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, 2011, 240328

Testosterone and the Male Skeleton: A Dual Mode of Action


Testosterone and the Male Skeleton: A Dual Mode of Action

Mieke Sinnesael et al. J Osteoporos.


Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor.


Figure 1
Figure 1
Metabolism of sex steroids. (i) Testosterone (T), that is secreted by the testes, can directly act on its receptor, the androgen receptor (AR), present in bone cells. (ii) T can also be converted locally to dihydrotestosterone (DHT) by 5α-reductase. (iii) In addition, T can undergo aromatization to 17β-estradiol (E2) by aromatase. E2acts on one or both estrogen receptors (ERα or ERβ). (iv) The adrenals secrete C19 androgens including dehydroepiandrosterone (DHEA) that can also be converted to (v) estrone (E1) and E2by aromatase, 17β-hydroxysteroid dehydrogenase (17β-HSD), and 3β-HSD or to T by 17β-HSD and/or 3β-HSD. (vi) In men and women, T and E2are predominantly bound to sex hormone binding globulin (SHBG), synthesized by the liver.

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