Neuroendocrine Regulation of Growth Hormone and Androgen Axes by Selective Estrogen Receptor Modulators in Healthy Men

Context: In men, the stimulation of GH and inhibition of LH secretion by testosterone requires aromatization to estradiol. Tamoxifen, a selective estrogen receptor modulator (SERM), possesses central estrogen antagonistic effect but peripheral hepatic agonist effect, lowering IGF-I. Thus, tamoxifen is likely to perturb the neuroendocrine regulation of GH and gonadal axes. Raloxifene, a SERM, is used for therapy of osteoporosis in both sexes. Its neuroendocrine effects in men are poorly understood. Objective: The aim was to compare the impact of raloxifene and tamoxifen on GH-IGF-I and gonadal axes in healthy men. Design: We conducted a randomized, open-label crossover study. Patients and Intervention: Ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d), with a 2-wk intervening washout period. Main Outcome Measures: We measured the GH response to arginine and circulating levels of IGF-I, LH, FSH, testosterone, and SHBG. Results: Tamoxifen, but not raloxifene, significantly reduced IGF-I levels by 25 ± 6% (P < 0.01) and increased SHBG levels by 20 ± 7% (P < 0.05) at the higher therapeutic dose. There was a nonstatistically significant trend toward a reduction in the GH response to arginine with both SERMs. Both drugs significantly increased LH, FSH, and testosterone concentrations. The mean increase in testosterone (40 vs. 25%; P < 0.05) and LH (70 vs. 30%; P < 0.01) was significantly greater with tamoxifen than with raloxifene treatment. Conclusions: Tamoxifen, but not raloxifene, reduces IGF-I levels. Both SERMs stimulate the gonadal axis, with tamoxifen imparting a greater effect. We conclude that in therapeutic doses, raloxifene perturbs the GH and gonadal axes to a lesser degree than tamoxifen. In therapeutic doses, raloxifene suppresses GH-IGF-I and stimulates the gonadal axes to a lesser degree than tamoxifen in men.