Some testosterone effects are regulated at a local tissue level by aromatisation to oestrogen. Testosterone stimulates GH secretion in men, an effect attenuated by tamoxifen (a SERM with central oestrogen receptor antagonistic and peripheral agonistic effect). It is unclear whether the blunting of testosterone-induced GH secretion by tamoxifen stems from oestrogen receptor modulation or blockade from aromatised oestrogens.
Objective: To investigate whether aromatase inhibition blunts the GH-IGF-I axis in healthy men.
Design: We compared the effects of letrozole, an aromatase inhibitor, and tamoxifen in an open-label cross-over study. Eight healthy men (BMI 25.5 kg/m2, age 59±1 y) received 2-week sequential treatments with tamoxifen (20 mg/d) and letrozole (2.5 mg/d) with a 4-week intervening washout period.
Outcome Measures: The GH response to arginine stimulation, and circulating levels of IGF-I, LH, testosterone.
Results: Letrozole significantly (p<0.05) reduced the peak GH response to arginine by 49±18%. Tamoxifen induced a small non-statistically significant reduction of peak GH response by 19±26% (p=0.1). The reduction in GH was significantly greater with letrozole. Both treatments significantly reduced mean circulating IGF-I levels, with tamoxifen having a significantly greater effect (∆ -34±3 vs -23±4%; p<0.05). Both drugs significantly increased LH and testosterone concentrations. The mean increases in testosterone (102% vs 32%; p<0.01) and LH (188% vs 37%; p<0.001) were significantly greater with letrozole than with tamoxifen treatment.
Summary and Conclusion: At the doses used, letrozole but not tamoxifen significantly reduced GH secretion, however tamoxifen reduced IGF-I to a greater degree. Both drugs stimulated the gonadal axis. We conclude that stimulation of the GH-IGF-I axis by testosterone is mediated centrally by oestrogens from aromatisation, as is the suppression of the gonadal axis. As oestrogens inhibit hepatic IGF-I production, the reduction of IGF-I by tamoxifen is mediated by an oestrogen effect on the liver.
Supported by the Princess Alexandra Hospital Research Support Scheme and NHMRC.