Abstract
Ovarian steroids, estradiol and progesterone, play central roles in regulating female reproduction by acting as both positive and negative regulators of gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. Recent studies have identified kisspeptin neurons of the hypothalamus as the target of estrogenic regulation of GnRH secretion. In this study, we aimed to determine the significance of progesterone receptor (PGR) expression in the kisspeptin neurons. To this end, the Pgr gene was selectively ablated in mouse kisspeptin neurons and the reproductive consequence assessed. The hypothalamus of the Pgr deficient female mouse expressed kisspeptin, the pituitary released LH in response to GnRH stimulation, and the ovary ovulated when stimulated with gonadotropins. However, the mutant mouse gradually lost cyclicity, was unable to generate a LH surge in response to rising estradiol, and eventually became infertile. Taken together, these results indicate that the loss of PGR impairs kisspeptin secretory machinery and therefore that PGR plays a critical role in regulating kisspeptin secretion.
Highlights
The ovarian steroids estrogen and progesterone regulate the central female reproductive axis [1, 2]
We aimed to determine if kisspeptin neurons are the target of progesterone action in regulating gonadotropin-releasing hormone (GnRH) release
The reproductive consequences of the selective ablation of progesterone receptor (PGR) gene in the kisspeptin neurons reveal that PGR plays a critical role in the kisspeptin neuron in regulating GnRH secretion
Summary
The ovarian steroids estrogen and progesterone regulate the central female reproductive axis [1, 2]. Estrogen provides positive feedback to the hypothalamus in the late follicular phase that is necessary for the induction of the GnRH-mediated preovulatory luteinizing hormone (LH) surge, whereas during the rest of reproductive cycle it exerts negative feedback on the release of GnRH [2, 3]. Progesterone is necessary for the induction of the preovulatory LH surge [1], but otherwise exerts negative feedback on GnRH release during the rest of the estrous cycle [4,5,6]. Estradiol and progesterone feedback regulation of the hypothalamus is, in part, mediated through kisspeptin neurons [7]. Spontaneous mutation in the human kisspeptin receptor gene, GPR54, results in severe infertility (hypogonadotropic hypogonadism) [10]
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