Changes in pituitary sensitivity to GnRH in estrogen-treated post-menopausal women: evidence that gonadotrophin surge attenuating factor plays a physiological role

BACKGROUND: The purpose of this study was to investigate changes in pituitary response to GnRH in post-menopausal women during substitution treatment with exogenous estrogen and progesterone. METHODS: Seven healthy post-menopausal women (group 1) were treated with various doses of E2 valerate for 43 days, so as the serum concentrations of E2 mimicked those of a follicular (FP-1), a luteal (LP) and a second follicular (FP-2) phase. During the LP, progesterone was also administered. The 30 min response of LH (DeltaLH) and FSH (DeltaFSH) to GnRH (10 microg i.v.) (pituitary sensitivity) was investigated every 24 h in group 1 and also in seven normally cycling women (group 2) during a spontaneous (control) follicular phase (FP). Based on the hormone profiles, day 32 in group 1 (FP-2) corresponded to day 2 in the spontaneous FP of group 2. RESULTS: Basal FSH concentrations were significantly higher in FP-2 than in the control FP (P < 0.05), while basal LH concentrations were similar in the two phases with higher values in FP-2 towards the end of the experiment (corresponding to days 10 and 11, P < 0.05). However, an LH surge was seen only in the control FP. DeltaFSH values remained stable in both phases and increased only in the control FP on days 12 and 13. DeltaLH values remained stable in the control FP and only increased on days 12 (P < 0.05) and 13 (P < 0.05), but in FP-2, DeltaLH values increased earlier (corresponding to day 7, P < 0.05). CONCLUSIONS: The present study demonstrates for the first time that in the absence of ovarian function, follicular phase E2 concentrations sensitize the pituitary to GnRH at an earlier stage (corresponding to the midfollicular phase) than in the normal menstrual cycle (late follicular phase). It is suggested that during the early to midfollicular phase the ovaries produce a gonadotrophin surge attenuating factor (GnSAF) that antagonizes the pituitary-sensitizing effect of E2 to GnRH.