Testosterone and the Male Skeleton: A Dual Mode of Action

Abstract

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.

Thromboembolism Peaking 3 Months after Starting Testosterone Therapy: Testosterone–Thrombophilia Interactions

“…TT increases circulating estrogens66 that subsequently play a role in thrombotic events 22. Since testosterone is aromatized to E2,67 it may be prothrombotic by the same mechanism as reported in women, where HRT interacts with the Factor V Leiden mutation to increase risk of VTE 27…”

The Association of Alpha-Blockers and 5-Alpha Reductase Inhibitors in Benign Prostatic Hyperplasia With Fractures

“…Current evidence suggests that estradiol, through the estrogen receptor and aromatization of androgens into estrogen, may have a greater role in maintenance of skeletal health in men than testosterone acting directly through the androgen receptor. 8,28 A possible explanation for the unchanged fracture risk with the use of 5-alpha reductase inhibitors is that decreased serum levels of DHT caused by 5-alpha reductase inhibitors may be compensated by increased testosterone levels and shunting of testosterone to estrogen in bone tissue. However, more studies are required to confirm this hypothesis.…”

“…Hypogonadal men are at increased risk for the development of fractures, and supplementation with testosterone decreases this risk. 28 The effect of testosterone on bone health is mediated through both androgen and estrogen receptors. Current evidence suggests that estradiol, through the estrogen receptor and aromatization of androgens into estrogen, may have a greater role in maintenance of skeletal health in men than testosterone acting directly through the androgen receptor.…”

The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]

“…However, elderly men have a clearly reduced BMD and increased risk for fractures [58]. Both androgens stably transfected with AR under the control of the type I collagen promoter (colAR-MC3T3), genes related with MAP kinase-mediated signaling were observed to be repressed by androgen with the most dramatic effect on Elk1 (ETS Transcription Factor, Elk1) expression.…”