Role of nuclear progesterone receptor isoforms in uterine pathophysiology

Abstract

Background: Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function.

Methods: Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed.

Results: Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain.

Conclusions: PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies.

Keywords: progesterone; progesterone receptors; uterine pathophysiology.

Figure 1

Structure of the human PR isoforms produced from the PGR gene. The major mRNA transcripts are derived from translational start sites controlled by the PR-B (distal) and PR-A (proximal) promoters. The major proteins products (boxed) are the full-length PR-B produced from PR-B mRNA and initiated from the first AUG, and the PR-A which is produced from PR-A mRNA and initiated from the second AUG. The receptors contain functional domains that are typical of the nuclear receptors family. The structures of other putative splice variants are shown below the boxed area.

Figure 2

Genomic signaling pathways for PR action. In response to ligand, PRs undergo a conformational change and dimerize. The receptors then translocate to the nucleus where they function as ligand-activated transcription factors. The receptors also activate cytoplasmic signaling cascades such as the ERK/MAPK pathway by interacting directly with extranuclear signaling molecules. BTA, basal transcriptional apparatus; CR, co-regulators.

Figure 3

Functional interaction between PR-A and PR-B. Upon ligand binding, the receptors form transcriptionally active homo- and hetero-dimers that affect the expression of specific and common gene sets. PR-A also acts as a trans-repressor of PR-B at some promoters.

Figure 4

(A) Sites for known serine phosphorylation and ubiquitination/sumoylation in PR-A and PR-B that are induced in response to ligand binding and/or in response to growth factors and other kinases. (B) It is proposed that post-translational modifications (PTMs) affect the targeting of ligand-activated PRs to specific gene promoter classes. This mechanism explains how the PRs mediate pleiotropic actions of progesterone in different cell types and different physiologic conditions.

Figure 5

Immunohistochemical localization of PR-A and PR-B at the human myometrial/endometrial interface during the secretory phase of the menstrual cycle. Total PR (PR-A and PR-B) was detected with antibody PgR1294 (Dako Corp) that reacts with an epitope in the N-terminal region common to both PR-A and PR-B. PR-B was detected with antibody C1A2 (Cell Signaling, Inc.) that reacts with an epitope in the N-terminus unique to PR-B. IgG represents the negative control using the non-immune immunoglobulin of the same isotype as the PgR1294 (mouse) and C1A2 (rabbit) primary antibodies. Positive staining is indicated by brown coloration. Sections were counterstained with hematoxylin (stains nuclei blue). Magnification = ×200.