Absent Progesterone Signaling in Kisspeptin Neurons Disrupts the LH Surge and Impairs Fertility in Female Mice

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estro-gen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought tomediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone recep-tors and display enhanced neuronal activation during the LH surge. However, although estrogen regulation of kisspeptin neurons has been well studied, the role of progesterone signaling in regulating kisspeptin neurons is unknown. Here we tested whether progesterone action specifi-cally in kisspeptin cells is essential for proper LH surge and fertility. We used Cre-lox technology to generate transgenic mice lacking progesterone receptors exclusively in kisspeptin cells (termed KissPRKOs). Male KissPRKOs displayed normal fertility and gonadotropin levels. In stark contrast, female KissPRKOs displayed earlier puberty onset and significant impairments in fertility, evi-denced by fewer births and substantially reduced litter size. KissPRKOs also had fewer ovarian corpora lutea, suggesting impaired ovulation. To ascertain whether this reflects a defect in the ability to generate sex steroid-induced LH surges, females were exposed to an estradiol-positive feedback paradigm. Unlike control females, which displayed robust LH surges, KissPRKO female