Pituitary and/or peripheral estrogen-receptor α regulates follicle-stimulating hormone secretion, whereas central estrogenic pathways direct growth hormone and prolactin secretion in postmenopausal women

Background: Estradiol (E-2) stimulates GH and prolactin secretion and suppresses FSH secretion in postmenopausal women. Whether central nervous system (CNS) or pituitary mechanisms ( or both) mediate such actions is not known. Objective: Our objective was to distinguish between hypothalamic and pituitary or peripheral (hepatic) actions of E-2. Setting: This study was performed in an academic medical center. Design: This was a double-blind, prospectively randomized, placebo (Pl)-controlled study. Methods: The capability of a selective, noncompetitive, non-CNS permeant estrogen receptor (ER)-alpha antagonist, fulvestrant (FUL) to antagonize the effects of transdermal E-2 and Pl on GH, prolactin, and FSH secretion was assessed in 43 women (ages 50-80 yr) in a four parallel-cohort study. Each woman received four secretagogue infusions to stimulate GH secretion. IGF-I and its binding proteins were measured secondarily. Results: Administration of Pl/E-2 increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by more than 50% ( each P <= 0.004 compared with Pl/Pl). Treatment with FUL/E-2 compared with Pl/E-2 partially relieved estrogen's inhibition of FSH secretion (P = 0.041), without altering E-2's stimulation of prolactin secretion. ANOVA further revealed that: 1) estrogen milieu (P = 0.014) and secretagogue type (P < 0.001) each determined GH concentrations; 2) FUL/Pl suppressed IGF-I concentrations (P < 0.001); 3) FUL abrogated estrogen's elevation of IGF binding protein-1 concentrations (P < 0.001); and 4) FUL did not oppose estrogen's suppression of IGF binding protein-3 concentrations (P < 0.001). Summary and Conclusions: Responses to a non-CNS permeant ER alpha antagonist indicate that E-2 inhibits FSH secretion in part via pituitary/peripheral ER alpha, drives prolactin output via nonpituitary/nonperipheral-ER alpha effects, and directs GH secretion and IGF-I-binding proteins by complex mechanisms.