Background Estradiol (E₂) stimulates GH and prolactin secretion and suppresses FSH secretion in postmenopausal women. Whether CNS or pituitary mechanisms (or both) mediate such actions is not known.

Objective To distinguish between hypothalamic and pituitary or peripheral (hepatic) actions of E₂.

Setting Academic medical center.

Design Double-blind, prospectively randomized, placebo-controlled.

Methods The capability of a selective, noncompetitive, nonCNS-permeant estrogen receptor-alpha antagonist, fulvestrant (FUL), to antagonize the effects of transdermal E₂ and placebo (Pl) on GH, prolactin and FSH secretion were assessed in 43 women (ages 50–80 yr) in a 4 parallel-cohort study. Each woman received 4 secretagogue infusions to stimulate GH secretion. IGF-I and its binding proteins were measured secondarily.

Results Administration of Pl/E₂ increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by > 50% (each P 0.004 compared with Pl/Pl). Treatment with FUL/E₂ compared with Pl/E₂ partially relieved estrogen's inhibition of FSH secretion (P = 0.041), without altering E₂'s stimulation of prolactin secretion. ANOVA further revealed that: (i) estrogen milieu (P = 0.014) and secretagogue type (P < 0.001) each determined GH concentrations; (ii) FUL/Pl suppressed IGF-I concentrations (P < 0.001); (iii) FUL abrogated estrogen's elevation of IGFBP-1 concentrations (P < 0.001); and (iv) FUL did not oppose estrogen's suppression of IGFBP-3 concentrations (P < 0.001).

Summary and Conclusions Responses to a nonCNS-permeant ER antagonist indicate that E₂ inhibits FSH secretion in part via pituitary/peripheral ER, drives prolactin output via nonpituitary/nonperipheral-ER effects, and directs GH secretion and IGF-I-binding proteins by complex mechanisms.