Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women

Abstract

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 17β-estradiol (E2) (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 μg/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 μg/kg). Under E2 (median E2 88 pg/mL), the ED50 of ghrelin declined in the presence of GHRH to 0.52 μg/kg. In contrast, the efficacy of ghrelin rose markedly during GHRH vs saline exposure with and without E2: placebo and saline 52±1.0 vs GHRH 173±3.8 μg/L; and E2 and saline 56±0.90 vs GHRH 174±3.7 μg/L. Sensitivity to ghrelin was similar under all conditions.

Summary: Short-term E2 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 E2 replacement in postmenopausal women.

Figure 1.

Schema of study protocol designed to estimate ghrelin dose-dependence in the presence of continuous saline, GHRH, or SS infusions.

Figure 2.

Non-decoded mean GH concentrations measured every 10 minutes for 19 hours overnight. Data comprise 6-hour baseline sampling (10:00 pm 4:00 am) followed by 13-hour subsequent sampling with 4 bolus iv ghrelin injections administered in randomized order every 3 hours (5:00 am, 8:00 am, 11:00 am, and 2:00 pm). Ghrelin pulses were superimposed upon constant iv infusions of saline, GHRH, or SS. Data are from 12 women treated with leuprolide plus placebo and 12 others treated with leuprolide plus E₂.

Figure 3.

Bar graphs of (mean ± SEM) summed GH secretory-burst mass (y axis) as a function of ghrelin dose (x axis). Stated P values are two-way ANCOVA estimates. Different letters denote significantly different means by peptide type. *, P < .01 for E₂ vs placebo by Tukey's test.

Figure 4.

Estimated ED₅₀ and efficacy values along with 95% CI values for ghrelin dose-response functions in 12 women given placebo and 12 others given E₂. Means with different letters differ at P < .05 by Tukey's multiple-comparison test.