Double Oestrogen Receptor α and β Knockout Mice Reveal Differences in Neural Oestrogen‐Mediated Progestin Receptor Induction and Female Sexual Behaviour

Abstract

To test the hypothesis that oestrogen receptor α (ERα) and ERβ act together to mediate the actions of oestrogen in the ventromedial hypothalamus (VMH), we used mice with single or double knockout mutations of the ERα and ERβ genes. Ovariectomized mice were implanted with 17β-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 ERβKO females. Analysis of specific VMH subregions revealed that PR-ir induction was limited to the caudal VMH in ERαKO and ERαβKO mice. In the rostral VMH, oestradiol only induced PR-ir in wild-type and ERβKO mice, and the number of PR-ir neurones in this region was greater in ERβKO than wild-type females. Next, we tested the ability of a dopamine agonist and progesterone to facilitate sexual behaviour in females lacking functional ERα, ERβ, 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. ERαKO and ERαβKO females failed to display lordosis under any testing conditions, while ERβKO 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 ERα and ERβ 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 ERα gene present in ERαKO brain. However, despite the presence of PR in VMH, females lacking a functional ERα gene do not display sexual behaviour, via either ligand-dependent or -independent activation.