Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive.

We postulated that short-term estradiol replacement in postmenopausal women may act, in part, by facilitating endogenous GHRH release or action. A prediction of this hypothesis is that estradiol repletion should enhance postsomatostatin rebound GH secretion, which appears to be driven by hypothalamic outflow of GHRH. To this end, we administered placebo and estradiol to eight healthy estrogen-withdrawn postmenopausal volunteers in a prospectively randomized, patient-blinded, within-subject crossover design for a total of 36 d. Rebound release of GH was assessed between d 7 and 36 of intervention on separate randomly ordered mornings after continuous iv infusion of saline or somatostatin (9 micro g/kg.h for 3 h). Secretion was quantitated by frequent (10-min) blood sampling for 7 h, GH chemiluminescence assay, and deconvolution analysis. Compared with placebo, estradiol replacement: 1) stimulated spontaneous pulsatile GH secretion by 3.5-fold (95% confidence interval, 2.1- to 5.6-fold) (P < 0.001); and 2) amplified the mass of GH secreted in response to abrupt somatostatin withdrawal by 2.1-fold (95% confidence interval, 1.3- to 3.4-fold) (P = 0.003). Estrogenic augmentation of rebound-like GH secretion was specific, because the pharmacological effects of exogenous GHRH (1 micro g/kg) and GH-releasing peptide-2 (1 micro g/kg, a synthetic ghrelin analog) were not affected. In summary, short-term supplementation with estradiol in postmenopausal individuals doubles the mass of rebound-like GH secretion induced by abrupt somatostatin withdrawal without modifying stimulation by a pharmacological dose of GHRH or GH-releasing peptide-2. Accordingly, we hypothesize that estradiol stimulates pulsatile GH secretion, at least in part, by enhancing the release and/or action of hypothalamic GHRH.