Oral estradiol administration modulates continuous intravenous growth hormone (GH)-releasing peptide-2-driven GH secretion in postmenopausal women

Exactly how estradiol (E-2) regulates the human GH-insulin-like growth fact or I axis is not known. Here, we explore the impact of oral E-2 supplementa tion on the stimulatory actions of a potent and specific synthetic GH-relea sing peptide (GHRP), GHRP-2. To this end, we studied 10 healthy postmenopau sal women following the administration of placebo or 17 beta -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 mug/kg .h) or saline contin uously iv for 24 h. Deconvolution analysis was used to quantitate the separ ate basal and pulsatile modes of GH secretion based on 24-h serum GH concen trations profiles collected at 10-min intervals and assayed by chemilumines cence, As complementary (nonpulsatile) measures, we used the approximate en tropy (ApEn) statistic and cosine regression to define feedback-dependent a nd circadian-related changes, respectively. E-2 administration amplified th e mass of GH secreted per burst by 1.9-fold over placebo, 24-h GHRP-2 infus ion by 7.0-fold, and, the two agonists together by 8.8-fold (P < 10(-14)). Intravenous GRRP-2 infusion augmented the basal (nonpulsatile) rate of GH s ecretion by 4.4-fold (P < 10(-4)). E-2 treatment had no effect alone, but d oubled the stimulatory effect of GHRP-2, on basal GH secretion. Neither E-2 nor GHRP-2 influenced 24-h GH pulse frequency, interburst interval, half-l ife or pulse duration. Combined E-2 and GHRP-2 elevated the ApEn of GH secr etory profiles significantly above control, thereby indicating a marked alt eration of within-ads feedback control (P = 0.00033). Dual stimulation with E-2 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 r elease) by 8.75 h, whereas combined treatment with E-2 and GHRP-2 normalize d the acrophase. Cross-correlation analysis showed that GHRP-2 infusion (bu t not E, administration) significantly synchronized paired 24-h serum GH co ncentration profiles (P < 10(-3)). In summary, short-term oral E-2 replacement in post-menopausal women strong ly modulates the actions of a synthetic hexapeptide GH secretagogue on thre e quantifiable modes of GH secretion [i.e. 1)basal (nonpulsatile) GH releas e; 2) feedback-dependent ApEn; and 3) the mesor, amplitude and timing of th e 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 E-2 with the GHRP-receptor/effector pathway in the aging and/or gonadopriv al human.