UC San Diego

In mammals, fertility is intricately linked to the hypothalamic-pituitary-gonadal (HPG) axis, beginning with GnRH neurons in the hypothalamus. These neurons stimulate the pituitary to release LH and FSH hormones, thereby activating the gonads. Ovulation, crucial for female fertility, is triggered by an estrogen-induced GnRH/LH surge. Although the exact mechanisms of the LH surge are not fully understood, Kiss1 neurons, which synthesize kisspeptin, are believed to play a pivotal role. Specifically, research suggests that Kiss1 neurons in the hypothalamic rostral periventricular area of the third ventricle (RP3V) are key in mediating estrogen's positive feedback, which induces the preovulatory GnRH/LH surge. However, their direct involvement in ovulation has not been functionally validated. This study employs THCre/KissFlox transgenic mice to investigate the consequences of knocking down kisspeptin in RP3V neurons on the processes that drive ovulation. By reducing kisspeptin levels in the RP3V region by 50-70%, we observed a diminished estrogen-induced LH surge magnitude and likelihood, although this did not directly cause infertility. We then compared ovary-intact mice with ovariectomized (OVX) mice, both receiving estrogen implants, to further elucidate the roles of ovaries in LH surge regulation. Notably, a significant proportion of ovary-intact mice did not show an estrogen-induced LH surge, unlike the OVX mice, and the increased activation levels of RP3V Kiss1 neurons in OVX mice again implied the role of RP3V Kiss1 neurons in initiating the LH surge. In conclusion, our findings reinforce the hypothesis that RP3V kisspeptin neurons are crucial for initiating the estrogen-induced LH surge, with their inhibition potentially leading to a reduced or absent surge. This research contributes to a deeper understanding of the mechanisms underlying female fertility, in particular the processes that trigger ovulation.