Suruchi Thakore

Role of nuclear progesterone receptor isoforms in uterine pathophysiology

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.

Human IFNε: Spaciotemporal expression, hormone regulation and innate immunity in the female reproductive tract

Interferon epsilon (IFNε) plays an important role in regulating protective immunity in the female reproductive tract in mouse models; but the expression and regulation of this IFNε in the human FRT had not yet been characterised. Here we show that IFNε is selectively and highly expressed in the human FRT, a unique characteristic among the many types of IFN. IFNε has distinct expression patterns in upper compared with lower FRT where it is predominantly expressed in the basal layers of the stratified squamous epithelia. We demonstrate direct regulation of IFNε expression is suppressed by progesterone consistent with its inverse correlation with progesterone receptor expression, but only in the endometrium where its expression therefore fluctuates throughout the menstrual cycle. We show that IFNε regulates immunoregulatory IFN regulated genes (IRGs) in FRT epithelial cells. The characterisation of huIFNε expression in both the upper and the lower FRT epithelia and its protective properties make this IFN well placed to be an important player in mediating hormonal control of FRT immune response and susceptibility to FRT infection. Summary Bourke et al. characterise the novel type I interferon epsilon (IFNε), as the only IFN constitutively expressed throughout the human female reproductive tract (FRT), where it is hormonally regulated and modules IFN dependent FRT immunity.

Primary Ovarian Insufficiency: Current Concepts.

Abstract A potential consequence of chemotherapy is the destruction of oocytes, resulting in primary ovarian insufficiency (POI) in young patients; this often results in secondary amenorrhea and necessitates hormone replacement therapy. Regardless of the etiology of POI, the chance of pregnancy is low in this patient population. Given the extent to which oocyte depletion or dysfunction is variable, there is the possibility of spontaneous ovulation on hormone replacement therapy and subsequent pregnancy, however. If pregnancy is not desired, contraception always should be discussed. In most patients, the etiology of POI will not be known, but the treatment for all patients includes estrogen and progesterone therapy, which ensures the development of secondary sex characteristics, acquisition of peak bone mass, and promotion of uterine growth and maturation. Early diagnosis, patient education, and emotional support are important to mitigate long-term sequelae.