DHEA: Dehydroepiandrosterone


Am J Health Syst Pharm. 2000;57(22) 

In This Article


In women, the synthesis of DHEA and DHEAS occurs almost exclusively in the adrenal cortex, whereas in men the testes secrete approximately 5% of DHEAS and 10-25% of DHEA.[3] Minute amounts are synthesized de novo in the brain.[3,13] In young adults the adrenal cortex secretes approximately 4 mg of DHEA and 25 mg of DHEAS per day.[2] During gestation, large amounts of DHEA and DHEAS are secreted by the fetal adrenal glands. At birth, output drops to negligible amounts in both sexes and remains that way until five to seven years of age. At the onset of adrenarche, the adrenal glands gradually resume DHEA and DHEAS production, which accelerates through puberty. DHEA and DHEAS output is maximal between the ages of 20 and 30 years and then starts a decline of approximately 2% per year, leaving a residual of 10-20% of the peak production by the eighth or ninth decade of life.[2,14,15,16]

DHEA and DHEAS are interconvertible by sulfohydrolases in peripheral and adrenal tissues.[3] Some 64-74% of the DHEAS produced each day is converted to DHEA, but only 13% of the DHEA produced is metabolized to DHEAS.[2,17,18] In humans, the brain-to-plasma ratios for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a neuroendocrine role for these hormones.[2,19,20]

DHEA and DHEAS serve as the precursors of approximately 50% of androgens in men, 75% of active estrogens in premenopausal women, and 100% of active estrogens after menopause.[2,16] There appears to be a sex-specific response to DHEA replacement therapy in humans. In postmenopausal women (ages 50-65), supraphysiological doses of 100 mg of DHEA per day have predominantly androgenic effects, increasing testosterone levels approximately 300% over baseline levels.[21] In older men (mean ± S.D. age, 58.8 ± 5.1 years), 100 mg/day did not affect testosterone or dihydrotestosterone levels, but 17 beta-estradiol and estrone levels were increased over baseline by 37% and 225%, respectively (p < 0.0001 for both).[22] It has been hypothesized that the increase in serum estrogens may provide a mechanism for beneficial cardiovascular effects in men; however, clinical studies addressing the possible cardioprotective effects of DHEA have been inconclusive.

Several mechanisms of action of DHEA and DHEAS other than their role as precursors of the sex hormones have been proposed. In the central nervous system, both DHEA and DHEAS appear to affect neurotransmitter receptors. In rodents, DHEAS binds to the -aminobutyric acid (GABA)/benzodiazepine-receptor complex (GABA-RC) and acts as a negative noncompetitive modulator of GABA-RC. DHEA, on the other hand, appears to have GABA-agonist effects on the GABA-RC. DHEA selectively enhances the neuronal response to N-methyl- D-aspartate.[3,4] Also, DHEA and DHEAS appear to have neurotrophic effects, increasing the number of neurofilament-positive neurons and regulating the motility and growth of corticothalamic projections in cultured mouse embryo brain cells.[23,24,25]

Supraphysiological oral doses of DHEA (100-300 mg/day) in humans have been found to inhibit the synthesis of thromboxane A 2 in activated platelets, reduce plasma plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen, increase serum levels of insulin-like growth factor 1 (IGF-1), and increase cyclic guanosine monophosphate and nitric oxide synthesis (either directly or via increased levels of IGF-1).[4,26,27,28] These effects suggest that DHEA may be beneficial in improving circulation in the microvasculature and regulating some of the risk factors of cardiovascular disease, such as platelet aggregation and ischemia. Clinical studies in this area have been equivocal, with a majority showing an inverse relationship between DHEA or DHEAS levels and cardiovascular morbidity and mortality in men but not in women.[29] However, a recently published five-year epidemiologic cohort study found no statistically significant correlation between serum DHEA or DHEAS levels and the development of atherosclerosis in men or women.[30]

DHEA may play a positive role in modulation of the immune response. Clinical studies in elderly persons have demonstrated that oral DHEA doses of 50 mg/day increase IGF-1 levels (p < 0.01) and cause functional activation of T cells (increases in CD8+ and CD56+ cells [natural killer cells] and enhanced cytotoxic activity).[4,9,31,32] Serum levels of interleukin- 6 (a proinflammatory cytokine involved in the pathogenesis of osteoporosis, rheumatoid arthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and beta-cell malignancies) increase significantly with age and are inversely correlated with serum DHEA and DHEAS levels (p < 0.001). In addition, DHEA, DHEAS, and androstenedione inhibit the production of interleukin-6 by peripheral blood mononuclear cells in a concentration-dependent manner (p < 0.001).[33]


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