Relationship of dehydroepiandrosterone and cortisol in disease

Medical Hypotheses (1997) 49, 85-91

© Pearson Professional Ltd 1997

Relationship of dehydroepiandrosterone and cortisol in disease O. HECHTER**, A GROSSMANt*, R. T. CHATTERTON Jr*,** *Departments of Physiology, tMolecular and Cell Biology and **Obstetrics & Gynecology, Northwestern University Medical School, Chicago, IL 60615, USA and ttDepartment of Pediatrics, Rush, Presbyterian, St Lukes Medical Center, Chicago IL 60612, USA (Correspondence to: Professor Oscar Hechter, Department of Physiology, Northwestern University Medical School, 303 E. Chicago Ave, Chicago, IL 60615, USA. Tel: 312 603 6451; Fax: 312 503 5101; e-mail: [email protected])

Abstract m Does dehydroepiandrosterone act as an adrenal hormone in humans to maintain cortisol homeostasis by serving as a cortisol antagonist? If so, dehydroepiandrosterone might block the development of the diverse pathological processes potentiated by prolonged cortisol hyperactivity. And the plasma concentrations of total dehydroepiandrosterone and total cortisol, expressed as a C/D ratio, would have an important influence on the development of age-related pathology in diseases exacerbated by cortisol hyperactivity. Several major age-related diseases, designated as cortisol-potentiated diseases, belong in this category. The C/D concept predicts, other factors being equal, that the risk of initiation and progression of these diseases at all ages is directly related to the C/D ratio, individuals with elevated C/D ratios being at high risk. Dehydroepiandrosterone (DHEA) and cortisol are the two steroid products of the normal human adrenal cortex secreted in greatest amount, the former in both free and sulfate-conjugated form (DHEA-S). As the principal glucocorticoid (GC) of humans, cortisol has anti-inflammatory/immunosuppressive activity and is critically involved in adaptation to stress and control of organic metabolism (l). DHEA has primarily been considered as a precursor of estrogens and more potent androgens. Although DHEA and cortisol can both be derived from the same precursor - - 17-hydroxy pregnenolone (Fig. 1) - - the plasma levels of total DHEA decline with aging (2), whereas cortisol levels remain relatively unchanged (see 3). The precise mechanisms

Cholesterol

DHENDHEAS

Pregnenolone

~

- ydroxypregnenolone

DiiStlilcllterone

~--

-y ro~yprogesterone

Cort,costerone "~

De°~iiiil '°1

Aldosterone Fig. 1 Adrenalsteroidogenic pathways.

Date received 16 November 1995 Date accepted 4 July 1996

85

86

which control the relative rates of 17-hydroxy pregnenolone conversion to DHEA and to cortisol from 17-hydroxy progesterone remain to be established. Following secretion, total DHEA in the circulation consists primarily of the sulfate conjugate DHEA-S, the concentration of free DHEA being less than 1% of total DHEA. Total cortisol comprises free and protein-bound cortisol, with cortisol predominately protein bound. Experimental studies in animals have demonstrated that DHEA has a wide spectrum of biological effects, including protective effects in rodent models of human disease, eg. obesity, diabetes, cancer and atherosclerosis (4-6). Recent studies indicate that DHEA has beneficial effects in elderly humans. DHEA administered to middle-aged and older adults stimulates natural killer cell activity (7), an important component of the immune defense system (8). In elderly subjects, DHEA also increased the bioavailability of insulin-like growth factor-1 (IGF-1) and in about 70% of the group tested, their feeling of 'well-being' and 'energy' was remarkably increased (9). We propose an even more significant role for DHEA. It is based upon the fact that chronic cortisol excess, as in Cushings syndrome, facilitates the development of a wide variety of pathological processes. To prevent this, we believe that a physiological antagonist opposes this aspect of cortisol action and that DHEA is that antagonist. We postulate that DHEA is an adrenal hormone in humans, and that one of its central roles is to maintain cortisol homeostasis by acting as a cortisol antagonist, particularly during periods of prolonged GC hyperactivity. Experimental evidence demonstrating that DHEA inhibits several classical GC effects in rodents (10-18) supports this view. This view is also consistent with the principle that 'fail-safe' mechanisms develop whenever a 'hormone-excess' has the potential to become lifethreatening. This is the case with cortisol, where feedback control of ACTH and cortisol plasma levels, achieved via the hypothalmic-pituitary-adrenal (HPA) axis, normally serves to keep circulating cortisol levels within a restricted normal range throughout the day. After cortisol levels are increased by acute stress, feedback control via the HPA axis acts to return cortisol to basal levels. Cortisol activity is also regulated by the plasma levels of transcortin (a cortisol binding globulin) which binds free cortisol, the biologically active form. If DHEA is indeed a cortisol antagonist, the relationship between the plasma concentrations of total cortisol and total DHEA, hereinafter referred to as the C/D pattern (mathematically expressed as a CID ratio) may be viewed as an 'indicator' of the func-

MEDICAL HYPOTHESES

tional state of cortisol activity. A second feature of the C/D concept is that a prolonged excess of cortisol activity, unopposed by adequate DHEA, is a major factor contributing to the initiation and/or progression of certain diseases. This latter view extends the previous suggestion by Sapolsky et al (19), that elderly people generally have some degree of cortisol hyperactivity which damages hippocampal neurons (producing memory deficits) and might be a contributing factor to the development of the diverse pathologies associated with aging. Elements of the CID concept were first presented by Svec and Lopez-S (10) in a short note, relating reported low levels of DHEA-S in Alzheimer's disease to cortisol hyperactivity. The present article extends the C/D concept to a set of diseases with important theoretical implications for clinical medicine.

Anti-glucocorticoid actions of DHEA The antagonist effects of DHEA against GC action have been clearly documented in the immune system. DHEA inhibits the classic effect of GCs to induce thymic involution in young mice (11,12). This form of thymic involution primarily involves the apoptosis of murine thymocytes (T cells) probably initiated by a GC-induced nuclease which degrades DNA (20). May et al (12), studying the effects of DHEA and GC, showed that GC induced T cell breakdown in vitro as well as in vivo. Although thymocytes from mice pretreated with DHEA incubated in vitro with GC maintain their viability, DHEA added in vitro without pretreatment was ineffective against GCinduced apotosis. Blauer et al (13) later reported that DHEA pretreatment of mice inhibited the in vitro effect of GC to suppress mitogen-induced splenic lymphocyte proliferation. The action of GC to suppress blastogenesis of murine lymphocytes could demonstrated both in vitro and in vivo but DHEA, effective in vivo, was completely ineffective in vitro. Padgett and Loria (18) recently reported in-vitro results which support and extend these results. They found that a trihydroxylated DHEA metabolite, but not DHEA, was effective in vitro in murine splenocytes as an antagonist of GC suppression of interleukin 2 (IL-2) production and Con A-induced splenocyte proliferation. This DHEA metabolite, 5-androstene-3[3, 713, 1713 triol (designated AET by the authors) acted directly on splenocytes, whereas DHEA addition inhibited both of these processes. Daynes and coworkers had previously reported a series of studies on murine T cells, with results fundamentally different from the previous studies cited. Specifically, the Daynes group studied the

87

DEHYDROEPIANDROSTERONE AND CORTISOL IN DISEASE

influence of DHEA and GCs on two established T cell growth factors, synthesized and secreted by 'helper' thymocytes (TH) cells - - (IL-2) and interleukin 4 (IL-4). They first found that GCs stimulated the synthesis of IL-4 and concurrently decreased IL-2 synthesis in T cells isolated from immunized mice both in vivo and in vitro (21). Physiological concentrations of DHEA added directly to activated T cells increased IL-2 secretion, decreased IL-4 and completely counteracted the suppressive in-vitro GC effect on IL-2 synthesis (14). The effects of DHEA in murine T cells were later shown to be mediated by a specific high-affinity DHEA receptor (22). The Daynes results suggest that the antagonism between DHEA and cortisol involves activation of two distinctive receptors on different subtypes of Th cells (Th-1 and Th-2, respectively each with a distinctive pattern of cytokines, where certain elements have the capacity to inhibit the other Th subtype (23). The question why DHEA added in vitro to T cells was effective as a GC antagonist in the Daynes studies, but ineffective in the Padgett/Loria study, as well as in the earlier studies of the May and Blauer groups, remains to be resolved. GC action to influence the transcriptional activity of a variety of genes is well established. The wellestablished GC effect to induce tyrosine aminotransferase (TAT) in liver and kidney is inhibited by DHEA activity in mice (15) and obese Zucker rats (16,17). Antagonism between DHEA and GC was also observed with GC-induced ornithine carboxylase synthesis in mouse liver and kidney (15). Acute DHEA treatment inhibiting enzyme induction did not influence GC-receptor (R) activity (17). Thus, DHEA inhibition of acute GC effects on enzyme induction does not involve antagonism at the GC-R level. However, long-term administration of DHEA clearly decreased GC-R activity in rat liver (17). The possibility must be considered that the protective effects of DHEA in animals destined to develop obesity, diabetes or cancer (see 7) may be due, in some part, to DHEA inhibition of GC-R activity. In all of the studies cited, DHEA antagonized acute effects of GCs on a very limited set of target systems, primarily in mice. Comparable experimental studies to determine whether DHEA administration would counteract the adverse effects of long-term cortisol excess on bone density, muscle wasting, fat distribution, etc. remain to be carried out. Do the DHEA anti-GC results described in rodents apply to humans? There is no compelling evidence which permits one to answer this question definitively. However, despite major difference in the response of circulating human and murine lymphocytes to GCs (24), Suzuki et al (25) reported that the

response of human and mouse CD4 ÷ T-cells to DHEA is similar. Thus, T cells isolated from blood samples of normal human donors, following activation, treated with physiological concentrations of DHEA in vitro had enhanced production of IL-2, and the cytotoxic activity of CD8 ÷ cells was increased. The enhancing effect of DHEA on IL-2 synthesis was also shown at the level of IL-2 mRNA, indicating that DHEA increases transcription of the IL-2 gene, extending the DHEA results obtained in mice to humans. Attempts to confirrn the results of Suzuki et al have not been successful (H. Zeh and M. Lotze, unpublished studies). Adverse effects of cortisol excess

The diverse pathological states produced by prolonged GC excess in humans unopposed by DHEA are illustrated by examination of the GC-induced iatrogenic Cushing's syndrome (see 1, 26). This syndrome arises when large doses of GCs are administered daily as anti-inflammatory agents (AIA) to treat certain chronic diseases (e.g. rheumatoid arthritis, systemic lupus erythematosis and other connective tissue diseases) or for immunosuppression following organ transplantation. The adverse GC side-effects produced may be viewed as the pathological exaggeration of normal physiological responses to cortisol. In the iatrogenic syndrome, exogenous GC inhibits the HPA axis, reducing ACTH levels with suppression of adrenal function and marked reduction of the plasma levels of endogenous cortisol and DHEA. The GC excess produced is thus not associated with a variable simultaneous increase in DHEA levels, as occurs in the spontaneous forms of Cushing's syndrome. Cortisone (converted to cortisol in vivo) was the first GC used as an AIA in chronic disease. Large doses were employed over prolonged periods and the plasma cortisol levels produced were sufficiently high to permit expression of the low mineralocorticoid (MC) activity of cortisol. Prednisone (converted to prednisolone in vivo) has largely replaced cortisol as the accepted AIA of choice, because this synthetic GC has little or no MC activity and is four times more active as an AIA than cortisol (27). GC-induced iatrogenic Cushing's syndrome depends on dose and the duration of treatment. When GCs are administered daily as AIA, some Cushingoid signs (which vary depending upon the individual) almost invariably develop within a few weeks. The signs and symptoms of iatrogenic Cushing's syndrome produced by oral prednisone include: obesity with a selective distribution of fat resulting in moon facies, buffalo neck, and pot belly; abnormal glucose

88

MEDICAL HYPOTHESES

tolerance and steroid diabetes; bone loss reulting in osteoporosis and bone necrosis; myopathy with muscle loss and weakness; skin thinning with stria and poor wound healing; moderate hypertension with cardiovascular complications; mental changes. Large GC doses given over protracted periods result in low resistance to infectious agents, glaucoma, cataract, and benign intracranial hypertension.

Table

I

Men

Women C / D r a t i o s d u r i n g t h e h u m a n life c y c l e

The mean values for the C/D ratios at various stages of the life-cycle in males and females, shown in Fig. 2, have been calculated from the mean AM plasma cortisol levels reported by Sippel et al (28) for different age/gender groups and comparable plasma DHEA-S levels reported by de Peretti and Forest (29) and by Orentreich et al (2). Infancy/early childhood and old age are the stages of the human life-cycle where the mean C/D ratio is highest. Young adulthood (15 to 30 years of age) is the period when mean C/D ratio lowest. In middle-age (40 to 60 years of age) the mean C/D ratio is intermediate between the ratios for young adults and the elderly. This division based on age involves very large populations in each group. At every age, for both sexes, the C/D ratio of individuals in every age/ gender group varies markedly, because of marked individual variation of cortisol and DHEA-S levels from the group mean. The degree of individual variation of DHEA-S levels at various ages is shown in Table 1. There is a similar degree of variation in the AM and PM levels of cortisol. For children as well as healthy men and women, independent of age, the

[1Femalel

.9 Q

N

0.1 \

1 \

S \

S \

15 \

20 30 40 \ \ \

50 \

60 >70 \

0.s s a 11 19 29 a9 49 59 59

Age in years

Fig. 2 Logarithmicplot of ratio of totalplasmacortisolto total DHEA(C/D) and age frombirth (N = newborn)throughadulthood in healthymale and femalesubjects.

Normal ranges for serum DHEA-S Age range (yr)

Concentration range (ng/ml)

15-39 40--49

1500-5500 1000-4000

50--59 >60 15-29 30-39 40--49 > 50

600-3000 300-2000 1000-5000 600-3500 400-2500 200-1500

Reproduced with kind permission of the Endocrine Society from Orentreich et al (2).

AM plasma cortisol levels range from 60-200 ng/ml (mean ~ 100 ng/ml) and 20-100 ng/mi (mean ~50 ng/ ml) for PM samples (30). Some young adults with consistently high C/D ratios have adrenal steroid patterns similar to the elderly. Contrariwise, some elderly individuals with very low C/D ratios have adrenal steroid patterns which may be classified as 'youthful'. Genetic differences are responsible, in part, for these variations in cortisol and DHEA levels (27,31).

Diseases exacerbated by hypercortisolism

Genetic, developmental and a host of 'environmental' factors (e.g. nutrition, life-style, medical and mental status and socio-cultural-economic-ecological factors) each participate to various degrees in determining what specific disease an individual develops. Our concept postulates that chronic cortisol hyperactivity is a biological risk factor in diseases, designated as cortisol-potentiated, where hypercortisolism has the potential to exacerbate disease. Cortisol hyperactivity may be a major risk factor in some diseases but play only a minor role in others. The significance of cortisol hyperactivity risk must be evaluated empirically, determining whether the C/D ratio in a given disease is directly correlated with disease initiation or progression. A disease is classified as cortisol-potentiated when a characterisitic feature is similar to one or more of the pathological features produced by prolonged hypercortisolism, as in Cushing's syndrome. To illustrate: osteoporosis, a characteristic feature of Cushing's syndrome, develops in post-menopausal women, primarily because of estrogen deficiency. Osteoporosis is classified as a cortisol-potentiated disease because cortisol hyperactivity can exacerbate

89

DEHYDROEPIANDROSTERONE AND CORTISOL IN DISEASE

bone loss. Cushingoid types of obesity, type II diabetes, endogenous depression, glaucoma, cataract, and infectious diseases generally are other disease processes which may be designated as cortisolpotentiated. The single common element in this set of diseases induced by different causative factors is the potential that cortisol hyperactivity may exacerbate the disease process. Other factors being equal, the C/D concept predicts that individual variability in the initiation and subsequent progression of cortisol-potentiated disease in all ages is directly related to the degree of individual deviation from the mean C/D ratio for the 15-30 year age group; the higher the ratio the greater the risk. Elevated C/D ratios have been discussed in relation to diseases where cortisol hyperactivity may potentiate diverse causative factors. Others have suggested that disease in itself may non-specifically lower the levels of DHEA-S and increase cortisol (see 32). Such changes in steroid pattern have been reported in patients with diverse types of chronic illness and designated as the 'secondary consequences' of illness, not necessarily related to disease causation. These distinctions are of minor consequence to our concept. In our view, the only disease where cortisol hyperactivity is causative may be Cushing's syndrome, in contrast to cortisol-potentiated diseases where hypercortisolism has the potential to exacerbate pathology. It is possible that in diseases generally, the greater the degree of chronic cortisol hyperactivity, reflected in high C/D ratios, the poorer the prognosis.

Diurnal variation of C/D pattern A single sample with high C/D ratio taken during the day, indicates the possibility of increased GC hyperactivity and increased risk of disease. Increased risk is established with a high degree of confidence when blood samples drawn at weekly intervals, at standardized periods of the day, show C/D ratios to be consistently elevated relative to the mean CID ratio of the appropriate age/gender group. The need for time standardization of sampling arises because the level of plasma cortisol normally varies throughout the day with a characteristic circadian rhythm, while the total DHEA level remains relatively constant. To illustrate the variation of the C/D ratio due to cortisol variability during the day, the mean plasma CID ratios determined in a group of healthy male adults (mean age 29 yr) taken during a 24 h day calculated from the data of Villette et al (33) were 0.050, 0.030, 0.23 and 0.010 on blood samples taken at 8:30, 12:30, 16:30 and 00.30, respectively.

Stress and the CID ratio The adrenals of young children (1-6 yr old) secrete cortisol at adult rates (28) but only trace amounts of DHEA (29). This pattern continues until children reach adrenarche at 7-9 yr of age. Stress-induced ACTH release in the very young thus increases cortisol levels without a concomitant increase in DHEA levels. At adrenarche and thereafter, the adrenals produce significant amounts of DHEA. Stress-induced increase of ACTH in healthy adolescents as well as young and middle-aged adults thus increases the secretion of DHEA as well as cortisol. In the elderly, as mean levels of DHEA-S decline, the DHEA response to ACTH likewise decreases. The elderly thus respond to ACTH with a normal increase in plasma cortisol, but few have a concomitant increase in the levels of free or total DHEA (34,35). Chronic stress in the elderly may thus further increase a basal C/D value which is already elevated.

Age-related diseases Many of the diseases which have been designated as 'cortisol-potentiated' occur most frequently in the elderly and are generally characterized as 'age-related', e.g. type II diabetes, obesity, osteoporosis, endogenous depression, cardiovascular disease, memory defects in aging and Alzheimer's disease, glaucoma and cataracts. In men at age 70 and thereafter, the mean basal CID ratio is increased about 10-fold over that of young men. There is a 40-fold increase in the mean CID ratio of women at age 70, relative to young women. Our concept predicts that the subgroup of elderly individuals with the highest CID ratios are at greatest risk for the initiation and rapid progression of disease processes potentiated by hypercortisolism. Young and middle-aged individuals who have elevated CID ratios, in the same range as the elderly, are likewise predicted to be at high risk for developing age-related disease.

Adverse GC side-effects Long-term GC ant-inflammatory treatment for chronic diseases is invariably associated with serious unwanted side-effects, independent of the GC employed. Since prolonged exogenous GC therapy suppresses the HPA axis and ACTH secretion, markedly reducing plasma levels of endogenous cortisol and DHEA, GC side effects develop under

90 conditions where endogenous D H E A is unavailable to act as a GC antagonist. The question arises: is the anti-GC activity of D H E A we postulate selective, so that D H E A blocks unwanted GC side-effects, while retaining GC antiinflammatory activity? The question posed cannot presently be answered. However, support for this possibility is provided by considering the similarities and differences between prolonged therapy with ACTH and corticosteroids. Long-term ACTH treatment induces hyperplasia of the adrenal cortex, resulting in supranormal levels of cortisol and D H E A (36). The therapeutic anti-inflammatory activity of ACTH and exogenous GC are equivalent (36). Thus, DHEA

does not block the anti-inflammatory activity of cortisol, induced by A CTH treatment. The conjecture that D H E A may block the unwanted side-effects of prolonged GC therapy is supported by the following differences between A C T H and corticosteroid therapy. 1. Orth and associates (1) in their authoritative review state that, in contrast to corticosteroid therapy, 'the administration of A C T H rarely results in iatrogenic Cushing's syndrome'. 2. Linear growth is suppressed in children treated with daily therapeutic doses of GC, but not with A C T H (37). This difference in growth may be due to ACTH-induced D H E A hypersecretion which increases the bioavailability of IGF- 1 (11) clearly involved in linear growth (see 38), whereas GCs inhibit this factor. 3. Carter and James (39) reported that prolonged GC treatment of a polyarthritis patient resulted in HPA suppression with cessation of A C T H release and subsequent adrenal atrophy; this did not occur with ACTH. Patients treated dally with therapeutic A C T H doses for 2 years or more retained pituitary-adrenal responsiveness to the stress of insulin hypoglycemia and surgical operations (39). They eliminated the possibility that the difference between exogenous cortisol and ACTH resulted from differences in plasma cortisol levels, and then tested the possibility that adrenal androgens produced by ACTH might be responsible for the failure of supranormal levels of cortisol to suppress the HPA axis. They reported that 25 mg of DHEAS (or androstenedione) administered to patients receiving 10-12.5 mg of prednisone (equivalent to 40-50 mg of cortisol) did not prevent GC-induced HPA suppression. No conclusion concerning D H E A antagonism of cortisol can be drawn from this DHEA-S experiment. The issue merits reinvestigation, testing D H E A (not DHEA-S) at

MEDICAL HYPOTHESES

higher doses (say 100-150 mg D H E A vs 10 mg prednisone) to determine whether or not D H E A blocks GC suppression.

Epilogue We are aware that the C/D concept presented rests upon several key assumptions that remain to be established. Great gaps remain in our understanding of the roles that cortisol and D H E A play in the diseases mentioned: the regulation of D H E A synthesis relative to cortisol, bioactive D H E A metabolites, as well as the multiplicity of D H E A actions both direct and indirect. Although the mechanisms of these actions remain to be resolved it should be emphasized that the C/D hypothesis does not depend upon a particular mechanism of D H E A action. The importance of this article relates to the questions and possibilities raised, not to the answers suggested. The 'questions' can be tested experimentally so that key aspects of the concept presented can be validated or rejected. If validated, in whole or in part, DHEA and/or its biologically active metabolites (see 18, 40) or analogs (41) merit serious consideration as adjuncts in the medical treatment of individuals with elevated C/D ratios.

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