Rethinking progesterone regulation of female reproductive cyclicity

Abstract

The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity.progesterone | rat | reproductive cycles | PGR T he fundamental elements regulating the female reproductive cycle have been universally accepted for decades and include a hierarchy of control involving the hypothalamic/anterior pituitary/ ovarian axis (1,2). The hypothalamus, through its secretion of gonadotropin-releasing hormone, drives anterior pituitary production of gonadotropins [luteinizing hormone (LH) and folliclestimulating hormone (FSH)], which act on the ovaries to promote follicle development, ovulation, formation of the corpus luteum, and secretion of sex steroid hormones estrogen and progesterone. These two sex steroid hormones possess well-established actions on the female reproductive tract. At the core of the female reproductive cycle is a balance of sex steroid hormone negative and positive feedback regulation of gonadotropin secretion. Both estrogen and progesterone signaling pathways have been implicated in feedback control of gonadotropins and regulation of the female reproductive cycle (3-5). These concepts have been reinforced through phenotypic examination of mice possessing null mutations at either Esr1 or Pgr loci (6-8), and through the use of pharmacologic inhibitors of estrogen and progesterone signaling. Esr1 and Pgr encode the estrogen receptor 1 (also referred to as ER alpha) and progesterone receptor, respectively. These two nuclear receptors mediate many of the actions of estrogen and progesterone on the fe...

Transcriptomic signatures for ovulation in vertebrates

“…In Pgr knockout (Pgr-KO) female zebrafish mature oocytes were trapped within follicular cells unable to ovulate, leading to infertility. Our results are consistent with the complete anovulatory and infertile phenotype reported in PGR-KO mice and rats (Lydon et al, 1995; Kubota et al, 2016). These results prompted us to hypothesize that ovulation is controlled by conserved genes and signaling pathways in vertebrates.…”

Morphological, Histological and Immunohistochemical Study of the Rabbit Uterus during Pseudopregnancy

“…The physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed from a single gene as two protein isoforms; progesterone receptors alpha (PR-A) and progesterone receptors beta (PR-B) and that are members of the nuclear receptor superfamily (NRS) of transcription factors [23,24]. Several in vivo and in vitro studies have demonstrated that the PR-A and PR-B proteins have different transcription activation properties when liganded to progesterone [25][26][27][28][29][30][31][32]. These studies elucidated that the ablation of PR-A does not affect response of the mammary gland or thymus to progesterone but results in severe abnormalities in ovarian and uterine function leading to female infertility.…”

Thirty years of neuroendocrinology: Technological advances pave the way for molecular discovery

“…81 This use of CRISPR demonstrates how it can be used to help identify the outcomes resulting from certain mutations. CRISPR editing of the PR has recently questioned the importance of PR in the role of female reproductive cyclicity in rodents, 83 which remained despite other expected outcomes of PR deletion. 82 This could suggest another important use of CRISPR as a therapeutic target for prostate cancer.…”

“…82 This could suggest another important use of CRISPR as a therapeutic target for prostate cancer. CRISPR editing of the PR has recently questioned the importance of PR in the role of female reproductive cyclicity in rodents, 83 which remained despite other expected outcomes of PR deletion. This shows how CRISPR can be used to further decipher the roles of hormone receptors.…”