Short-Term Estradiol Supplementation Potentiates Low-Dose Ghrelin Action in the Presence of GHRH or Somatostatin in Older Women

Context: Ghrelin is a potent gastric-derived GH-releasing peptide. How ghrelin interacts with sex steroids, GHRH, and somatostatin (SS) is not known. Objective: Our objective was to test the hypotheses that ghrelin's interactions with GHRH (synergistic) and SS (disinhibitory) are ghrelin dose-dependent and amplified by estrogen. Subjects, Setting, and Design: Healthy postmenopausal women were treated with placebo (n = 12) or 17 beta-estradiol (E-2) (n = 12) at the Center for Translational Science Activities in a randomized double-blind prospective study. Methods: Ghrelin dose-dependence was assessed by nonlinear curve fitting of the relationship between deconvolved GH secretory-burst mass and 5 randomly ordered ghrelin doses (0, 0.03, 0.135, 0.6, and 2.7 mu g/kg bolus iv) during saline, GHRH, and SS infusion. Results: Under placebo, neither GHRH nor SS altered the ED50 of ghrelin (range 0.64-0.67 mu g/kg). Under E-2 (median E-2 88 pg/mL), the ED50 of ghrelin declined in the presence of GHRH to 0.52 mu g/kg. In contrast, the efficacy of ghrelin rose markedly during GHRH vs saline exposure with and without E-2: placebo and saline 52 +/- 1.0 vs GHRH 173 +/- 3.8 mu g/L; and E-2 and saline 56 +/- 0.90 vs GHRH 174 +/- 3.7 mu g/L. Sensitivity to ghrelin was similar under all conditions. Summary: Short-term E-2 supplementation in postmenopausal women reduces the ED50 (increases the potency) of ghrelin when GHRH is present, without altering ghrelin efficacy (maximal effect) or hypothalamo-pituitary sensitivity (slope of dose response) to ghrelin. The data suggest possible physiological interactions among sex steroids (endogenous), ghrelin, and GHRH during E-2 replacement in postmenopausal women.