Androgens and bone

Abstract

Testosterone is the major gonadal sex steroid produced by the testes in men. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These androgens collectively affect skeletal homeostasis throughout life in both men and women, particularly at puberty and during adult life. Because testosterone can be metabolized to estradiol by the aromatase enzyme, there has been controversy as to which gonadal sex steroid has the greater skeletal effect. The current evidence suggests that estradiol plays a greater role in maintenance of skeletal health than testosterone, but that androgens also have direct beneficial effects on bone. Supraphysiological levels of testosterone likely have similar effects on bone as lower levels via direct interaction with androgen receptors, as well as effects mediated by estrogen receptors after aromatization to estradiol. Whether high doses of synthetic, non-aromatizable androgens may, in fact, be detrimental to bone due to suppression of endogenous testosterone (and estrogen) levels is a potential concern that warrants further study.

Figure 1

Changes in serum concentrations of Bone Specific Alkaline Phosphatase and Osteocalcin and urinary excretion of Deoxypyridinoline and N-Telopeptide in men with prostate cancer treated with Leuprolide alone or Leuprolide and Pamidronate. Values are expressed as the mean (± SE) percentage of the baseline value. P values are for the treatment effect according to the repeated-measures analysis of covariance controlled for the baseline value. Standard error bars that are not visible are covered by the symbol.

Figure 2

Measured areal and volumetric BMD in patients with complete androgen insensitivity syndrome (cAIS) and in controls (C). In each group, dark circles are prepubertal patients, and open circles are pubertal patients.

Figure 3

Changes in lumbar spine BMD measurement in individual patients during treatment with testosterone. Error bars show mean ± 95% confidence intervals.

Figure 4

The testosterone treatment effect on BMD change during 36 months of testosterone treatment in men over 65 years of age as a function of the pretreatment serum testosterone concentration. The lower the pretreatment serum testosterone concentration, the greater the effect of testosterone treatment on BMD. This relationship was derived from linear regression analysis of the pretreatment serum testosterone concentrations and the increments in BMD of all 108 men in the study who were treated with testosterone or placebo. The values shown are the mean (± SE) changes in BMD during the 36 months of treatment in the testosterone-treated subjects minus those in the placebo-treated subjects for pretreatment testosterone concentrations from 100–500 ng/dL. The testosterone treatment effect was statistically significant (P < 0.01) for pretreatment serum testosterone concentrations of 100–300 ng/dL.