Progesterone receptor in regulating Kisspeptin secretion

PCOS imageA subset of hypothalamic neurons releases a neuropeptide that stimulates GnRH neurons to secrete GnRH. This molecule, Kisspeptin, is a 10-amino acid long small peptide synthesized by a post-translational cleavage of a pro-peptide. Kisspeptin neurons are localized to two hypothalamic nuclei: anteroventral paraventricular nucleus (AVPV) and acute nucleus (ARC). Estrogens via its receptor, estrogen receptor alpha (ERĪ± or ESR1), positively regulate Kisspeptin secretion in the AVPV but negatively in the ARC. Upon stimulation by Kisspeptin, GnRH neurons release GnRH that in turn stimulates the pituitary gonadotrophs to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH) leading to ovarian follicle growth and ovulation.

PCOS imageProgesterone receptor (PGR) is a nuclear receptor transcription factor. In the ovary, PGR plays a critical role in ovulation and corpus luteum (CL) formation.  Formation of CL is necessary to support pregnancy by virtue of progesterone production by the newly formed CL. Progesterone also positively and negatively regulates the estrous cycle, likely through interactions with its receptor. In the hypothalamus, PGR is expressed in the Kisspeptin neurons in both the AVPV and ARC and its expression levels fluctuate during the estrous cycle.

In the Ko Laboratory, I am investigating the functional role that PGR plays in kisspeptin neurons. I hypothesize that PGR plays a critical role in releasing Kisspeptin. To facilitate the investigation, our laboratory developed a unique mouse model in which Pgr is deleted specifically in the Kisspeptin neurons. I find that the conditional Pgr knockout mice are born fertile, but lose fertility prematurely. In support of my hypothesis, these mice display a significantly lower basal serum LH level, indicating defective GnRH secretion presumably caused by reduced stimulation by its upstream regulation, Kisspeptin.