Disparate effect of aromatization on the central regulation of GH secretion by estrogens in men and postmenopausal women

Context: Estrogen receptor antagonism by tamoxifen inhibits GH secretion in both men and postmenopausal women, suggesting that estrogen albeit at low concentration stimulates GH secretion. However, systemic estrogen replacement in postmenopausal women does not enhance GH secretion. To clarify the role of estrogen in mediating GH secretion, we investigated the effect of estrogen deprivation using aromatase inhibitors. Aim: To determine whether estrogens mediate GH secretion in men and in postmenopausal women. Design: The effects of letrozole, an aromatase inhibitor, and tamoxifen were compared in an open-label cross-over study. Eight men and 14 women received treatments with tamoxifen (20 mg/d) and letrozole (2.5 mg/d) for 2 weeks each. The primary endpoints were GH response to arginine stimulation and gonadal steroid levels. Results: In men, letrozole significantly (p<0.05) reduced the peak GH response to arginine (∆ -49.4 ± 18.1%). Tamoxifen also reduced the mean peak GH, however this did not reach statistical significance. In postmenopausal women, letrozole did not affect, while tamoxifen significantly (p<0.05) reduced peak GH concentration (∆ -47.3 ± 10%). In men, letrozole reduced circulating estradiol (from 43.1 ± 2.8 to 12.7 ± 1.3 pmol/L; p<0.001), whereas in women estradiol was undetectable (<11 pmol/L) at baseline and throughout letrozole therapy. Conclusion: As estrogen deprivation reduced circulating GH, we conclude that estrogens regulate GH secretion in men. In postmenopausal women, the neutral effect of aromatase inhibition is likely explained by pre-existing estrogen deficiency. The inhibition of GH secretion by tamoxifen in the menopause suggest a non-ER mediated mechanism of action. In contrast to men, estrogen is unlikely to mediate GH secretion in the postmenopausal women.