Paracrine Regulation of Growth Hormone Secretion by Estrogen in Women

Context: Paracrine regulation is emerging as a discrete control mechanism in the endocrine system. In hypogonadal men, stimulation of GH secretion by testosterone requires prior aromatization to estradiol, a paracrine effect unmasked by central estrogen receptor blockade with tamoxifen. In hypogonadal women, estrogen replacement via a physiological non-oral route fails to enhance GH secretion, indicating an absence of an endocrine effect. The aim was to investigate whether local estrogens produced from aromatization regulate GH secretion. Design: We conducted an open-label, two-phase, crossover study. Patients and Intervention: We compared the effects on GH secretion of tamoxifen with estradiol valerate in postmenopausal women. Ten women were treated with tamoxifen (10 and 20 mg/d) and estradiol valerate (2 mg/d) via oral route for 2 wk each, with a washout period of at least 6 wk. Main Outcome Measures: We measured the GH response to arginine and circulating levels of IGF-I and SHBG, markers of hepatic estrogen effect. Results: The GH response to arginine was reduced by 10- and 20-mg tamoxifen in a dose-dependent manner and potentiated significantly (P < 0.05) by estradiol valerate. Mean IGF-I concentration was reduced significantly with high-dose tamoxifen (P < 0.01) and estradiol valerate treatment (P < 0.05), whereas mean SHBG levels rose with both (P < 0.01). Conclusions: Blunted GH response to stimulation occurring in the face of reduced IGF-I feedback inhibition with tamoxifen indicates that GH secretion was suppressed by estrogen receptor antagonism. Because circulating estradiol was unaffected, these data indicate a significant role of local estrogen in the central control of GH secretion. We conclude that aromatase mediates the paracrine control of GH secretion in women. (J Clin Endocrinol Metab 95: 3771-3776, 2010)