evidence of a feedback relationship between the immune system and the hypothalamic-pituitary-adrenal axis, and with the increasing awareness not only that the immune process provides protection against infection, but also that its impairment seems to be involved in the development of autoimmune disorders, malignancies and the acquired immunodeficiency syndrome (AIDS).
Introduction
Much has transpired since the publication by this author of a review article on the clinical uses of ACTH and cortisone in 1955 (1). At that time, it was thought that their beneficial effects in disorders such as arthritis and allergies depended upon the production of an excess of glucocorticoid effect in the body, and it was hoped that the introduction of derivatives such as prednisone would enable beneficial effects to be obtained without the risk of undesirable side-effects. Un-
fortunately, this hope was not realized. As reports of grim side-effects accumulated, physicians became reluctant to prescribe any glucocorticoid and these agents developed a reputation for being risky to use under any circumstances. This is not surprising, because the dosages in general use have been those that would be expected to produce unpleasant or even dangerous side-effects if continued for a sufficient length of time. The fact that cortisol, the chief glucocorticoid produced by the human adrenal cortex, is a normal hormone, in fact it is essential for life, has been largely
Date received 20 July 1990 Date accepted 20 August 1990
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forgotten. Prednisone, triamcinolone, dexamethasone and similar commercially popular steroids are more potent derivatives of cortisol (hydrocortisone) or cortisone, with less sodium-retaining effect, but with other side-effects that may be equally or more serious. One of the more dangerous side-effects that is common to all known glucocorticoids is that of lowering resistance to infection. Yet from the earliest reports of studies of adrenocortical function there has been impressive evidence that adrenocortical hormone, and more specifically cortisol, is essential for normal immunity. Because the potentially harmful effects of cortisol and other glucocorticoids upon immunity are well known, in an attempt to restore perspective it might be helpful to review the evidence for beneficial effects of cortisol upon immunity, especially since there has been increasing evidence through the years, culminating in recent reports, that this hormone may have untapped therapeutic potential in safe, physiologic dosages.
to be steroids, had important roles in maintenance of optimum health and energy. An additional property of adrenal cortical secretion became evident from early experiments. An adrenalectomized rat, if given proper amounts of food, salt, water and rest at proper intervals, and if protected against infection, would survive, but if any one of these essentials were changed, the animal would die. Any alteration of an optimum environment is a stress, hence the adrenocortical hormones protect against stress. Protection against all of these stresses except the last can be explained by the three actions listed above, but protection against infection involves a beneficial effect upon immunity, which not only does not seem to relate to any of these fundamental actions, but also is contrary to well-established evidence that glucocorticoids impair immunity. Thus an enigma was presented that continues to cause confusion. Pre-cortisol studies
Historical background Our knowledge of the function of adrenocortical hormones is relatively recent. In the 193Os, while I was a medical student, a heated controversy existed between one group of investigators who contended that the primary action of adrenocortical hormone was the maintenance of electrolyte balance, and another group who were equally convinced that it was the regulation of carbohydrate metabolism. Later, it became evident that not just one, but several hormones were produced by the adrenal cortex, and that each had one or more of three fundamental actions in varying degrees: the regulation of electrolyte metabolism (sodium-retaining and potassium-losing effect), the ability to promote conversion of precursors to glucose (gluconeogenesis), and the promotion of growth and repair of protein tissue (anabolism). Since sodium is the chief cation in extracellular fluid and potassium the chief cation of intracellular fluid, the regulation of their relative concentrations is essential for maintenance of normal circulation and blood pressure; since glucose is the chief source of energy of the body and the sole source of energy for the brain, the ability to maintain adequate levels under conditions in which food supply might vary is obviously critical; and since growth and repair of protein tissue are necessary for normal growth and development, it became evident that the adrenal cortical hormones, which were found
During World War I, fatal cases of various types of infections were noted to have striking morphologic changes in the adrenals. These were described by Aschoff (2) and by Goldzieher (3), and included postmortem studies on subjects with fatal cases of diphtheria, scarlet fever, malaria, peritonitis, gas gangrene, streptococcal infections, and every other septic condition noted during the war. Then changes included evidence of degeneration and necrosis of the adrenal cortex with marked edema, regression of lipoid material, hemorrhages, and arterial thromboses, without similar changes in other organs. With such evidence of serious damage to the adrenals in the course of severe infections, the question of its significance arose. In 1926, Jaffe and Plavska (4) in studies of susceptibility of adrenalectomized rats to typhoid vaccine, noted that the adrenal cortex seemed to be more important than the medulla in providing resistance. In 1931, Perla and MarmorstonGottesman (5) reported that adrenal cortical extract was primarily responsible for maintaining the resistance of adrenalectomized rats to histamine poisoning, supporting the impression that the adrenal cortex, not the medulla, was primarily responsible for resistance to toxins. The following year, Hartman and Scott (6) reported that adrenocortical extract restored the resistance of adrenalectomized rats to bacterial intoxication almost to normal. The same year Whitehead and Smith (7) reported that injections of adrenocor-
200 tical extract into patients with severe infections such as typhoid fever, undulant fever, cellulitis, and sinusitis seemed to be symptomatically beneficial. In 1936, Ingle reported further evidence that the adrenal cortex was more important than the medulla in maintaining resistance of rats to histamine shock (8). The following year Pottenger and Pottenger (9) reported that injections of adrenocortical extract helped to protect guinea pigs against experimental tuberculosis infection. They also reported that injections of adrenocortical extract into patients with tuberculosis improved their energy and lessened fatigue. In 1941, Kendall (10) reported that as little as 30 mcg of Compound E, a steroid of the adrenal cortex that later was named cortisone, would protect an adrenalectomized rat against 25 minimum lethal doses of typhoid vaccine. Perla and Marmorston, in their book Natural Resistance and Clinical Medicine, that was published in 1941 (II), reviewed evidence for a relationship between suprarenal (adrenal) function and resistance to infection up to that time, and they concluded that ‘The suprarenal glands are important in the maintenance of the natural resistance of the body to intoxications, poisons, and bacterial and protozoa1 infections.’ They further stated that ‘The depression in natural resistance following suprarenal insufficiency is probably dependent upon loss of cortical function, since injections of the cortical hormone raise the resistance of suprarenalectomized animals to the normal level.’ In the same year, 1941, Ingle published the first (12) of a series of studies that culminated in two reviews (13, 14) in which he presented certain fundamental principles that apply to actions not only of adrenocortical hormones, but also of other hormones, principles which, if they had been better borne in mind, might have helped to prevent some of the confusion that later developed regarding glucocorticoid therapy. First, he pointed out the difference between a specific action that is caused by an increased amount of a hormone and an action in which the hormone is not the exciting or regulatory agent, but in its absence the normal signs of response fail to occur. He termed the latter type of action a ‘permissive’ action, one that ‘supports or normalizes the capacity of a system to respond to an active cause’ (13). As an example, other hormones, such as thyroid, growth and probably gonadal hormones, may not have normal effects if adrenocortical hormones, especially
MEDICAL HYPOTHESES
cortisol, are deficient. Similarly, other hormones, including adrenocortical hormones, may not have normal effects if thyroid hormone is deficient. In these instances adrenal and thyroid hormones act as permissive factors. Other fundamentals principles that he described included ‘the nature of a response (to a hormone) may be reversed as dosage is changed’. A classic example had been seen in studies of thyroid function in experimental animals: a deficiency of thyroid hormone impaired growth, euthyroidism was essential for normal growth, yet an excess of thyroid hormone again impaired growth. He suggested that a similar relationship might exist between adrenocortical function and anabolism. He also pointed out that, ‘in addition to the size of the dose, the route and frequency of hormone administration are important factors affecting doseresponse relationships’. The same total dosage administered in divided portions at frequent intervals produces a greater effect than when administered at longer intervals. This characteristic affects replacement therapy with cortisol, but it has apparently not received much attention. He further noted that ‘the size of an optimum replacement dosage for adrenocortical insufficiency varies with the degree of stress being experienced by the experimental subject’. In an extension of this concept, he stated ‘The increased secretion of adrenal hormones serves to meet an increased need during stress and tends to maintain homeostasis rather than to disturb it. The increased secretion does not cause a state of hypercorticism such as develops when the titer of these hormones is increased artificially in the absence of need’ (15). Hence, the harmful side effects that have given cortisol and other glucocorticoids such a bad reputation are a result of the patient getting an excessive amount of steroid and, in some instances at least, may not be a necessary complication of therapeutic effects; perhaps an initial larger dosage might be necessary to correct an abnormal state, but, once corrected, the improvement might be maintained by continuing a smaller, physiologic dosage without producing undesirable side-effects. He also called attention to two other fundamental principles that should be borne in mind in planning or evaluating studies of hormone action: ‘the amount of hormone required to elicit a standard response varies greatly among individuals,’ and ‘the sensitivity of experimental animals and of man to hormones and drugs varies with age’. These probably contribute to the relatively broad ranges of normal
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values for cortisol and other hormones, and they also imply that the finding that a patient’s hormone level falls within the normal range does not necessarily mean that it is normal for that patient or that that patient has normal function of that particular hormone. Studies with cortisone or cortisol After cortisone and cortisol became available for clinical use in 1949, a few reports continued to suggest a potential beneficial effect upon immunity, but the obvious harmful effects of the pharmacologic dosages that were in widespread use caused them to be generally overlooked. In 1953, Kass and Finland (16) reported that the amount of cortisone required to restore the resistance of adrenalectomized mice to approximately their original state of resistance to infection was five to ten times the amount that maintained uninfected adrenalectomized mice in an apparently normal state, whereas approximately 20 - 50 times the minimum maintenance dosage must be given to depress the mouse’s resistance below that of an intact animal. This was a nice demonstration of Ingle’s principle that the nature of a response to a hormone may be reversed as the dosage is changed. In 1954, Benedek and Montgomery (17) reported that patients with rheumatoid arthritis experienced fewer infections during 465 months of cortisone and/or ACTH therapy than during 411 months without such therapy. In 1960, Spink (I@, in a report of the effects of administration of adrenal steroids to patients with infectious diseases, stated, ‘Judicious use of corticotropin and corticosteroids frequently contributed to immediate improvement in the condition of patients seriously ill with infections and their complications.’ He further stated, ‘An inventory of the 81 patients treated in this study has revealed no significant ill effects when steroids were administered for only a few days, even when large dosages were used.’ in a series of reviews of the relationships between glucocorticoids and immunity (16, 19-25), the apparently contradictory effects of these agents upon immunity were discussed, and it was concluded that more studies were necessary to clarify this paradox. In 1969, Beisel and Rapaport (26), in a review of the interrelations between adrenocortical functions and infectious illness, summarized this problem. They stated ‘that the human host does fare best when his own pituitary-adrenal axis is nor-
201 mally responsive (or when exogenous hormone is given in optimal replacement dose after adrenalectomy) is a conclusion based upon extensive clinical data and well-confirmed evidence in laboratory animals.’ They also stated that ‘present information suggests that secretion of all major corticosteroid hormones is stimulated early in the course of acute infectious illness,’ and that ‘all available data support the concept that the glucocorticoid increase in the period of early symptoms varies in magnitude with the clinical severity of the infectious illness.’ It did not seem logical that nature would, at the onset of an infection, produce an increased amount of a substance that would impair resistance to the infection, and they concluded that ‘It is to be hoped that an understanding of the mechansism by which normal adrenal responsiveness is protective (in contrast to the harmful nature of hypercorticism or hypocorticism) will provide a useful approach to the treatment of infectious illness.’ Some studies have suggested mechanisms by which adrenocortical hormone may enhance immunity. In 1945, Dougherty, Chase and White (27) reported that a single injection of adrenocortical extract or ACTH into rabbits or mice produced a release of antibody from lymphocytes, and they concluded that ‘These data establish the role of pituitary-adrenal cortical secretion in the controlling mechanism for the release of antibody from lymphocytes.’ Later, the validity of this study was questioned because other studies failed to confirm this effect; however, none of the studies that failed to confirm the effect used the same protocol as that employed by Dougherty’s group. In 1964, Ambrose (28) reported evidence that hydrocortisone was necessary for the formation of antibody in tissue cultures, and in 1970 (29), he further reported that a physiologic level of glucocorticoid appeared to be essential for the initiation of the immune process. In 1972, Smith, Sherrman and Middleton (30) reported evidence that hydrocortisone in low concentrations produced increased immunoglobulin (Ig) synthesis and secretion by human peripheral lymphocytes in vitro, whereas higher concentrations resulted in a suppressor effect. In the same year, Tuchenda, Newcomb and DeVald (31) reported that prednisone treatment seemed to improve immune response in children with asthma. In 1975, Rusu and Cooper (32) reported that in young chickens treatment with cortisone produced a mobilization of B lymphocytes and enhancement of differen-
202 tiation into mature Ig-producing plasma cells in peripheral lymphoid tissue. In 1977, Fauci, Pratt and Whalen (33) reported that hydrocortisone in physiologic concentration in vitro enhanced the response of normal human peripheral blood B lymphocytes, whereas much larger concentrations suppressed early B cell activation. In 1981, Grayson and her associates (34) reported that addition of hydrocortisone in low concentration to peripheral blood lymphocytes in culture resulted in dramatic induction of immunoglobulin production, including IgG, IgA and IgM. This effect occurred only with glucocorticoids, and not with estrogens or androgens, and they suggested that glucocorticoids might play a role in the normal function of the immune system. Orson and associates (35,36), in a continuation of the in vitro work of this group, reported that glucocorticoids induce the synthesis and secretion of all classes of immunoglobulins and that a steroiddependent cytokine appeared to participate in this response. In 1982, Nouri-Aria et al (37) reported that physiologic concentrations of glucocorticoids may inhibit natural killer (NK) cell activity in vitro and that continuation of low dosages may maintain remissions in patients with autoimmune hepatitis. In 1985, Cupps et al (38) reported that the effect of corticosteroids upon B cells varied not only with the amount of steroid but also with the phase of the B cell cycle, enhancement of secretion of immune globulins occurring in the later stages of the cycle. In the same year, Levo, Harbeck and Kirkpatrick (39) confirmed that cortisol in low concentrations enhanced synthesis of immune globulins, whereas high concentrations inhibited such synthesis. Hence, it appears that the initial observations of Dougherty et al (27) were valid and that failure to reproduce their results may have been due to differences in dosage of steroid administered, in the stage of the B cell cycle at which the steroid was added, or in other aspects of protocols. Evidence that physiologic dosages of glucocorticoids can improve immunity in respiratory infections in patients with adrenocortical insufficiency is impressive, although it has apparently received little attention. When cortisone and cortisol first became available for administration to such patients, there was concern regarding their effect upon immunity, which was already diminished in this disorder, but it eventually became evident that administration of physiologic dosages not only did not impair immunity, but it actually seemed to en-
MEDICAL HYPOTHESES
hance resistance to common respiratory infections (40). Patients who previously had experienced several respiratory infections per year reported few, if any, such infections while taking these steroids, and the infections they had seemed less severe, especially if they doubled their maintenance dosage as they were instructed to do during times of increased stress. In fact, a prompt increase in dosage at the onset of symptoms of incipient respiratory illness was sometimes followed by a disappearance of symptoms without recurrence when the dosage was returned to maintenance level, suggesting that the illness had been aborted. Meanwhile, other members of the patients’ families seemed to have their usual quota of respiratory illnesses, so the decrease in such illnesses in the patients apparently could not be attributed to lack of exposure to the viruses. Later, patients who were receiving prolonged treatment with physiologic dosages of cortisone acetate or cortisol for other conditions reported similar apparent protection against common respiratory illnesses. In the course of over 2000 patient-years of experience with physiologic dosages of cortisol or cortisone acetate, this observation has been repeatedly confirmed. When those who reported apparent protection were compared with those who did not, it appeared that the difference was frequently related to whether a patient smoked. The non-smokers seemed to experience most benefit in their resistance, and those who continued to smoke during infections seemed to benefit least. A beneficial effect of glucocorticoid therapy upon more severe respiratory infections has also been noted. After an influenza epidemic in Malmo, Sweden in 1957, Skanse and Miorner (41), in a report of the presence of untreated adrenal insufficiency in several patients who succumbed, noted that ‘resistance to Asian influenza appears to be lowered more by untreated adrenocortical insufficiency than by chronic cardiac or renal disease.’ They further noted that patients with adrenal insufficiency receiving adequate substitution therapy tolerated an attack of influenza as well as, or better than, patients with normal adrenals. They concluded that ‘in all cases of severe influenza any suspected adrenal insufficiency should be compensated.’ During an influenza epidemic in London in 1958, Mickerson (42) noted that urinary steroid excretion of patients was subnormal, and that improvement occurred after intramuscular administration of ACTH or oral administration of prednisolone, 2.5 mg three times
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daily. During an influenza epidemic in the U S in 1976, Rivera and I (40) noted that plasma cortisol levels of acutely ill patients were low, and that impressive clinical improvement occurred with the administration of cortisol, 20 mg orally four times daily, tapering and discontinuing the medication over a four day period after the patients felt well. The low cortisol levels responded to stimulation with cosyntropin, suggesting that the viral infection had temporarily impaired normal ACTH secretion. The few patients studied had no complicating bacterial infections, but if such occur, suitable antibiotic therapy should be added. Another sometimes severe respiratory illness is infectious mononucleosis. In 1962, Chappel (43) reported beneficial effects of cortisone therapy in 111 cases of this disorder, with control of symptoms within a few days and elimination of long periods of bed rest and disability. In a study of 66 students with severe but uncomplicated infectious mononucleosis, Bender (44) reported that treatment with ACTH or prednisolone resulted in a significant shortening of illness and loss of time from classes compared with matched controls. Additional reports of similar beneficial effects of glucocorticoids upon this illness have been published. in 1974, Mangi et al (45) reported evidence that cell-mediated immunity is impaired during acute infectious mononucleosis. This observation, plus the more recent evidence of impaired adrenocortical response to acute influenza cited above, suggests that the effect of other viral infections upon the hypothalamic-pituitary-adrenal system and the immune response should be studied. It is possible that different viruses may impair immunity in different ways. Because adrenal insufficiency can cause chronic fatigue, and because at least some viral infections may be associated with adrenal insufficiency, patients with unexplained chronic fatigue may benefit from studies of adrenal function as well as tests for obscure infection (40). More recently, a series of reports (46 - 50) have described abnormalities of adrenocortical function, either primary or secondary to pituitary or hypothalamic effects, in patients with the acquired immunodeficiency syndrome (AIDS), so the possibility that this might be a factor in the development or the progress of this alarming disorder is raised. Administration of replacement dosages of glucocorticoids resulted in impressive clinical improvement in some cases, suggesting that this type of treatment might be helpful in at least some patients with this disease.
203 During the past decade, immunologists have reported increased evidence of a relationship between the neuroendocrine and the immune system that has been summarized by Blalock (51) and by Bateman et al (52). Interest in the relationship between these two systems has intensified with the evidence that cells of the immune system can have a direct influence on pituitary and adrenal function. During the past five years progressive evidence for an immunoregulatory feedback relationship between monocytes and hypothalamus has been reported, some aspects of which have interesting clinical implications. In 1985, Woloski et al (53) reported that interleukin-1 (11 - l), a protein produced by monocytes in response to inflammatory challenge, stimulated pituitary cells to release ACTH. The following year, Besedovsky et al (54) reported evidence for the specificity of this feedback, and that the production of 11 - 1 is inhibited by glucocorticoid. This suggests one mechanism by which excessive amounts of cortisol might impair immunity. In 1987, Sapolsky et al (55) and Berkenbosch and associates (56) reported evidence that II- 1 stimulated ACTH release, not through a direct effect on the pituitary, but by stimulating production of corticotropin-releasing factor (CRF) from the hypothalamus. During the past year, Sternberg and her associates (57, 58) have reported that a strain of rats that is inherently susceptible to experimental arthritis produced by injection of a preparation derived from streptococcal cell walls demonstrated defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis with a defective CRF production, whereas another strain that is resistant to such arthritis had a normal CRF response. When the resistant strain was treated with the glucocorticoid receptor antagonist, RU 486, thus interrupting the HPA axis at its end point, it became susceptible to the experimental arthritis. Because the challenge that produced the arthritis in susceptible animals was derived from streptococcal cell walls, a defect in immune response in these animals seems likely. It would be interesting, therefore, to determine whether susceptible rats develop autoantibodies in the course of their response to the injections. These observations suggest that autoimmune disorders such as rheumatoid arthritis may be associated with a defective HPA response to infection or other stress that might not be detected by routine studies of adrenocortical function if the defect is at the hypothalamic level. Hence re-
204 sponses of patients with these disorders to tests that determine the integrity of the entire HPA response should be studied. It is also possible that persistent treatment of patients with these disorders with physiologic dosages of cortisol, in contrast to the intermittent administration of large, pharmacologic dosages of stronger steroid derivatives that is customary, may be more helpful and also may avoid the side-effects produced by pharmacologic dosages. This possibility is consistent with the evidence reported by Nouri-Aria and associates (37) that continuation of low dosages of glucocorticoids may maintain remissions in patients with autoimmune hepatitis. It appears that an increased amount of cortisol is necessary for normal response to infection and to other stresses, and that an inadequate increase may in some way play a part in the development of autoimmune disorders. Munck and his associates (59) have suggested that the increased production of cortisol that accompanies the onset of infection may serve to limit the immune reaction from overshooting and hence may, be consistent with the, well-known anti-immune effects of pharmacologic dosages. This interesting idea might explain one aspect of adrenocortical function in response to infection, but it does not explain why adrenally insufficient patients have deficient immune responses, nor why physiologic dosages seem to enhance the immune response, nor is it consistent with the impression of Ingle (15) that the increased production of adrenal hormone in response to stress helps to maintain a physiologic state instead of producing pharmacologic effects. Present status The studies reporting beneficial effects of glucocorticoids upon infections and immunity have received little attention, and medical textbooks, emphasizing the serious hazards of glucocorticoid therapy, continue to imply that there is no safe dosage of these agents. Even the package inserts for cortisone acetate and cortisol fail to differentiate between physiologic and pharmacologic dosages, and they imply that any dosage might produce any of the alarming side-effects that occur only with dosages in excess of body requirements. With the variation in dosages and in steroids used in reports of glucocorticoid therapy and with the dynamic nature of normal adrenocortical re-
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sponse to stress, it is not surprising that confusion has developed regarding physiologic dosages. First, it should be remembered that the chief glucocorticoid produced normally by human adrenals is cortisol. Cortisone is also produced in small amounts, but it is converted to cortisol before having physiologic effects. Prednisone, triamcinolone, dexamethasone and other similar steroids are synthetic derivatives of cortisone or cortisol with much greater potency of glucocorticoid effect per milligram, but sometimes with different pharmacologic effects. Although some of these steroids have been reported to have similar beneficial effects upon infections, their comparable safety and effectiveness to the natural steroids in physiologic dosages have not been investigated. The safety of physiologic dosages of cortisol or cortisone acetate has been observed by endocrinologists treating patients with adrenal insufficiency over the past 40 years, but this safety has not been publicized. This safety in our experience with over 1000 patient-years of treatment with physiologic dosages was reported (60), but has apparently received little attention. The only undesirable sideeffects encountered have been acid indigestion in susceptible persons or skin rashes in patients who are allergic to an ingredient in the filler of the steroid tablets. What then is a physiologic dosage of cortisol? Under unstressed circumstances, human adrenals produce 15 - 20 mg of this steroid per day, with a diurnal variation depending upon the sleepwake schedule, but a totally adrenalectomized person receiving cortisol by mouth requires approximately twice this amount as a maintenance dosage, presumably because such a replacement schedule is less efficient than the production and release of hormone directly into the blood stream according to need in a person with normal adrenals. Because the effect of a single dose of cortisol or cortisone acetate seems to last a maximum of 8 h (61), and because normal cortisol production occurs in spurts rather than in a continuous, smooth manner, and also because, as Ingle pointed out (13), the same total amount of adrenocortical hormone given in divided doses at frequent intervals is more effective than when given at less frequent intervals, for optimum physiologic effect these steroids should be given several times daily, and a suitable schedule for both patient compliance and therapeutic effect seems to be four times daily, before meals and at bedtime. Studies on a normal subject indicated that
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2.5 mg cortisone acetate four times daily by mouth suppressed endogenous cortisol production by approximately 30%, and 5 mg four times daily by approximately 609’0, confirming that 35 - 40 mg daily in divided dosage should be proper replacement for a totally adrenalectomized person under non-stressed conditions (60). With such small dosages there appears to be no significant difference between the effects of same dosages of cortisone acetate and cortisol when taken by mouth, but because preparations of cortisone for parenteral use are much more slowly effective than those of cortisol, under conditions where rapid effect is desired cortisol preparations should be administered intramuscularly or intravenously. A dosage of 10 mg cortisol four times daily will usually produce optimum glucocorticoid effect in an unstressed totally adrenalectomized patient. Some patients prefer a schedule of 15, 10, 10 and 5 mg, which more closely approximates the usual diurnal pattern. With increased stress, requirements are greater, varying from 20 mg cortisol by mouth four times daily, which seems to provide adequate replacement during the common cold, influenza and infectious mononucleosis, to 100 mg hydrocortisone sodium succinate intramuscularly one hour before major surgery and continuing at 8 h intervals in decreasing doses, tapering to the baseline maintenance dosage over the next 6- 8 days, meanwhile returning to oral therapy as soon as the patient’s condition permits. In cases of overwhelming sepsis, such as intestinal rupture with peritonitis, even larger dosages may be necessary. Hence, a physiologic dosage may vary, depending upon the degree of stress the patient is experiencing. This has undoubtedly contributed to the confusion that exists regarding the safety of cortisol therapy, but it is consistent with the principle emphasized by Ingle that the increased amount of cortisol that is required during stress helps to maintain homeostasis and does not produce the hypercorticism that the same amount would produce in an unstressed state (15). Although as a maintenance dosage 10 mg cortisol four times daily will not produce any of the effects of hypercorticism, it will inhibit endogenous adrenocortical activity in the unstressed state, so for patients other than those who have been totally adrenalectomized, smaller maintenance dosages are preferable. The effectiveness and safety of dosages of 5 mg or less four times daily of cortisol or cortisone acetate in patients with milder endocrine or autoimmune disorders
has been reported (60), but confirmatory reports from other clinics have not been forthcoming, possibly because the general fear of side-effects of glucocorticoid thereapy at any dosage level may have discouraged therapeutic trials, plus other factors that have prevented pharmaceutical companies from advertizing the safety and effectiveness of small, physiologic dosages (62). Conclusions Although much has been learned in recent years regarding the various components of the immune system, such as T cells, B cells, macrophages, interferon and the interleukins, little is known about the manner in which the human body regulates this system. With evidence that the production of cortisol may play an important role in initiating and possibly regulating activity of the immune system, further studies of the relationship between normal adrenocortical function and immunity should be rewarding. The distinction between physiologic and pharmacologic dosages of cortisol and possibly other normal adrenocortical steroids needs to be further clarified, and the possibilities must be considered that, in addition to the size of the dosage administered and the degree of stress being experienced, the timing of administration of cortisol either before or after exposure to stress or infection, or changes in levels of other normal adrenal steroids or of other hormones, may affect the response of the host. Low levels of excretion of dehydroepiandrosterone in patients with rheumatoid arthritis have been reported from two clinics (60, 63), but these studies have not been extended. The possibility that patients with autoimmune disorders might have abnormal feed-back responses to infection or to other stresses and that they might benefit from continuation of physiologic maintenance dosages of cortisol after remissions have been attained with larger dosages of glucocorticoid should also be further investigated. An increased amount of cortisol appears to be necessary for a normal response to infection or to any other stress, and hence an inadequate increase in cortisol may in some way contribute to the development of autoimmunity. It is interesting to note that cortisol is the only known substance produced by the human body that benefits autoimmune disorders, and that it and epinephrine are the only known natural hormones that counteract allergic reactions. Hence, the possibility that aller-
206 gies might be associated with defects in immune response should also be further explored. In order to learn more about physiologic versus pharmacologic dosages and responses, before glucocorticoid therapy is prescribed for any patient baseline tests of adrenocortical function, including blood cortisol and ACTH levels and response of cortisol to cosyntropin, would be helpful, and suitable tests might be repeated at intervals to clarify the response to such treatment. Tests of baseline hormone function are customary before administering other hormones, but they are seldom obtained before administration of glucocorticoids. It is therefore possible that milder degrees of abnormality of cortisol production have been overlooked and that some patients whose symptoms improve with glucocorticoid therapy may have had relative insufficiency of cortisol before treatment was started. Normal ranges of tests of adrenocortical function have been based on tests performed on patients with obvious deficiency (Addison’s Disease) or excess (Cushing’s Syndrome) of cortisol, so these ranges may need to be revised to detect milder degrees of insufficiency. It should also be borne in mind that a cortisol level within the normal range does not rule out the possibility that a patient might benefit from a physiologic dosage of cortisol. When small dosages of cortisol are given, beneficial effects may not appear until lo- 14 days after therapy is initiated (60), and if an active infection or inflammatory process is present, larger dosages may be necessary initially combined with suitable antibiotic agents, so these observations must be considered in therapeutic studies. The possibility that, in addition to influenza and infectious mononucleosis, other viral infections may temporarily impair the normal immune response should be studied, and the nature of such impairment must be determined. The potential benefit of treatment with physiologic dosages of cortisol in patients with influenza, infectious mononucleosis and possibly other viral disorders including AIDS also needs further study. In view of recent advances in technics for studying immunity, plus evidence that decreased immunity may not only contribute to susceptibility to infections, including the common cold and influenza, but also may be associated with the development of malignancies, autoimmune disorders, and AIDS, any increase in knowledge of the manner in which the human body regulates the immune process would be especially timely. The un-
MEDICAL HYPOTHESES
derstandable fear of glucocorticoids as pharmacologic agents must be kept in proper perspective so that the mechanisms of the life-saving effects of physiologic amounts of cortisol can be elucidated and hopefully utilized therapeutically. References 1. Jefferies WMcK. The present status of ACTH, cortisone and related steroids in clinical medicine. N Engl J Med 253: 441, 1955. 2. Aschoff L. Lectures on Pathology,. Hoeber, New York, ~~118-25, 1924. 3. Goldzieher M. The Adrenals: Their Physiology, Pathology and Diseases. Macmillan, New York, pp177 -93, 1929. 4. Jaffe HL, Plavska A. Functioning autoplastic suprarenal transplants. Proc. Sot. Exper. Biol. Med. 23: 528, 1926. J. Effect of injections 5. Perla D, Marmorston-Gottesman of cortin on resistance of suprarenalectomized rats to histamine poisoning. Proc. Sot. Exper. Biol. Med. 28: 650, 1931. 6. Hartman FA, Scott WJM. Protection of adrenalectomized animals against bacterial intoxication by extract of the adrenal cortex. J Exper Med 55: 63, 1932. 7. Whitehead RW, Smith C. The effect of adrenal cortex extract on the course of certain human infections. Proc. Sot. Exper. Biol. Med. 29: 672, 1932. 8. Ingle DJ. Resistance of the rat to histamine shock after destruction of the adrenal medulla. Merck, General Physiology 11: 57, 1936. 9. Pottenger RM, Pottenger RT. Evidence of the protective influence of adrenal hormone against tuberculosis in guinea pigs. Endocrinology 21: 529, 1937. 10. Kendall EC. The adrenal cortex. Archives of Pathology 32: 488, 1941. 11. Perla D, Marmorston J. Natural Resistance and Clinical Medicine. Little, Boston, pp475 - 514, 1941. 12. Ingle DJ. Diabetogenic effect of stilbestrol in force-fed normal and partially depancreatized rats. Endocrinology 29: 838, 1941. 13. Ingle DJ. Parameters of metabolic functions, in Recent Progress in Hormone Research, Volume VI, edited by G. Pincus. Academic Press, Inc., New York, ~~159-94, 1951. 14. Ingle DJ. Principles of Research in Biology and Medicine. Lippincott, Philadelphia. pp27 - 41, 1958. 15. Ingle DJ. Some further studies of the relationship of adrenal cortical hormones to experimental diabetes. Diabetes 1: 345, 1952. 16. Kass EH, Finland M. Adrenocortical hormones in infection and immunity. Ann Rev Microbial 7: 361, 1953. 17. Benedek TG, Montgomery MM. The influence of ACTH and cortisone on the incidence of infections. J Lab Clin Med 44: 766, 1954. 18. Spink WW. Adrenocortical steroids in the management of selected patients with infectious diseases. Ann Intern Med 53: 1, 1960. 19. Kass EH, Finland M. The role of adrenal steroids in infection and immunity. New Engl J Med 244: 464, 1951. 20. Thomas L. The effects of cortisone and adrenocorticotropic hormone on infection. Ann Rev Med 3: 1, 1952. 21. Kass EH, Finland M. Adrenocortical hormones in infec-
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tion and immunity. Ann Rev Microbial 7: 361, 1953. Germuth FGJr. The role of adrenocortical steroids in infection, immunity and hypersensitivity. Pharmacol Rev 8: 1, 1956. Robinson HJ. Adrenal cortical hormones and infection. Pediatrics 17: 770, 1956. Kass EH, Finland M. Adrenocortical hormones and the management of infection. Ann Rev Med 8: 1, 1957. Kass EH. Finland M. Corticosteroids and infections. In Advances in Internal Medicine. (W. Dock, I Snapper, eds). Year Book Medical Publishers, Inc., Chicago. 9: 45 - 80, 1958. Beisel WR, Rapaport MI. Interrelations between adrenocortical functions and infectious illness. N Engl J Med 280: 541-6, 596-604, 1969. Dougherty TF, Chase JH, White A. Pituitary-adrenal cortical control of antibody release from lymphocytes. An explanation of the anamnestic response. Proc Sot Exper Biol Med 58: 135, 1945. Ambrose CT. The requirement for hydrocortisone in antibody-forming tissue cultivated in serum-free medium. J Exper Med 119: 1027, 1964. Ambrose CT. The essential role of corticosteroids in the induction of the immune response in vitro. In Hormones and the Immune Response. (GEW Wolstenholme, .I Knight, eds) Ciba Foundation Study Group No 36. Churchill, London ~~100-25, 1970. Smith RS, Sherrman NA, Middleton E. Effect of hydrocortisone on immunoglobulin synthesis and secretion by human peripheral lymphocytes in vitro. Int Arch Allergy 43: X59, 1912. Tuchenda M, Newcomb RW, DeVald BL. Effect of prednisone treatment on the human immune response to keyhole limpet hemocyanin. Int Arch Allergy 42: 533, 1972. Rusu UM, Cooper MD. In vivo effects of cortisone on the B cell line in chickens. J Immunol 115: 1370, 1975. Fauci AS, Pratt KR, Whalen G. Activation of human B lymphocytes. IV. Regulatory effects of corticosteroids on the triggering signal in the plaque-forming cell response of human peripheral blood B lymphocytes in polyclonal activation. J lmmunol 119: 598, 1977. Grayson J, Dooley NJ, Koski ,IR, Blaese RM. Immunoglobulin production induced in vitro by glucocorticoid hormones: T-cell dependent stimulation of immunoglobulin production without B cell proliferation in cultures of human peripheral blood lymphocytes. J Clin Invest 68: 1539, 1981. Orson FM, Grayson J, Pike S, DeSeau V, Blaese RM. T cell-replacing factor for glucocorticosteroid-induced immunoglobutin production. A unique steroid-dependent cytokine. J Exp Med 158: 1473, 1983. Orson FM, DeSeau V, Pike S, Btaese M. Glucocorticosteroids stimulate polyclonal immunoglobulin production by I,ord blood mononuclear cells. J Immunol 133: 208, 1984. Nouri-Aria KT, Hegarty JE, Alexander GJM, Eddle.ston ALWF. Williams R. Effect of corticosteroids on suppressor-cell activity in ‘autoimmune’ and viral chronic active hepatitis. N Engl J Med 307: 1301, 1982. Cupps TR, Gerrard TL, Falkoff RJM, Whalen G, Fauci AS. Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation. J Clin Invest 75: 754, 1985. Levo Y, Harbeck RJ, Kirkpatrick CH. Regulatory effect of hydrocortisone on the in vitro synthesis of IgE by hu-
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man lymphocytes. Int Archs Allergy Appl Immun 77: 413. 1985. Jefferies WMcK. Safe Uses of Cortisone. Thomas, Springfield. pp 124-42, 1981. Skanse B, Miorner G. Asian influenza with adrenocortical insufficiency. Lancet 1: 1121, 1959. Mickerson JN. Influenza1 pituitary suppression. Lancet I: 1118, 1959. Chappel MR. Infectious mononucleosis. Southwest Med 43: 253, 1962. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. JAMA 199: 529, 1967. Manji RJ, Niederman JC, Kelleher JEJr, Dwyer JM. Evans AS, Kantor ES. Depression of cell-mediated immunity during acute infectious mononucleosis. N Engl. J Med 291: 1149, 1974. Tapper ML, Rotterdam HZ, Lerner CW, Al’Khafaji K. Seitzman PA. Adrenal necrosis in the acquired immunodeficiency syndrome. Ann Intern Med 100: 239, 1984. Greene LN, Cole W, Greene JB, Levy B. Louie E, Raphael B, Waitkevitz J, Blum M. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med 101: 497, 1984. Glasgow BJ, Steinsapir KD, Anders K, Layfield LJ. Adrenal pathology in the acquired immunodeficiency syndrome. Am J Chn Pathol 84: 594, 1985. Hilton CW, Harrington PT, Prasad C, Svec F. Adrenal insufficiency in the acquired immunodeficlency syndrome. South Med J 81: 1493, 1988. Membreno L, Irony I, Dere W, Klein R, Biglieri EC. Cobb E. Adrenocortical function in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 65: 482, 1987. Blalock JE 1987 New concepts in endocrinology: Neuroendocrine and immune system interactions. In 1987 Yearbook of Endocrinology. (JD Bagdade, ed). Yearbook Medical Publishers, Chicago, pp15 -28, 1987. Bateman A, Singh A, Kral T, Solomon S. The immunehypothalamic-pituitary-adrenal axis. Endocr Rev 10: 92. 1989. Woloski. BMRNJ, Smith EM, Meyer WJIII, Fuller GM, Blalock JE. Corticotropin-releasing activity of monokines. Science 230: 1035, 1985. Besedovsky HO, Del Ray AE, Sorkin E, Dinarello CA. Immuno-regulatory feedback between interleukin-l and glucocorticoid hormones. Science 233: 652, 1986. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238: 522, 1987. Berkenbosch F, Oers JV, Del Ray A, Titders F, Besedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-I. Science 238: 524, 1987. Sternberg EM, Hill JM, Chrousos GP, Kamitaris T, Listwak LJ. Gold PW, Wilder RL. Inflammatorv mediatorinduced hypothalamic-pituitary-adrenal axis is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci USA 86: 2374, 1989. Sternberg EM, Young WSIII, Bernadine R, Calogero AE, Chrousos GP, Gold PW, Wilder RL. A central nervous system defect in biosynthesis of corticotropm-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Nat1 Acad Sci USA 86: 4771, 1989. Munck 4, Guyre M. Holbrook NJ. Physiological func-
208 tions of glucocorticoids in stress and their relation to pharmacologic actions. Endocr Rev 5: 25, 1984. 60. Jefferies WMcK. Low dosage glucocorticoid therapy. Arch Int Med 119: 265, 1967. 61. Jefferies WMcK, Kelley LWJr, Sydnor KL, Levy RP, Cooper G. Metabolic effects of a single intravenous infusion of hydrocortisone related to plasma levels in a normal versus an adrenally insufficient subject. J Clin Endocrinol Metab 17: 186, 1957.
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62. Jefferies WMcK. Glucocorticoid therapy: An overmaligned reputation with untapped potential benefit. In Controversies in Internal Medicine II. (FJ Inglefinger, RV Ebert, M Finland, AS Kelman, eds). Saunders, Philadelphia, pp439 - 45, 1974. 63. Hill SR, Dempsey H. Steroid excretion patterns in rheumatoid arthritis. In Inflammation and Diseases of Connective Tissue. (LC Mills, JH Moyer, eds). Saunders, Philadelphia, pp529- 37, 1961.
Cortisol and Immunity W. McK. JEFFERIES 2423 Newbury Drive, Cleveland, Ohio 44 7 78, USA
Abstract - The relationship between adrenocortical function and immunity is a complex one. In addition to the well-known detrimental effects of large, pharmacologic dosages of glucocorticoids upon the immune process, there is impressive evidence that physiologic amounts of cortisol, the chief glucocorticoid normally produced by the human adrenal cortex, is necessary for the development and maintenance of normal immunity. This evidence is reviewed, and the importance of differentiating between physiologic and pharmacologic dosages and effects is discussed. The popular use of synthetic derivatives of cortisol, which differ greatly from the natural hormone in strength, and the dynamic nature of the normal adrenocortical response, which varies with the degree of stress being experienced, have contributed to the confusion. Further studies of the nature of the beneficial effect of cortisol, and possibly of other normal adrenocortical hormones, upon immunity in humans are needed, especially in view of recent evidence of a feedback relationship between the immune system and the hypothalamic-pituitary-adrenal axis, and with the increasing awareness not only that the immune process provides protection against infection, but also that its impairment seems to be involved in the development of autoimmune disorders, malignancies and the acquired immunodeficiency syndrome (AIDS).
Introduction
Much has transpired since the publication by this author of a review article on the clinical uses of ACTH and cortisone in 1955 (1). At that time, it was thought that their beneficial effects in disorders such as arthritis and allergies depended upon the production of an excess of glucocorticoid effect in the body, and it was hoped that the introduction of derivatives such as prednisone would enable beneficial effects to be obtained without the risk of undesirable side-effects. Un-
fortunately, this hope was not realized. As reports of grim side-effects accumulated, physicians became reluctant to prescribe any glucocorticoid and these agents developed a reputation for being risky to use under any circumstances. This is not surprising, because the dosages in general use have been those that would be expected to produce unpleasant or even dangerous side-effects if continued for a sufficient length of time. The fact that cortisol, the chief glucocorticoid produced by the human adrenal cortex, is a normal hormone, in fact it is essential for life, has been largely
Date received 20 July 1990 Date accepted 20 August 1990
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forgotten. Prednisone, triamcinolone, dexamethasone and similar commercially popular steroids are more potent derivatives of cortisol (hydrocortisone) or cortisone, with less sodium-retaining effect, but with other side-effects that may be equally or more serious. One of the more dangerous side-effects that is common to all known glucocorticoids is that of lowering resistance to infection. Yet from the earliest reports of studies of adrenocortical function there has been impressive evidence that adrenocortical hormone, and more specifically cortisol, is essential for normal immunity. Because the potentially harmful effects of cortisol and other glucocorticoids upon immunity are well known, in an attempt to restore perspective it might be helpful to review the evidence for beneficial effects of cortisol upon immunity, especially since there has been increasing evidence through the years, culminating in recent reports, that this hormone may have untapped therapeutic potential in safe, physiologic dosages.
to be steroids, had important roles in maintenance of optimum health and energy. An additional property of adrenal cortical secretion became evident from early experiments. An adrenalectomized rat, if given proper amounts of food, salt, water and rest at proper intervals, and if protected against infection, would survive, but if any one of these essentials were changed, the animal would die. Any alteration of an optimum environment is a stress, hence the adrenocortical hormones protect against stress. Protection against all of these stresses except the last can be explained by the three actions listed above, but protection against infection involves a beneficial effect upon immunity, which not only does not seem to relate to any of these fundamental actions, but also is contrary to well-established evidence that glucocorticoids impair immunity. Thus an enigma was presented that continues to cause confusion. Pre-cortisol studies
Historical background Our knowledge of the function of adrenocortical hormones is relatively recent. In the 193Os, while I was a medical student, a heated controversy existed between one group of investigators who contended that the primary action of adrenocortical hormone was the maintenance of electrolyte balance, and another group who were equally convinced that it was the regulation of carbohydrate metabolism. Later, it became evident that not just one, but several hormones were produced by the adrenal cortex, and that each had one or more of three fundamental actions in varying degrees: the regulation of electrolyte metabolism (sodium-retaining and potassium-losing effect), the ability to promote conversion of precursors to glucose (gluconeogenesis), and the promotion of growth and repair of protein tissue (anabolism). Since sodium is the chief cation in extracellular fluid and potassium the chief cation of intracellular fluid, the regulation of their relative concentrations is essential for maintenance of normal circulation and blood pressure; since glucose is the chief source of energy of the body and the sole source of energy for the brain, the ability to maintain adequate levels under conditions in which food supply might vary is obviously critical; and since growth and repair of protein tissue are necessary for normal growth and development, it became evident that the adrenal cortical hormones, which were found
During World War I, fatal cases of various types of infections were noted to have striking morphologic changes in the adrenals. These were described by Aschoff (2) and by Goldzieher (3), and included postmortem studies on subjects with fatal cases of diphtheria, scarlet fever, malaria, peritonitis, gas gangrene, streptococcal infections, and every other septic condition noted during the war. Then changes included evidence of degeneration and necrosis of the adrenal cortex with marked edema, regression of lipoid material, hemorrhages, and arterial thromboses, without similar changes in other organs. With such evidence of serious damage to the adrenals in the course of severe infections, the question of its significance arose. In 1926, Jaffe and Plavska (4) in studies of susceptibility of adrenalectomized rats to typhoid vaccine, noted that the adrenal cortex seemed to be more important than the medulla in providing resistance. In 1931, Perla and MarmorstonGottesman (5) reported that adrenal cortical extract was primarily responsible for maintaining the resistance of adrenalectomized rats to histamine poisoning, supporting the impression that the adrenal cortex, not the medulla, was primarily responsible for resistance to toxins. The following year, Hartman and Scott (6) reported that adrenocortical extract restored the resistance of adrenalectomized rats to bacterial intoxication almost to normal. The same year Whitehead and Smith (7) reported that injections of adrenocor-
200 tical extract into patients with severe infections such as typhoid fever, undulant fever, cellulitis, and sinusitis seemed to be symptomatically beneficial. In 1936, Ingle reported further evidence that the adrenal cortex was more important than the medulla in maintaining resistance of rats to histamine shock (8). The following year Pottenger and Pottenger (9) reported that injections of adrenocortical extract helped to protect guinea pigs against experimental tuberculosis infection. They also reported that injections of adrenocortical extract into patients with tuberculosis improved their energy and lessened fatigue. In 1941, Kendall (10) reported that as little as 30 mcg of Compound E, a steroid of the adrenal cortex that later was named cortisone, would protect an adrenalectomized rat against 25 minimum lethal doses of typhoid vaccine. Perla and Marmorston, in their book Natural Resistance and Clinical Medicine, that was published in 1941 (II), reviewed evidence for a relationship between suprarenal (adrenal) function and resistance to infection up to that time, and they concluded that ‘The suprarenal glands are important in the maintenance of the natural resistance of the body to intoxications, poisons, and bacterial and protozoa1 infections.’ They further stated that ‘The depression in natural resistance following suprarenal insufficiency is probably dependent upon loss of cortical function, since injections of the cortical hormone raise the resistance of suprarenalectomized animals to the normal level.’ In the same year, 1941, Ingle published the first (12) of a series of studies that culminated in two reviews (13, 14) in which he presented certain fundamental principles that apply to actions not only of adrenocortical hormones, but also of other hormones, principles which, if they had been better borne in mind, might have helped to prevent some of the confusion that later developed regarding glucocorticoid therapy. First, he pointed out the difference between a specific action that is caused by an increased amount of a hormone and an action in which the hormone is not the exciting or regulatory agent, but in its absence the normal signs of response fail to occur. He termed the latter type of action a ‘permissive’ action, one that ‘supports or normalizes the capacity of a system to respond to an active cause’ (13). As an example, other hormones, such as thyroid, growth and probably gonadal hormones, may not have normal effects if adrenocortical hormones, especially
MEDICAL HYPOTHESES
cortisol, are deficient. Similarly, other hormones, including adrenocortical hormones, may not have normal effects if thyroid hormone is deficient. In these instances adrenal and thyroid hormones act as permissive factors. Other fundamentals principles that he described included ‘the nature of a response (to a hormone) may be reversed as dosage is changed’. A classic example had been seen in studies of thyroid function in experimental animals: a deficiency of thyroid hormone impaired growth, euthyroidism was essential for normal growth, yet an excess of thyroid hormone again impaired growth. He suggested that a similar relationship might exist between adrenocortical function and anabolism. He also pointed out that, ‘in addition to the size of the dose, the route and frequency of hormone administration are important factors affecting doseresponse relationships’. The same total dosage administered in divided portions at frequent intervals produces a greater effect than when administered at longer intervals. This characteristic affects replacement therapy with cortisol, but it has apparently not received much attention. He further noted that ‘the size of an optimum replacement dosage for adrenocortical insufficiency varies with the degree of stress being experienced by the experimental subject’. In an extension of this concept, he stated ‘The increased secretion of adrenal hormones serves to meet an increased need during stress and tends to maintain homeostasis rather than to disturb it. The increased secretion does not cause a state of hypercorticism such as develops when the titer of these hormones is increased artificially in the absence of need’ (15). Hence, the harmful side effects that have given cortisol and other glucocorticoids such a bad reputation are a result of the patient getting an excessive amount of steroid and, in some instances at least, may not be a necessary complication of therapeutic effects; perhaps an initial larger dosage might be necessary to correct an abnormal state, but, once corrected, the improvement might be maintained by continuing a smaller, physiologic dosage without producing undesirable side-effects. He also called attention to two other fundamental principles that should be borne in mind in planning or evaluating studies of hormone action: ‘the amount of hormone required to elicit a standard response varies greatly among individuals,’ and ‘the sensitivity of experimental animals and of man to hormones and drugs varies with age’. These probably contribute to the relatively broad ranges of normal
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values for cortisol and other hormones, and they also imply that the finding that a patient’s hormone level falls within the normal range does not necessarily mean that it is normal for that patient or that that patient has normal function of that particular hormone. Studies with cortisone or cortisol After cortisone and cortisol became available for clinical use in 1949, a few reports continued to suggest a potential beneficial effect upon immunity, but the obvious harmful effects of the pharmacologic dosages that were in widespread use caused them to be generally overlooked. In 1953, Kass and Finland (16) reported that the amount of cortisone required to restore the resistance of adrenalectomized mice to approximately their original state of resistance to infection was five to ten times the amount that maintained uninfected adrenalectomized mice in an apparently normal state, whereas approximately 20 - 50 times the minimum maintenance dosage must be given to depress the mouse’s resistance below that of an intact animal. This was a nice demonstration of Ingle’s principle that the nature of a response to a hormone may be reversed as the dosage is changed. In 1954, Benedek and Montgomery (17) reported that patients with rheumatoid arthritis experienced fewer infections during 465 months of cortisone and/or ACTH therapy than during 411 months without such therapy. In 1960, Spink (I@, in a report of the effects of administration of adrenal steroids to patients with infectious diseases, stated, ‘Judicious use of corticotropin and corticosteroids frequently contributed to immediate improvement in the condition of patients seriously ill with infections and their complications.’ He further stated, ‘An inventory of the 81 patients treated in this study has revealed no significant ill effects when steroids were administered for only a few days, even when large dosages were used.’ in a series of reviews of the relationships between glucocorticoids and immunity (16, 19-25), the apparently contradictory effects of these agents upon immunity were discussed, and it was concluded that more studies were necessary to clarify this paradox. In 1969, Beisel and Rapaport (26), in a review of the interrelations between adrenocortical functions and infectious illness, summarized this problem. They stated ‘that the human host does fare best when his own pituitary-adrenal axis is nor-
201 mally responsive (or when exogenous hormone is given in optimal replacement dose after adrenalectomy) is a conclusion based upon extensive clinical data and well-confirmed evidence in laboratory animals.’ They also stated that ‘present information suggests that secretion of all major corticosteroid hormones is stimulated early in the course of acute infectious illness,’ and that ‘all available data support the concept that the glucocorticoid increase in the period of early symptoms varies in magnitude with the clinical severity of the infectious illness.’ It did not seem logical that nature would, at the onset of an infection, produce an increased amount of a substance that would impair resistance to the infection, and they concluded that ‘It is to be hoped that an understanding of the mechansism by which normal adrenal responsiveness is protective (in contrast to the harmful nature of hypercorticism or hypocorticism) will provide a useful approach to the treatment of infectious illness.’ Some studies have suggested mechanisms by which adrenocortical hormone may enhance immunity. In 1945, Dougherty, Chase and White (27) reported that a single injection of adrenocortical extract or ACTH into rabbits or mice produced a release of antibody from lymphocytes, and they concluded that ‘These data establish the role of pituitary-adrenal cortical secretion in the controlling mechanism for the release of antibody from lymphocytes.’ Later, the validity of this study was questioned because other studies failed to confirm this effect; however, none of the studies that failed to confirm the effect used the same protocol as that employed by Dougherty’s group. In 1964, Ambrose (28) reported evidence that hydrocortisone was necessary for the formation of antibody in tissue cultures, and in 1970 (29), he further reported that a physiologic level of glucocorticoid appeared to be essential for the initiation of the immune process. In 1972, Smith, Sherrman and Middleton (30) reported evidence that hydrocortisone in low concentrations produced increased immunoglobulin (Ig) synthesis and secretion by human peripheral lymphocytes in vitro, whereas higher concentrations resulted in a suppressor effect. In the same year, Tuchenda, Newcomb and DeVald (31) reported that prednisone treatment seemed to improve immune response in children with asthma. In 1975, Rusu and Cooper (32) reported that in young chickens treatment with cortisone produced a mobilization of B lymphocytes and enhancement of differen-
202 tiation into mature Ig-producing plasma cells in peripheral lymphoid tissue. In 1977, Fauci, Pratt and Whalen (33) reported that hydrocortisone in physiologic concentration in vitro enhanced the response of normal human peripheral blood B lymphocytes, whereas much larger concentrations suppressed early B cell activation. In 1981, Grayson and her associates (34) reported that addition of hydrocortisone in low concentration to peripheral blood lymphocytes in culture resulted in dramatic induction of immunoglobulin production, including IgG, IgA and IgM. This effect occurred only with glucocorticoids, and not with estrogens or androgens, and they suggested that glucocorticoids might play a role in the normal function of the immune system. Orson and associates (35,36), in a continuation of the in vitro work of this group, reported that glucocorticoids induce the synthesis and secretion of all classes of immunoglobulins and that a steroiddependent cytokine appeared to participate in this response. In 1982, Nouri-Aria et al (37) reported that physiologic concentrations of glucocorticoids may inhibit natural killer (NK) cell activity in vitro and that continuation of low dosages may maintain remissions in patients with autoimmune hepatitis. In 1985, Cupps et al (38) reported that the effect of corticosteroids upon B cells varied not only with the amount of steroid but also with the phase of the B cell cycle, enhancement of secretion of immune globulins occurring in the later stages of the cycle. In the same year, Levo, Harbeck and Kirkpatrick (39) confirmed that cortisol in low concentrations enhanced synthesis of immune globulins, whereas high concentrations inhibited such synthesis. Hence, it appears that the initial observations of Dougherty et al (27) were valid and that failure to reproduce their results may have been due to differences in dosage of steroid administered, in the stage of the B cell cycle at which the steroid was added, or in other aspects of protocols. Evidence that physiologic dosages of glucocorticoids can improve immunity in respiratory infections in patients with adrenocortical insufficiency is impressive, although it has apparently received little attention. When cortisone and cortisol first became available for administration to such patients, there was concern regarding their effect upon immunity, which was already diminished in this disorder, but it eventually became evident that administration of physiologic dosages not only did not impair immunity, but it actually seemed to en-
MEDICAL HYPOTHESES
hance resistance to common respiratory infections (40). Patients who previously had experienced several respiratory infections per year reported few, if any, such infections while taking these steroids, and the infections they had seemed less severe, especially if they doubled their maintenance dosage as they were instructed to do during times of increased stress. In fact, a prompt increase in dosage at the onset of symptoms of incipient respiratory illness was sometimes followed by a disappearance of symptoms without recurrence when the dosage was returned to maintenance level, suggesting that the illness had been aborted. Meanwhile, other members of the patients’ families seemed to have their usual quota of respiratory illnesses, so the decrease in such illnesses in the patients apparently could not be attributed to lack of exposure to the viruses. Later, patients who were receiving prolonged treatment with physiologic dosages of cortisone acetate or cortisol for other conditions reported similar apparent protection against common respiratory illnesses. In the course of over 2000 patient-years of experience with physiologic dosages of cortisol or cortisone acetate, this observation has been repeatedly confirmed. When those who reported apparent protection were compared with those who did not, it appeared that the difference was frequently related to whether a patient smoked. The non-smokers seemed to experience most benefit in their resistance, and those who continued to smoke during infections seemed to benefit least. A beneficial effect of glucocorticoid therapy upon more severe respiratory infections has also been noted. After an influenza epidemic in Malmo, Sweden in 1957, Skanse and Miorner (41), in a report of the presence of untreated adrenal insufficiency in several patients who succumbed, noted that ‘resistance to Asian influenza appears to be lowered more by untreated adrenocortical insufficiency than by chronic cardiac or renal disease.’ They further noted that patients with adrenal insufficiency receiving adequate substitution therapy tolerated an attack of influenza as well as, or better than, patients with normal adrenals. They concluded that ‘in all cases of severe influenza any suspected adrenal insufficiency should be compensated.’ During an influenza epidemic in London in 1958, Mickerson (42) noted that urinary steroid excretion of patients was subnormal, and that improvement occurred after intramuscular administration of ACTH or oral administration of prednisolone, 2.5 mg three times
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daily. During an influenza epidemic in the U S in 1976, Rivera and I (40) noted that plasma cortisol levels of acutely ill patients were low, and that impressive clinical improvement occurred with the administration of cortisol, 20 mg orally four times daily, tapering and discontinuing the medication over a four day period after the patients felt well. The low cortisol levels responded to stimulation with cosyntropin, suggesting that the viral infection had temporarily impaired normal ACTH secretion. The few patients studied had no complicating bacterial infections, but if such occur, suitable antibiotic therapy should be added. Another sometimes severe respiratory illness is infectious mononucleosis. In 1962, Chappel (43) reported beneficial effects of cortisone therapy in 111 cases of this disorder, with control of symptoms within a few days and elimination of long periods of bed rest and disability. In a study of 66 students with severe but uncomplicated infectious mononucleosis, Bender (44) reported that treatment with ACTH or prednisolone resulted in a significant shortening of illness and loss of time from classes compared with matched controls. Additional reports of similar beneficial effects of glucocorticoids upon this illness have been published. in 1974, Mangi et al (45) reported evidence that cell-mediated immunity is impaired during acute infectious mononucleosis. This observation, plus the more recent evidence of impaired adrenocortical response to acute influenza cited above, suggests that the effect of other viral infections upon the hypothalamic-pituitary-adrenal system and the immune response should be studied. It is possible that different viruses may impair immunity in different ways. Because adrenal insufficiency can cause chronic fatigue, and because at least some viral infections may be associated with adrenal insufficiency, patients with unexplained chronic fatigue may benefit from studies of adrenal function as well as tests for obscure infection (40). More recently, a series of reports (46 - 50) have described abnormalities of adrenocortical function, either primary or secondary to pituitary or hypothalamic effects, in patients with the acquired immunodeficiency syndrome (AIDS), so the possibility that this might be a factor in the development or the progress of this alarming disorder is raised. Administration of replacement dosages of glucocorticoids resulted in impressive clinical improvement in some cases, suggesting that this type of treatment might be helpful in at least some patients with this disease.
203 During the past decade, immunologists have reported increased evidence of a relationship between the neuroendocrine and the immune system that has been summarized by Blalock (51) and by Bateman et al (52). Interest in the relationship between these two systems has intensified with the evidence that cells of the immune system can have a direct influence on pituitary and adrenal function. During the past five years progressive evidence for an immunoregulatory feedback relationship between monocytes and hypothalamus has been reported, some aspects of which have interesting clinical implications. In 1985, Woloski et al (53) reported that interleukin-1 (11 - l), a protein produced by monocytes in response to inflammatory challenge, stimulated pituitary cells to release ACTH. The following year, Besedovsky et al (54) reported evidence for the specificity of this feedback, and that the production of 11 - 1 is inhibited by glucocorticoid. This suggests one mechanism by which excessive amounts of cortisol might impair immunity. In 1987, Sapolsky et al (55) and Berkenbosch and associates (56) reported evidence that II- 1 stimulated ACTH release, not through a direct effect on the pituitary, but by stimulating production of corticotropin-releasing factor (CRF) from the hypothalamus. During the past year, Sternberg and her associates (57, 58) have reported that a strain of rats that is inherently susceptible to experimental arthritis produced by injection of a preparation derived from streptococcal cell walls demonstrated defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis with a defective CRF production, whereas another strain that is resistant to such arthritis had a normal CRF response. When the resistant strain was treated with the glucocorticoid receptor antagonist, RU 486, thus interrupting the HPA axis at its end point, it became susceptible to the experimental arthritis. Because the challenge that produced the arthritis in susceptible animals was derived from streptococcal cell walls, a defect in immune response in these animals seems likely. It would be interesting, therefore, to determine whether susceptible rats develop autoantibodies in the course of their response to the injections. These observations suggest that autoimmune disorders such as rheumatoid arthritis may be associated with a defective HPA response to infection or other stress that might not be detected by routine studies of adrenocortical function if the defect is at the hypothalamic level. Hence re-
204 sponses of patients with these disorders to tests that determine the integrity of the entire HPA response should be studied. It is also possible that persistent treatment of patients with these disorders with physiologic dosages of cortisol, in contrast to the intermittent administration of large, pharmacologic dosages of stronger steroid derivatives that is customary, may be more helpful and also may avoid the side-effects produced by pharmacologic dosages. This possibility is consistent with the evidence reported by Nouri-Aria and associates (37) that continuation of low dosages of glucocorticoids may maintain remissions in patients with autoimmune hepatitis. It appears that an increased amount of cortisol is necessary for normal response to infection and to other stresses, and that an inadequate increase may in some way play a part in the development of autoimmune disorders. Munck and his associates (59) have suggested that the increased production of cortisol that accompanies the onset of infection may serve to limit the immune reaction from overshooting and hence may, be consistent with the, well-known anti-immune effects of pharmacologic dosages. This interesting idea might explain one aspect of adrenocortical function in response to infection, but it does not explain why adrenally insufficient patients have deficient immune responses, nor why physiologic dosages seem to enhance the immune response, nor is it consistent with the impression of Ingle (15) that the increased production of adrenal hormone in response to stress helps to maintain a physiologic state instead of producing pharmacologic effects. Present status The studies reporting beneficial effects of glucocorticoids upon infections and immunity have received little attention, and medical textbooks, emphasizing the serious hazards of glucocorticoid therapy, continue to imply that there is no safe dosage of these agents. Even the package inserts for cortisone acetate and cortisol fail to differentiate between physiologic and pharmacologic dosages, and they imply that any dosage might produce any of the alarming side-effects that occur only with dosages in excess of body requirements. With the variation in dosages and in steroids used in reports of glucocorticoid therapy and with the dynamic nature of normal adrenocortical re-
MEDKAL
HYPOTHESES
sponse to stress, it is not surprising that confusion has developed regarding physiologic dosages. First, it should be remembered that the chief glucocorticoid produced normally by human adrenals is cortisol. Cortisone is also produced in small amounts, but it is converted to cortisol before having physiologic effects. Prednisone, triamcinolone, dexamethasone and other similar steroids are synthetic derivatives of cortisone or cortisol with much greater potency of glucocorticoid effect per milligram, but sometimes with different pharmacologic effects. Although some of these steroids have been reported to have similar beneficial effects upon infections, their comparable safety and effectiveness to the natural steroids in physiologic dosages have not been investigated. The safety of physiologic dosages of cortisol or cortisone acetate has been observed by endocrinologists treating patients with adrenal insufficiency over the past 40 years, but this safety has not been publicized. This safety in our experience with over 1000 patient-years of treatment with physiologic dosages was reported (60), but has apparently received little attention. The only undesirable sideeffects encountered have been acid indigestion in susceptible persons or skin rashes in patients who are allergic to an ingredient in the filler of the steroid tablets. What then is a physiologic dosage of cortisol? Under unstressed circumstances, human adrenals produce 15 - 20 mg of this steroid per day, with a diurnal variation depending upon the sleepwake schedule, but a totally adrenalectomized person receiving cortisol by mouth requires approximately twice this amount as a maintenance dosage, presumably because such a replacement schedule is less efficient than the production and release of hormone directly into the blood stream according to need in a person with normal adrenals. Because the effect of a single dose of cortisol or cortisone acetate seems to last a maximum of 8 h (61), and because normal cortisol production occurs in spurts rather than in a continuous, smooth manner, and also because, as Ingle pointed out (13), the same total amount of adrenocortical hormone given in divided doses at frequent intervals is more effective than when given at less frequent intervals, for optimum physiologic effect these steroids should be given several times daily, and a suitable schedule for both patient compliance and therapeutic effect seems to be four times daily, before meals and at bedtime. Studies on a normal subject indicated that
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2.5 mg cortisone acetate four times daily by mouth suppressed endogenous cortisol production by approximately 30%, and 5 mg four times daily by approximately 609’0, confirming that 35 - 40 mg daily in divided dosage should be proper replacement for a totally adrenalectomized person under non-stressed conditions (60). With such small dosages there appears to be no significant difference between the effects of same dosages of cortisone acetate and cortisol when taken by mouth, but because preparations of cortisone for parenteral use are much more slowly effective than those of cortisol, under conditions where rapid effect is desired cortisol preparations should be administered intramuscularly or intravenously. A dosage of 10 mg cortisol four times daily will usually produce optimum glucocorticoid effect in an unstressed totally adrenalectomized patient. Some patients prefer a schedule of 15, 10, 10 and 5 mg, which more closely approximates the usual diurnal pattern. With increased stress, requirements are greater, varying from 20 mg cortisol by mouth four times daily, which seems to provide adequate replacement during the common cold, influenza and infectious mononucleosis, to 100 mg hydrocortisone sodium succinate intramuscularly one hour before major surgery and continuing at 8 h intervals in decreasing doses, tapering to the baseline maintenance dosage over the next 6- 8 days, meanwhile returning to oral therapy as soon as the patient’s condition permits. In cases of overwhelming sepsis, such as intestinal rupture with peritonitis, even larger dosages may be necessary. Hence, a physiologic dosage may vary, depending upon the degree of stress the patient is experiencing. This has undoubtedly contributed to the confusion that exists regarding the safety of cortisol therapy, but it is consistent with the principle emphasized by Ingle that the increased amount of cortisol that is required during stress helps to maintain homeostasis and does not produce the hypercorticism that the same amount would produce in an unstressed state (15). Although as a maintenance dosage 10 mg cortisol four times daily will not produce any of the effects of hypercorticism, it will inhibit endogenous adrenocortical activity in the unstressed state, so for patients other than those who have been totally adrenalectomized, smaller maintenance dosages are preferable. The effectiveness and safety of dosages of 5 mg or less four times daily of cortisol or cortisone acetate in patients with milder endocrine or autoimmune disorders
has been reported (60), but confirmatory reports from other clinics have not been forthcoming, possibly because the general fear of side-effects of glucocorticoid thereapy at any dosage level may have discouraged therapeutic trials, plus other factors that have prevented pharmaceutical companies from advertizing the safety and effectiveness of small, physiologic dosages (62). Conclusions Although much has been learned in recent years regarding the various components of the immune system, such as T cells, B cells, macrophages, interferon and the interleukins, little is known about the manner in which the human body regulates this system. With evidence that the production of cortisol may play an important role in initiating and possibly regulating activity of the immune system, further studies of the relationship between normal adrenocortical function and immunity should be rewarding. The distinction between physiologic and pharmacologic dosages of cortisol and possibly other normal adrenocortical steroids needs to be further clarified, and the possibilities must be considered that, in addition to the size of the dosage administered and the degree of stress being experienced, the timing of administration of cortisol either before or after exposure to stress or infection, or changes in levels of other normal adrenal steroids or of other hormones, may affect the response of the host. Low levels of excretion of dehydroepiandrosterone in patients with rheumatoid arthritis have been reported from two clinics (60, 63), but these studies have not been extended. The possibility that patients with autoimmune disorders might have abnormal feed-back responses to infection or to other stresses and that they might benefit from continuation of physiologic maintenance dosages of cortisol after remissions have been attained with larger dosages of glucocorticoid should also be further investigated. An increased amount of cortisol appears to be necessary for a normal response to infection or to any other stress, and hence an inadequate increase in cortisol may in some way contribute to the development of autoimmunity. It is interesting to note that cortisol is the only known substance produced by the human body that benefits autoimmune disorders, and that it and epinephrine are the only known natural hormones that counteract allergic reactions. Hence, the possibility that aller-
206 gies might be associated with defects in immune response should also be further explored. In order to learn more about physiologic versus pharmacologic dosages and responses, before glucocorticoid therapy is prescribed for any patient baseline tests of adrenocortical function, including blood cortisol and ACTH levels and response of cortisol to cosyntropin, would be helpful, and suitable tests might be repeated at intervals to clarify the response to such treatment. Tests of baseline hormone function are customary before administering other hormones, but they are seldom obtained before administration of glucocorticoids. It is therefore possible that milder degrees of abnormality of cortisol production have been overlooked and that some patients whose symptoms improve with glucocorticoid therapy may have had relative insufficiency of cortisol before treatment was started. Normal ranges of tests of adrenocortical function have been based on tests performed on patients with obvious deficiency (Addison’s Disease) or excess (Cushing’s Syndrome) of cortisol, so these ranges may need to be revised to detect milder degrees of insufficiency. It should also be borne in mind that a cortisol level within the normal range does not rule out the possibility that a patient might benefit from a physiologic dosage of cortisol. When small dosages of cortisol are given, beneficial effects may not appear until lo- 14 days after therapy is initiated (60), and if an active infection or inflammatory process is present, larger dosages may be necessary initially combined with suitable antibiotic agents, so these observations must be considered in therapeutic studies. The possibility that, in addition to influenza and infectious mononucleosis, other viral infections may temporarily impair the normal immune response should be studied, and the nature of such impairment must be determined. The potential benefit of treatment with physiologic dosages of cortisol in patients with influenza, infectious mononucleosis and possibly other viral disorders including AIDS also needs further study. In view of recent advances in technics for studying immunity, plus evidence that decreased immunity may not only contribute to susceptibility to infections, including the common cold and influenza, but also may be associated with the development of malignancies, autoimmune disorders, and AIDS, any increase in knowledge of the manner in which the human body regulates the immune process would be especially timely. The un-
MEDICAL HYPOTHESES
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