The human adrenal cortex secretes not only the essential hormones cortisol and aldosterone, but also DHEA and large amounts of DHEAS (DHEA Sulfate). The serum concentration of DHEAS is 20 times that of serum cortisol, and the concentration of DHEA is 1/20 that of cortisol. The very high concentration of DHEAS reflects its high rate of secretion and low rate of metabolic clearance. DHEA and its sulfate are interconvertible. The sulfate is mainly formed from DHEA in the adrenal gland and in the liver, and many organs that are targets of androgens and estrogens convert DHEAS back to DHEA, which can then be transformed by the same organs into active androgens and estrogens.
In normal individuals, serum concentrations of DHEA and its sulfate are highest in the third decade of life, after which the concentrations of both gradually decrease, so that by the age of 70 to 80 years, the values are about 20 percent of peak values in men and 30 percent of peak values in women. This decrease has led to the suggestion that DHEA might prevent aging. Since the ovaries do not secrete DHEA (the testis secretes only small amounts), women with primary and secondary adrenal insufficiency have very low, often unmeasurable serum concentrations of DHEA and its sulfate and active androgens. The disappearance of axillary and pubic hair and osteoporosis are clinical correlates of these deficiencies.
The authors of this NEJM study administered DHEA orally in a dose of 50 mg per day or placebo for four months to adrenally insufficient women and evaluated the effects on well-being, sexuality, and serum hormone and other biochemical values. Psychological evaluation with the use of five questionnaires revealed significant positive effects of DHEA, as compared with placebo, on the scores for depression, anxiety, general well-being, and the psychological and physical aspects of sexuality. There was a small but significant rise in serum insulin-like growth factor I concentrations (a mediator of some effects of growth hormone in the liver) and a small decrease in serum total and low-density lipoprotein cholesterol concentrations. The latter effect was probably caused by active androgens formed from DHEA. Other androgenic effects were greasy skin, acne, and increased growth of hair, reported by five women.
The positive effects of DHEA on mood, well-being, and sexuality could be due to the formation of active androgens by peripheral tissues. DHEA itself does not bind to androgen or estrogen receptors. In the brains of rats, however, DHEAS and, to a lesser extent, DHEA are inhibitory modulators of the (gamma)-aminobutyric acid-benzodi-azepine receptor complex, and DHEA enhances the effect of excitatory amino acids on the N-methyl-d-aspartate receptor. If the results of these receptor studies in rats (a species with extremely low serum DHEA concentrations) are relevant to human physiology, the steroids might have clinically beneficial effects in the central nervous system. (1) In addition, DHEA can be synthesized in the brains of rats from cholesterol, like other so-called neurosteroids.
Other possible indications for therapy with DHEA are depression, prolonged high-dose glucocorticoid therapy, and postmenopausal osteoporosis. In a recent placebo-controlled trial involving patients with major depression, treatment with 30 to 90 mg of DHEA per day resulted in marked improvement in some patients. Serum DHEA and DHEAS concentrations are low in patients with inflammatory disorders who are receiving high-dose glucocorticoid therapy, because the glucocorticoid suppresses corticotropin secretion. Such patients, especially those with rheumatoid arthritis and systemic lupus erythematosus, are at high risk for osteoporosis and other catabolic complications of glucocorticoid therapy. Prophylactic administration of DHEA might reduce the risk of these complications.
N Engl J Med September 30, 1999;341:1013-1020,1073-1074.