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Pituitary and/or Peripheral Estrogen-Receptor Regulates Follicle-Stimulating Hormone Secretion, Whereas Central Estrogenic Pathways Direct Growth Hormone and Prolactin Secretion in Postmenopausal Women

Endocrine Research Unit (M.C., J.B., J.M.M., J.D.V.), Department of Internal Medicine, Clinical Translational Science Unit, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Division of Endocrinology (C.Y.B.), Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Clinical Translational Science Unit, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Background: Estradiol (E₂) 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)- 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 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 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.

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