Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Abstract

Veldhuis JD, Keenan DM, Bowers CY. Peripheral estrogen receptor-␣ selectively modulates the waveform of GH secretory bursts in healthy women. Am J Physiol Regul Integr Comp Physiol 293: R1514-R1521, 2007. First published August 8, 2007; doi:10.1152 doi:10. /ajpregu.00438.2007 drives growth hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ER␣ is expressed in GH releasing hormone (GHRH) neurons and GH-secreting cells (somatotropes). Moreover, estrogen regulates receptors for somatostatin, GHR peptide (GHRP, ghrelin), and GH itself, while potentiating signaling by IGF-I. Given this complex network, one cannot a priori predict the selective roles of hypothalamic compared with pituitary ER pathways. To make such a distinction, we introduce an investigative model comprising 1) specific ER␣ blockade with a pure antiestrogen, fulvestrant, that does not penetrate the blood-brain barrier; 2) graded transdermal E 2 administration, which doubles GH concentrations in postmenopausal women; 3) stimulation of fasting GH secretion by pairs of GHRH, GHRP-2 (a ghrelin analog), and L-arginine (to putatively limit somatostatin outflow); and 4) implementation of a flexible waveform deconvolution model to estimate the shape of secretory bursts independently of their size. The combined strategy unveiled that 1) E 2 prolongs GH secretory bursts via fulvestrant-antagonizable mechanisms; 2) fulvestrant extends GHRH/GHRP-2-stimulated secretory bursts; 3) L-arginine/GHRP-2 stimulation lengthens GH secretory bursts whether or not E 2 is present; 4) E2 limits the capability of L-arginine/GHRP-2 to expand GH secretory bursts, and fulvestrant does not inhibit this effect; and 5) E 2 and/or fulvestrant do not alter the time evolution of L-arginine/GHRH-induced GH secretory bursts. The collective data indicate that peripheral ER␣-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity. somatotropin; ghrelin; growth hormone releasing hormone; somatostatin; secretagogues; female; human GROWTH HORMONE (GH) secretion is at least 90% pulsatile in the healthy human and strongly controlled by sex steroid hormones (17,19). Individual GH secretory bursts are believed to reflect the concerted effects of somatotrope stimulation by GH-releasing hormone (GHRH), inhibition by somatostatin (SS), and amplification by the potent GHR peptide (GHRP) ghrelin (14,45). Estrogen supplementation stimulates pulsatile GH secretion in postmenopausal women and girls with ovarian dysgenesis (32, 38). Putative mechanisms include the capability of estradiol (E 2 ) to potentiate GHRH drive (reduce the halfmaximally stimulatory dose), augment GHRP stimulation (increase apparent efficacy), and antagonize SS inhibition (increase the half-maximally inhibitory dose) (2, 5, 41, 43). The topographic sites at which estrogen exerts such effects are not known (45). However, E 2 can upregulate pituitary SS-type 2 and hypothalamic GHRP receptors and...

Novel Relationships of Age, Visceral Adiposity, Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein Concentrations to Growth Hormone (GH) Releasing-Hormone and GH Releasing-Peptide Efficacies in Men during Experimental Hypogonadal Clamp

“…Whether excessive hypothalamic SS release accounts for this abbreviation of GH secretory bursts in aging individuals is not known. However, our finding that higher E 2 concentrations predict more extended GHRP-2-induced (but not GHRH-induced) GH secretory bursts in the 25 men studied here emulates a similar relationship observed recently in postmenopausal women (35). The latter effect was reversed by an estrogen receptor-␣ blocker.…”

Relative effects of estrogen, age, and visceral fat on pulsatile growth hormone secretion in healthy women

“…Deconvolution analysis corroborated an earlier finding that E 2 is able to prolong GHRH-stimulated (albeit not GHRPstimulated) GH secretory-burst duration in POST women (51). Extended release of GH within individual secretory bursts could reflect a reduction in hypothalamic outflow of, or pituitary inhibition by, SS (54).…”