Hypothalamic progesterone receptor-A mediates gonadotropin surges, self priming and receptivity in estrogen-primed female mice

Ovarian progesterone (Prog) is an essential steroid hormone for the secretion of GnRH and reproductive behavior. It exerts primary effects through the progesterone receptor (PR). When analyzed separately in vitro, PR isoforms (PR-A, PR-B) display striking differences in transcriptional activity. The present study was undertaken to determine the in vivo impact of each isoform on hypothalamic function in female mice with ablation of a single isoform, either PR-A or PR-B. To this end, we used single-cell RNA analyses, reverse transcriptase real-time (q)PCR mRNA analyses of punched-out tissue, immunohistochemistry, and reproductive behavior. We provide evidence for the requirement of PR-A in individual ventrolateral ventromedial nucleus (vIVMN) neurons for Prog-facilitated proceptive and receptive behaviors in estrogen benzoate (EB)-primed females and the reciprocal male interactions. We clarify histological and molecular mechanisms of PR isoform activity by showing that (1) PR-A is predominant in individual vIVMN neurons controlling female lordosis circuitry, whilst (2) PR-B is predominant in those VMN subdivisions that provide for amplification of PR-A activity. We go on to demonstrate that PR-A is dominant in the anteroventral periventricular nucleus but not the arcuate nucleus that feed fibers into and around the VMN. In the medial preoptic area, high levels of GnRH RNA in EB-primed PR-A-expressing mice were seen coincident with increased plasma LH levels. Two consecutive GnRH pulses enhanced LH only in primed PR-A-expressing females. In all, the findings are consistent with the hypothesis that hypothalamic PR-A-mediated genomic activities result in reproductive behavior coordinated with ovulation.