IntroductionWhile the role of estrogen (E) in regulating bone metabolism in women is well established, the relative contributions of E versus testosterone (T) in regulating bone turnover in men remain unclear. Since T is the dominant sex steroid secreted in men, the traditional belief has been that E is the major sex steroid regulating bone metabolism in women and T is the major sex steroid regulating bone metabolism in men. This concept has been challenged, however, by the description of several "experiments of nature." A male carrying homozygous mutations in the E receptor-α (ER-α) gene (who was unable to respond to E) (1) and two males with homozygous mutations in the aromatase gene (who were unable to synthesize E) (2-4) had osteopenia, unfused epiphyses, and elevated indices of bone turnover. Moreover, E therapy in the two aromatasedeficient males corrected these abnormalities (3-5).These reports have led to a reconsideration of the possible role of E in regulating the male skeleton, although several questions remain. The major unresolved issue is whether E acts on the male skeleton mainly to enhance bone mass during growth and maturation, or whether it also acts to retard bone loss in aging individuals. Thus, since the ER-α mutant and aromatase-deficient males had immature skeletons, it is possible that E primarily plays a role in determining skeletal modeling and the acquisition of peak bone mass, but not in regulating bone turnover (and hence, bone loss) in aging men.Several cross-sectional observational studies (6-10) have attempted to address this issue by relating bone mineral density (BMD) to sex steroids in elderly men. In these studies, E (and in particular, the bioavailable or non-sex hormone binding globulin [non-SHBG] bound fraction) did correlate better with BMD than T. However, since both T and E levels are correlated with each other (7), these observational data could not conclusively separate the relative contributions of each to skeletal metabolism in elderly men. In addition, since BMD in elderly men is a function both of peak bone mass and bone loss with aging, they also could not dissociate the effects of E on the acquisition of peak bone mass in early adulthood from its effects on continued bone loss later in life.In addition to its intrinsic importance for our understanding of skeletal physiology, this issue also has significant practical implications. Thus, while men lack the rapid phase of bone loss present at menopause in women, they lose substantial amounts of bone with aging (11)(12)(13)(14). In addition, population-based studies have shown that bone resorption increases with age in Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus...

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