Deletion of Nuclear Progesterone Receptors From Kisspeptin Cells Does Not Impair Negative Feedback in Female Mice

Reproductive function in mammals depends on the ability of progesterone (P4) to suppress pulsatile gonadotrophin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in a homeostatic-negative feedback loop. Previous research identified that cells upstream from GnRH neurons expressing the nuclear progesterone receptor (PGR) are required for P4-negative feedback. However, the identity of these cells and the mechanism by which they reduce GnRH/LH pulsatile secretion is unknown. We aimed to address the hypothesis that PGR expressed by a neural population in the arcuate nucleus recently identified as the GnRH pulse generator, cells expressing kisspeptin, neurokinin B, and dynorphin (KNDy cells), mediate P4-negative feedback. To achieve this, we used female mice with the PGR gene conditionally deleted from kisspeptin cells (KPRKO mice) and observed a substantial decrease in the percentage of KNDy neurons coexpressing PGR messenger RNA (mRNA) (11% in KPRKO mice vs 86% in wild-type [WT] mice). However, KPRKO mice did not display changes in the frequency or amplitude of LH pulses in diestrus or estrus, nor in the ability of exogenous P4 to blunt a postcastration increase in LH. Further, mRNA expression of arcuate kisspeptin and dynorphin, which are excitatory and inhibitory to GnRH secretion, respectively, remained unaltered in KPRKO mice compared to WT controls. Together, these findings show that the near-complete loss of PGR signaling from KNDy cells does not affect negative feedback regulation of GnRH pulse generation in mice, suggesting that feedback through this receptor can occur via a small number of KNDy cells or a yet unidentified cell population.