Effects of testosterone replacement therapy on bone metabolism in male post-surgical hypogonadotropic hypogonadism: focus on the role of androgen receptor CAG polymorphism

Introduction and aim The relationship between androgen receptor (AR) CAG polymorphism and bone metabolism is highly controversial. We, therefore, aimed to evaluate the independent role of AR CAG repeat polymorphism on bone metabolism improvement induced by testosterone replacement therapy (TRT) in male post-surgical hypogonadotropic hypogonadism, a condition frequently associated with hypopituitarism and in which the effects of TRT have to be distinguished from those resulting from concomitant administration of pituitary function replacing hormones. Methods 12 men affected by post-surgical hypogonadotropic hypogonadism [mean duration of hypogonadism 8.3 +/- 2.05 (SD) months] were retrospectively assessed before and after TRT (from 74 to 84 weeks after the beginning of therapy). The following measures were studied: parameters of bone metabolism [serum markers and bone mineral density (BMD)], pituitary dependent hormones and genetic analysis (AR CAG repeat number). Results Total testosterone, estradiol, free T4 (FT4) and insulin-like growth factor-1 (IGF-1) increased between the two phases, while follicle stimulating hormone (FSH) decreased. While serum markers did not vary significantly between the two phases, BMD improved slightly but significantly in all the studied sites. The number of CAG triplets correlated negatively and significantly with all the variations (Delta-) of BMDs. Conversely, Delta-testosterone correlated positively and significantly with all studied Delta-BMDs, while Delta-FSH, Delta-estradiol, Delta-FT4, and Delta-IGF-1 did not correlate significantly with any of the Delta-BMDs. Multiple linear regression analysis, after correction for Delta-testosterone, showed that CAG repeat length was negatively and significantly associated with Delta-BMD of all measured sites. Conclusions Our data suggest that, in post-surgical male hypogonadotropic hypogonadism, shorter AR CAG tract is independently associated with greater TRT-induced improvement of BMD.