Double oestrogen receptor alpha and beta knockout mice reveal differences in neural oestrogen-mediated progestin receptor induction and female sexual behaviour.

To test the hypothesis that oestrogen receptor alpha (ERalpha) and ERbeta act together to mediate the actions of oestrogen in the ventromedial hypothalamus (VMH), we used mice with single or double knockout mutations of the ERalpha and ERbeta genes. Ovariectomized mice were implanted with 17beta-oestradiol and killed 5 days later. Oestradiol treatment promoted progestin receptor (PR)-immunoreactivity (-ir) in the VMH of all genotypes, but was maximal in brains of wild-type and ERbetaKO females. Analysis of specific VMH subregions revealed that PR-ir induction was limited to the caudal VMH in ERalphaKO and ERalphabetaKO mice. In the rostral VMH, oestradiol only induced PR-ir in wild-type and ERbetaKO mice, and the number of PR-ir neurones in this region was greater in ERbetaKO than wild-type females. Next, we tested the ability of a dopamine agonist and progesterone to facilitate sexual behaviour in females lacking functional ERalpha, ERbeta, or both receptors. Ovariectomized mice were implanted with oestradiol, and tested for sexual behaviour three times after administration of the dopamine agonist, apomorphine, followed by two tests concurrent with progesterone treatment and a final test with just apomorphine treatment. ERalphaKO and ERalphabetaKO females failed to display lordosis under any testing conditions, while ERbetaKO females exhibited lordosis behaviour equal to that of wild-type females. Our data show that a subpopulation of PR-ir neurones is induced by oestradiol in the caudal VMH of female mice lacking both ERalpha and ERbeta genes. We hypothesize that this action of oestradiol is either mediated by a novel ER or by the mutant portion of the AF2 subregion of the ERalpha gene present in ERalphaKO brain. However, despite the presence of PR in VMH, females lacking a functional ERalpha gene do not display sexual behaviour, via either ligand-dependent or -independent activation.