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Dehydroepiandrosterone supplementation in elderly men: the role of estrogens versus androgens on the male skeleton.

Khosla et al. (1) recently demonstrated that estrogens and androgens may have opposite effects on biochemical markers of bone metabolism in elderly men. In their elegant study, men were rendered acutely hypogonadal using a GnRH agonist and treated with an aromatase inhibitor to block conversion of androgens to estrogens, before receiving 17 -estradiol alone, testosterone alone, or both 17 -estradiol and testosterone, to distinguish the differential effects of androgens and estrogens on male bone metabolism (1). Although estrogen replacement in these men increased circulating levels of the antiresorptive decoy receptor osteoprotegerin (OPG), an essential regulator of osteoclast function and bone metabolism (2), androgen replacement suppressed OPG levels (1). Thus, that study has provided further support for the hypothesis that estrogens are essential for bone metabolism in men and that androgens and estrogens have distinct skeletal effects and are not interchangeable (1, 3). Dehydroepiandrosterone (DHEA) is the crucial precursor of human sex steroid biosynthesis and can be converted toward both androgens and estrogens. In men, oral administration of DHEA increased circulating levels of estrogens and androgen metabolites (4). To gain further insight into the bone-specific action(s) of DHEA, we evaluated serum OPG concentrations in healthy elderly men (n 22; age range, 50–69 yr) with low endogenous serum DHEA sulfate levels, who were receiving DHEA supplementation at a daily dose of 50 mg for 4 months in a randomized, placebo-controlled crossover trial, as reported elsewhere (5). In this study, DHEA treatment did not affect biochemical markers of bone formation (serum osteocalcin) and resorption (urinary pyridinoline and deoxypyridinoline excretion; Ref. 5), which is consistent with two similar studies (6, 7). Serum OPG concentrations measured with an enzyme-linked immunosorbent assay (Immundiagnostik, Bensheim, Germany) were not significantly different at baseline and after 1 and 4 months of DHEA administration compared with the placebo group. In conclusion, DHEA administration had no effect on serum OPG levels in healthy elderly men. The results of Khosla et al. (1) suggest a differential response of circulating OPG levels to sex steroid treatment in men. Thus, the observed lack of changes in serum OPG levels during DHEA administration in healthy elderly men may result from a combined stimulatory and inhibitory effect on OPG production due to conversion of DHEA toward both estrogenic and androgenic steroids.