Context: Gonadal steroid withdrawal increases bone turnover and causes bone loss in men, but the underlying mechanisms have not been defined. We have previously reported that gonadal steroid deprivation increases the skeletal sensitivity to the bone resorbing properties of parathyroid hormone (PTH) infusion in men but it is not known if this effect is mediated by the absence of androgens, estrogens, or both.

Objective: To determine the selective effects of testosterone and estradiol withdrawal on the skeletal sensitivity to PTH infusion in healthy adult men.

Design and Setting: We randomly assigned 58 healthy men between the ages of 20-45 to receive treatment with combinations of a GnRH analog, an aromatase inhibitor, and hormone add-back therapy to produce the following treatment groups: Group 1 (testosterone and estradiol deficient, n = 16), Group 2 (testosterone sufficient but estradiol deficient, n = 12), Group 3 (testosterone deficient but estradiol sufficient, n = 14), and group 4 (testosterone and estradiol sufficient, n = 16). Twenty-four-hour PTH infusions were performed at baseline and after 6 weeks of therapy. Serum N-telopeptide (NTX), C-telopeptide (CTX), osteocalcin (OC), and amino-terminal propeptide of type I procollagen (P1NP) were measured every 6 h during the PTH infusions.

Results: Serum testosterone levels fell into the castrate range in groups 1 and 3 while estradiol levels were similarly reduced in groups 1 and 2. Gonadal steroid levels in the replaced groups were unchanged from baseline. Serum NTX levels measured before PTH infusion did not change in the group 4, (+T+E) but increased significantly in all other groups. A similar pattern was observed in serum CTX though the increase in group 2 (+T, -E) was not significant (P = 0.12). Pre-infusion concentrations of both OC and P1NP fell in most groups but these changes were significant in group 2 (+T, -E) for both OC and P1NP and in group 4 (+T, +E) for P1NP only. Serum NTX and CTX increased during PTH infusions in all groups at all time points (P < 0.001). In the eugonadal group (Group 4 +T+E), the increase in NTX was the same at week 0 and week 6, whereas in all the other groups, the PTH-induced increase in serum NTX was significantly greater at week 6 compared with week 0. The same pattern emerged for CTX, though the difference in group 3 (-T,+E) was not significant (P = 0.12). Serum OC and P1NP levels fell during PTH infusions in all groups and at all time points (P < 0.001), but no significant differences were observed between week 0 and week 6 in any group.

Conclusions: These results demonstrate that the selective suppression of testosterone, estradiol, or both hormones increases the skeletal responsiveness to the bone resorbing effects of PTH in men. These findings underscore the importance of both androgens and estrogens in male skeletal homeostasis and suggest that changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.