Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women

Abstract

Context: Studies in humans and animals indicate that estrogen negative feedback occurs at the level of the hypothalamus, but it is unclear whether estrogen also exerts an inhibitory effect directly at the pituitary.

Objectives: The aim of the study was to determine whether estrogen has a direct negative feedback effect at the pituitary and whether this varies with aging.

Design and setting: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness before and after estrogen administration in Clinical Research Center studies at an academic medical center.

Subjects: Subjects were healthy postmenopausal women aged 48-56 yr (n = 8) or 70-75 yr (n= 8).

Interventions: A suppressive dose of the NAL-GLU GnRH antagonist was administered, followed by graded doses of GnRH before and after 1 month of estrogen administration.

Results: LH and FSH responses to GnRH decreased after estrogen administration (P = 0.01 and P = 0.0001, respectively). The ratio of FSH to LH amplitudes decreased in response to estrogen (P = 0.04) indicating a greater sensitivity of FSH than LH to inhibition by estrogen. The inhibitory effect of estrogen on FSH was attenuated with aging (P = 0.02), but was maintained for LH (P = 0.4).

Conclusions: Studies that control for endogenous GnRH and estradiol demonstrate a direct pituitary site of estrogen negative feedback on LH and FSH responsiveness to GnRH in women. The effect of estrogen on FSH responsiveness is greater than on LH and is attenuated with aging. These studies indicate that estrogen negative feedback occurs directly at the pituitary and contributes to the differential regulation of FSH and LH secretion.

Trial registration: ClinicalTrials.gov NCT00386022.

Figure 1

Serum LH during the 28-h study before (closed circles) and after (open circles) 1 month of estrogen administration in representative younger and older subjects. Beginning at 0800 h, blood was sampled every 30 min for 4 h to assess baseline secretion. The subjects then received a sc injection of 150 μg/kg of the NAL-GLU GnRH antagonist. Seven hours after the injection, sampling frequency increased to every 10 min; 8 h after injection, GnRH doses of 25, 75, 250, and 750 ng/kg were administered iv in random order in 4-h intervals. Note the order of doses for both subjects as indicated. LH is expressed in international units per liter, as equivalents of the 2nd International Reference Preparation of human menopausal gonadotropins.

Figure 2

LH (upper panel) and FSH (lower panel) responsiveness to GnRH before and after 1 month of estrogen exposure, as indicated, in postmenopausal women (young and old combined), showing an inhibitory effect of estrogen on pituitary responsiveness to GnRH. Absolute LH and FSH amplitudes are shown in response to increasing doses of GnRH (25, 75, 250, and 750 ng/kg). LH and FSH amplitude are expressed in international units per liter, as equivalents of the 2nd International Reference Preparation of human menopausal gonadotropins.

Figure 3

The ratio of FSH to LH amplitude decreased in response to estrogen administration in postmenopausal women (younger and older combined) (P = 0.04), indicating a greater sensitivity of FSH than LH to estrogen negative feedback at the pituitary. *, P = 0.05; **, P < 0.01.

Figure 4

Change in LH (upper panel) and FSH (lower panel) responses to increasing doses of GnRH (25, 75, 250, and 750 ng/kg) after 1 month of estrogen administration in younger vs. older postmenopausal women indicates that aging attenuates the FSH (P < 0.02), but not the LH response (P = 0.4) to estrogen negative feedback at the pituitary.