Peripheral estrogen receptor-alpha selectively modulates the waveform of GH secretory bursts in healthy women.
Estradiol (E(2)) drives growth hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ERalpha 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 ERalpha 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) E(2) 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 ERalpha-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity.
Veldhuis
Johannes D
JD
Endocrine Research Unit, Mayo Medical and Graduate Schools, Clinical Translational Research Unit, Mayo Clinic, Rochester, MN 55905, USA. Veldhuis.Johannes@mayo.edu
Keenan
Daniel M
DM
Bowers
Cyril Y
CY
D000279:Administration, Cutaneous; D000368:Aged; D001120:Arginine / Q000494:pharmacology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000097:blood / Q000378:metabolism*; D000077267:Fulvestrant; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D017698:Postmenopause; D013004:Somatostatin; D013997:Time Factors
D047628:Estrogen Receptor alpha; D009842:Oligopeptides; D000077267:Fulvestrant; D004958:Estradiol; D013004:Somatostatin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D001120:Arginine; C091874:growth hormone-releasing peptide-2