title: 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.
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160; msoares@kumc.edu kkubota@kumc.edu.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Pramod
authors.initials: P
authors.lastname: Dhakal
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wolfe
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: M A Karim
authors.initials: MA
authors.lastname: Rumi
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Jay L
authors.initials: JL
authors.lastname: Vivian
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Roby
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160 msoares@kumc.edu kkubota@kumc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soares
mesh_terms: D000818:Animals; D005091:Exons; D005260:Female; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D011374:Progesterone / Q000235:genetics / Q000502:physiology*; D051381:Rats; D012098:Reproduction / Q000502:physiology*
chemical_list: D015735:Mifepristone; D011374:Progesterone; D007986:Luteinizing Hormone
keywords: PGR; progesterone; rat; reproductive cycles