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

Abstract

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors 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 specifically 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, evidenced 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 females did not generate notable LH surges and expressed significantly blunted cfos induction in anterior ventral periventricular nucleus kisspeptin neurons, indicating that progesterone receptor signaling in kisspeptin neurons is required for normal kisspeptin neuronal activation and LH surges during positive feedback. Our novel findings demonstrate that progesterone signaling specifically in kisspeptin cells is essential for the positive feedback induction of normal LH surges, ovulation, and normal fertility in females.

The Role of Central Androgen Receptor Actions in Regulating the Hypothalamic-Pituitary-Ovarian Axis

“…These data are also similar to our previous report of reduced AVPV Kiss1 in the female global ARKO at proestrus [19]. These findings highlight the importance of AR signalling, which can now be added with progesterone receptor [44] and E2 signalling [45] as regulators of positive feedback induction of LH surges and ovulation. Interestingly, Kiss1 mRNA expression in the AVPV was also reduced during diestrus, indicating an overall reduction in expression or even neuron number.…”

Rethinking progesterone regulation of female reproductive cyclicity

“…Such observations are provocative. They contrast with the reported phenotype of Pgr mutant mice (19,20,29,30), insights gained from hormone replacement experiments (13,32), and the reported neuroendocrine actions of progesterone receptor antagonists (25)(26)(27)(28) and demand a rethinking of the hormonal control of reproductive cyclicity.…”

“…Variability in the mouse estrous cycle is often addressed by experimental simulations of specific estrous cycle events, including pheromone-activated LH surges and hormone-activated LH surges in ovariectomized mice. Pgr mutant mice show deficits in both pheromone-and hormone-activated LH surges (19,20,29,30). Because Pgr null rats exhibit robust and well-defined reproductive cycles, it is not necessary to artificially simulate events within the estrous cycle, making direct comparisons between mouse and rat Pgr mutants problematic.…”

Neuroprogesterone signals through Src kinase within RP3V neurons to induce the luteinizing hormone surge in female rats

“…As the rat cycle progresses into proestrus, estradiol concentrations rapidly rise inducing so-called estrogen positive feedback, in the afternoon, triggering the preovulatory LH surge that stimulating ovarian follicle ovulation and luteinization of the remaining follicular cells (Chazal, Faudon, Gogan, & Laplante, 1974). Positive feedback levels of estradiol induce hypothalamic astrocytes to synthesize neuroprogesterone (neuroP) that acts on induced PGR in neurons to release kisspeptin onto GnRH neurons triggering the LH surge (Mittelman-Smith, Wong, Kathiresan, & Micevych, 2015;Mittelman-Smith, Wong, & Micevych, 2018;Stephens et al, 2015;Zwain & Yen, 1999). Since the kisspeptin neurons that regulated the surge release of GnRH are located in the rostral periventricular region of the third ventricle (RP3V; (Clarkson & Herbison, 2006;Han et al, 2005;Liu, Lee, & Herbison, 2008;Wintermantel et al, 2006)), we hypothesized that neuroP acts on PGRs in these kisspeptin neurons to induce the LH surge (Delhousay, Chuon, Mittleman-Smith, Micevych, & Sinchak, 2019;Hu et al, 2015;Mittelman-Smith et al, 2018).…”

“…This hypothesis is supported by experiments that demonstrated estradiol stimulated neuroP in hypothalamic astrocytes, without which there is no LH surge. Significantly, PGRs are required to initiate and reach the full magnitude and duration of the LH surge (Mahesh & Brann, 1998;Micevych, Matt, & Go, 1981), the LH surge cannot be induced in PGR knockout mice (Chappell et al, 1999;Mahesh & Brann, 1992;Micevych et al, 2003), and the removal of PGR from kisspeptin neurons causes infertility, the loss of puberty, and loss of the LH surge (Stephens et al, 2015).…”