VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice.

17α-estradiol (17α-E2) extends median lifespan and improves metabolic homeostasis in male mice through estrogen receptor α (ERα)-dependent mechanisms, but female mice are largely unresponsive unless ovariectomized or subjected to chronic high-fat feeding. Whether the gradual hormonal transition of natural reproductive aging similarly unmasks female responsiveness to 17α-E2 remains unknown. We tested whether 4-vinylcyclohexene diepoxide (VCD)-induced depletion of the ovarian reserve would render female mice responsive to 17α-E2 by treating wild-type (WT) and ERα knockout (ERαKO) littermates with VCD followed by 16 weeks of 17α-E2 administration. VCD-induced estropause was confirmed by elevated FSH, anestrus, and reduced ovarian size, but did not adversely affect metabolic phenotypes in WT mice. 17α-E2 treatment elicited modest improvements in adiposity and glucose tolerance, suppressed circulating IL-1β and IL-6, and reversed estropause-induced uterine atrophy in WT mice, but failed to rescue endometrial fibrosis. All 17α-E2-mediated effects were absent in ERαKO mice. These findings demonstrate that estropause does not unmask broad female responsiveness to 17α-E2 and indicate that the sex-specific actions of 17α-E2 extend beyond competitive receptor occupancy by endogenous 17β-E2.