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

Abstract

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 E2.

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 E2 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/E2 increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by more than 50% (each P<or=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: 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 ERalpha antagonist indicate that E2 inhibits FSH secretion in part via pituitary/peripheral ERalpha, drives prolactin output via nonpituitary/nonperipheral-ERalpha effects, and directs GH secretion and IGF-I-binding proteins by complex mechanisms.

Figure 1

Schema of volunteer recruitment and protocol randomization with time line of procedures followed in 43 postmenopausal women (Subjects and Methods). **, Continuous infusion.

Figure 2

E₂ concentrations monitored every 4 d during outpatient escalation of the transdermal E₂ dose. Data are the mean ± sem in which N indicates group size. FUL had no effect on E₂ profiles. Multiply E₂ concentration by 3.67 to convert pg/ml to pmol/liter. none, Absence of any E₂ patch; Pl, inactive vehicle for FUL.

Figure 3

Effects of Pl/Pl, Pl/E₂, FUL/Pl, and FUL/E₂ on secretagogue-induced increments in GH concentrations in postmenopausal women. Data are the mean ± sem. Columns surmounted by different (unshared) alphabetical superscripts have significantly different means as tested by Tukey’s HSD test (e.g. A differs from B, but not from AB).

Figure 4

Absolute decrements in FSH and LH (top panel) and increments in prolactin and SHBG (bottom panel) concentrations compared with baseline (no drug or hormone exposure). Treatment was with E₂, Pl, and/or FUL. Data are the mean ± sem. P values denote overall interventional effects assessed by one-way ANOVA. Uppercase letters apply to FSH and prolactin data, and lowercase to LH and SHBG data. Means with no shared alphabetical superscripts differ significantly by the post hoc Tukey HSD test (e.g. A differs from B or C, but not from AB).

Figure 5

Incremental or decremental changes in fasting concentrations of IGF-I (A), IGFBP-1 (B), and IGFBP-3 (C) during outpatient escalation of transdermal E₂ doses, and administration of Pl and/or FUL. The overall P value is based upon two-way ANOVA. Significant contrasts are denoted by different (unshared) alphabetical superscripts at the end of each row (e.g. B differs from A and C, but not from BC). Data are the mean ± sem. Increments were calculated as the difference between the concentration on the indicated day and that on the first day of Pl or E₂ administration.

Figure 6

Model of proposed sites of action of E₂ and FUL on GH, FSH, and prolactin secretion inferred from the assumption that FUL does not cross the blood-brain barrier. Estrogen’s stimulation of both GH and prolactin secretion includes CNS (FUL resistant) pathways, whereas its inhibition of FSH secretion includes both brain and pituitary (FUL antagonized) mechanisms.