Negative feedback effects of gonadal steroids are preserved with aging in postmenopausal women

There is now evidence for alterations in the neuroendocrine control of the reproductive axis with aging, but its sensitivity to gonadal steroid negative feedback remains controversial. To examine the independent effect of age and gonadal steroid negative feedback, younger (45-55 yr; n = 7) and older (70-80 yr; n = 6) postmenopausal women (PMW) were studied at baseline on no HRT, after 1 month of transdermal estrogen (50 microg/d; E) and again after a further month of E and 7 d of transvaginal progesterone (P) (100 mg bid; E + P). At each admission, blood was sampled every 5 min for 8 h for measurement of gonadotropin free alpha-subunit (FAS), which was used as a marker of GnRH pulse frequency. LH and FSH were measured in pooled samples. Midfollicular and midluteal phase levels of E2 and P were achieved during the E and E + P treatments and were not different between younger and older PMW. There was a negative feedback effect of E and E + P on mean LH (P < 0.0001) and an additional effect of age (P < 0.003), with older women having lower values throughout. Mean FSH was also decreased with E and E + P (P < 0.0001) and was consistently lower in the older women (P < 0.05). Mean FAS levels decreased with hormonal treatment (P < 0.0001) and age (P < 0.001), but the effect of hormonal treatment was attenuated in the older group (P < 0.005). FAS pulse frequency was unchanged with addition of E, but dramatically decreased with E + P (P < 0.002). Both hormonal replacement (P < 0.05) and age (P < 0.005) decreased FAS pulse amplitude, an effect that was attributable entirely to E as there was no additional change with E + P. These studies indicate that: 1) both age and gonadal steroids independently decrease mean LH, FSH, and FAS in PMW; 2) responsiveness to steroid negative feedback on FAS is attenuated with aging in absolute but not relative terms, whereas the effect on mean levels of LH and FSH is clearly preserved; and 3) FAS pulse frequency is unchanged with E2 administration but decreases dramatically with addition of P in both old and young PMW.