Sex Steroids, GHRH, Somatostatin, IGF-I, and IGFBP-1 Modulate Ghrelin's Dose-Dependent Drive of Pulsatile GH Secretion in Healthy Older Men

Abstract

Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant i.v. infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus i.v. doses of ghrelin (0.03, 0.135, 0.60, and 2.7 μg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-I on ghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.