Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice.

ABSTRACT

Mice, rats, and humans have two types of estrogen receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). Estrogen receptor-alpha gene-disrupted (ERalpha-disrupted) mice bear two nonfunctional copies of the ERalpha gene. This mutation blocks the synthesis of full-length ERalpha, renders the animals infertile, and inhibits the induction of female sexual behaviors by estradiol and progesterone. It is likely that many of the processes contributing to the regulation of sexual receptivity by estradiol and progesterone are compromised in ERalpha-disrupted mice. However, given the importance of progesterone in the regulation of sexual receptivity and given the importance of progestin receptors (PRs) in mediating the responses of females to progesterone, we investigated the effects of ERalpha disruption on the induction of PRs by estradiol in the forebrain. We hypothesized that estradiol would induce PRs in wild-type mice but not in ERalpha-disrupted mice. Ovariectomized wild-type and ERalpha-disrupted mice were implanted with either estradiol-filled capsules or empty capsules for 5 d, after which their brains were processed for the immunocytochemical detection of PR. Estradiol increased the number of PR-immunoreactive cells in both wild-type and ERalpha-disrupted mice. The residual responsiveness of ERalpha-disrupted mice to estradiol could be accounted for by an ERbeta-dependent mechanism or another as yet unidentified estrogen receptor; however, because ERalpha-immunoreactivity and PCR product representing the 3' end of ERalpha mRNA were found in at least one PR-containing region of the ERalpha-disrupted mice, an ERalpha splice variant may also mediate the induction of PR-immunoreactivity in ERalpha-disrupted mice.