Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA-S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA-S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA-S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA-S concentrations, as well as concentrations of DHEA and DHEA-S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA-S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.

DHEA and DHEA-S: a review.

Sex hormones as immunomodulators in health and disease.

From the compendium presented above, the following statements become evident: 1) Inappropriately low secretion of cortisol in relation to inflammation is a typical feature of the inflammatory disease in patients with RA. 2) The secretion of adrenal androgens is significantly reduced, which is a problem in postmenopausal women and elderly men due to a lack of downstream sex hormones. 3) Serum levels of testosterone are markedly reduced in RA. 4) Sympathetic nerve fibers are markedly reduced in the synovial tissue of patients with RA, whereas proinflammatory sensory fibers (substance P) are present. 5) Substance P serves to continuously sense painful stimuli in the periphery, and the nociceptive input from the inflamed joint shows a large amplification in the spinal cord. This leads to continuous pain with stabilization of the afferent sensory input and continuous release of proinflammatory substance P into the lumen of the joint. From these facts it is obvious that alterations of the systemic antiinflammatory feedback systems contribute significantly to the pathogenesis of RA. Disease therapy directed at these alterations must provide a mechanism to replace the adrenal glands (glucocorticoids), the gonadal glands (androgens), and the sympathetic nervous system (adenosine increase by low-dose MTX, sulfasalazine, and salicylates) in order to integrate their immunosuppressive effects at the local site of synovial inflammation. Although local processes of the adaptive immune system are important in pathogenesis in the acute phase of RA, these mechanisms may be less important during the chronic phase of the disease in the absence of a specific trigger. We believe that a defect of systemic antiinflammatory feedback systems is an important factor in the perpetuation of RA. This review reinforces the belief that combined therapeutic approaches on a neuroendocrine immune basis are of crucial importance in a pathogenetically oriented therapy of RA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200103%2944%3A3%3C493%3A%3AAID-ANR95%3E3.0.CO%3B2-U

Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role.

Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.

Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

CD4+CD25+Foxp3+ Treg cells are crucial for the maintenance of immunological homeostasis. Androgens significantly induce Foxp3 expression in humans and regulate the differentiation of Treg cells. A ...

Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

In a clinical study the blood levels of dehydroepiandrosterone sulphate (DHEAS), pregnenolone sulphate (5-PS), testosterone sulphate (TS) and their respective unconjugated steroids were measured in: 20 patients with systemic lupus erythematosus (SLE) who were receiving either no treatment (11 patients) or else treatment with chloroquine (9 patients), in some cases combined with non-steroidal anti-inflammatory drugs (NSAIDs); in 26 patients receiving corticosteroid (Prednisolone) treatment; and in healthy men and women. The patients not on corticosteroid exhibited substantially reduced DHEAS, 5-PS and TS levels (geom. mean: 2300 vs. normal 4300 nmol/l DHEAS; 200 vs. 320 nmol/l 5-PS; and 120 vs. 360 nmol/l TS; p less than 0.001), irrespective of the difference in sex, age or chloroquine treatment. The patients on corticosteroid treatment displayed a similar pattern of levels, but the reduction was much more marked than in the patients not on the steroid (geom. mean: 610 nmol/l DHEAS, 55 nmol/l 5-PS; and 35 nmol/l TS; p less than 0.001). No consistent changes were observed in the unconjugated steroid levels, although they were also reduced by the treatment with prednisolone. The data indicate that a deficiency in sulpho-conjugated steroids is a permanent feature of patients with SLE and that this is accentuated by the administration of corticosteroid derivatives. Further studies are needed to establish the pathophysiological significance of these findings.

Low sulpho-conjugated steroid hormone levels in systemic lupus erythematosus (SLE).

Blood levels of dehydroepiandrosterone sulphate (DHEAS) were measured by radioimmunoassay (RIA) in patients with: a) polymyalgia rheumatica/giant cell arteritis (PMR:TA; N = 25), with and without cortisone derivative treatment (N = 10 and N = 15, respectively); and b) primary fibromyalgia (PF; N = 15). The mean DHEAS levels were found to be significantly reduced in PMR:TA, compared to those in PF (Geom. mean 820 vs. 2300 nmol/l, respectively; p < 0.001), and the reduction was more marked in patients on cortisone derivative treatment. The DHEAS levels found in PF were found to be normal and consistent with those previously reported in non-immune mediated rheumatological diseases such as osteoarthritis, and in healthy subjects, using the same method of analysis. The low levels found in patients with PM:TA are in accordance with those previously reported in immune-mediated diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, suggesting that diminution of DHEAS is a constant endocrinologic feature in these categories of patients. The pathophysiological significance of these low DHEAS levels needs to be investigated.

Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell arteritis and primary fibromyalgia.

To assess the relationship between blood and tissue steroid levels, cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured by radioimmunoassay (RIA) in blood and joint tissues from a group of patients with RA (N = 29) ranging in age from 26 to 80 years (mean 63, SD: 13) and another group with secondary osteoarthritis (OA; N = 23), ranging in age from 47 to 86 years (mean 66, SD: 9), all of whom were scheduled for surgical correction of joint dysfunction. Seventeen of the RA patients were on steroid treatment at the time of the study. Assessing all the patients together, it was found that the tissue concentrations of DHEAS very closely paralleled the blood levels (r = 0.875; p < 0.001). The mean blood and tissue concentrations of DHEAS were found to be significantly reduced in RA, compared to those in OA (geometric means 540 vs. 2100 nmol/l blood, respectively, and 160 vs. 420 nmol/kg tissue, p < 0.001). Individual data indicated, however, that: (a) 3/29 patients with RA exhibited normal levels; (b) the reduction was more accentuated in those patients on steroid treatment; and (c) 5/23 patients with OA, who were treated for cardiovascular disorders, also had reduced DHEAS levels. Significant differences were not found between the mean cortisol levels in RA and those in OA, nor was there a correlation between the blood and tissue levels of this steroid. The possible influence of reduced DHEAS levels on immune-mediated diseases and/or pathophysiology is unknown, and needs to be investigated.

Relationship between blood and joint tissue DHEAS levels in rheumatoid arthritis and osteoarthritis.

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Low sulpho-conjugated steroid hormone levels in systemic lupus erythematosus (SLE).

Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell arteritis and primary fibromyalgia.

Relationship between blood and joint tissue DHEAS levels in rheumatoid arthritis and osteoarthritis.