Oral Estradiol Administration Modulates Continuous Intravenous Growth Hormone (GH)-Releasing Peptide-2-Driven GH Secretion in Postmenopausal Women1

Exactly how estradiol (E2) regulates the human GH-insulin-like growth factor I axis is not known. Here, we explore the impact of oral E2 supplementation on the stimulatory actions of a potent and specific synthetic GH-releasing peptide (GHRP), GHRP-2. To this end, we studied 10 healthy postmenopausal women following the administration of placebo or 17beta-estradiol (1 mg twice daily orally) for 7-12 days in a prospectively randomized, double-blind, within-subject crossover design. To drive GH secretion via the GHRP-receptor/ effector pathway, we infused GHRP-2 (1 microg/kg x h) or saline continuously iv for 24 h. Deconvolution analysis was used to quantitate the separate basal and pulsatile modes of GH secretion based on 24-h serum GH concentrations profiles collected at 10-min intervals and assayed by chemiluminescence. As complementary (nonpulsatile) measures, we used the approximate entropy (ApEn) statistic and cosine regression to define feedback-dependent and circadian-related changes, respectively. E2 administration amplified the mass of GH secreted per burst by 1.9-fold over placebo, 24-h GHRP-2 infusion by 7.0-fold, and, the two agonists together by 8.8-fold (P < 10(-14)). Intravenous GHRP-2 infusion augmented the basal (nonpulsatile) rate of GH secretion by 4.4-fold (P < 10(-4)). E2 treatment had no effect alone, but doubled the stimulatory effect of GHRP-2, on basal GH secretion. Neither E2 nor GHRP-2 influenced 24-h GH pulse frequency, interburst interval, half-life or pulse duration. Combined E2 and GHRP-2 elevated the ApEn of GH secretory profiles significantly above control, thereby indicating a marked alteration of within-axis feedback control (P = 0.00033). Dual stimulation with E2 and GHRP-2 also synergistically increased the amplitude (by 11-fold, P < 10(-11)) and the mesor (by 10-fold, P < 10(-10)) of the 24-h GH rhythm. Infusion of GHRP-2 advanced the GH acrophase (time of daily maximum of GH release) by 8.75 h, whereas combined treatment with E2 and GHRP-2 normalized the acrophase. Cross-correlation analysis showed that GHRP-2 infusion (but not E2 administration) significantly synchronized paired 24-h serum GH concentration profiles (P < 10(-3)). In summary, short-term oral E2 replacement in post-menopausal women strongly modulates the actions of a synthetic hexapeptide GH secretagogue on three quantifiable modes of GH secretion [i.e. 1) basal (nonpulsatile) GH release; 2) feedback-dependent ApEn; and 3) the mesor, amplitude and timing of the 24-h GH rhythm]. Moreover, a continuous GHRP-2 stimulus also synchronizes inter diem GH secretory patterns. The present pharmacological study, thus, offers a further framework for exploring the nature of the interactions of E2 with the GHRP-receptor/effector pathway in the aging and/or gonadoprival human.