Sam Mesiano

Background/Objectives: The objective of this exploratory study was to test the hypothesis that endometriosis is associated with altered abundance and cellular location of nuclear progesterone receptor (PR) isoforms in eutopic endometrium. Methods: Immunohistochemistry (IHC) was used to compare total PR (PR-A/B), PR-B, and pSer344/345-PR staining in endometrium from patients with and without endometriosis and between eutopic endometrium and ectopic endometriotic lesions in patients with endometriosis. Reproductive-age female patients undergoing laparoscopy for endometriosis (n = 10), or for other indications and without a diagnosis of endometriosis (n = 10), were included in this case–control study. Results: Eutopic endometrium from patients with endometriosis demonstrated increased total PR (PR-A/B) staining relative to PR-B staining compared with patients without endometriosis; a similar staining pattern was observed in ectopic lesions. Because PR-A was not measured directly and the total PR and PR-B antibodies may differ in affinity and dynamic range, these findings provide indirect evidence of altered relative PR isoform abundance rather than direct demonstration of a PR-A-dominant state. pSer344/345-PR staining did not differ significantly between groups, although a nonsignificant trend toward higher staining was observed in endometriosis. Conclusions: These preliminary findings support further study of PR isoform balance and site-specific phosphorylation in progesterone resistance associated with endometriosis.

Intrauterine infection and inflammation are major causes of preterm labor, yet antibiotics alone often fail to prevent preterm birth despite achieving microbial clearance. Interleukin1 (IL1) is a key mediator of intra-amniotic inflammation and functional progesterone withdrawal, processes linked to labor initiation. We tested whether IL1 blockade with the clinically approved IL1 receptor antagonist, anakinra, could reduce inflammation and preterm labor in a Rhesus macaque model of intra-amniotic Escherichia coli infection followed by delayed antibiotic treatment. Here we show that anakinra reduced the incidence of preterm labor by 40% (p=0.07), attenuated inflammation in the fetal membranes and cervix, and preserved progesterone receptor-B abundance in the fetal membranes. These effects were most pronounced in animals protected from preterm labor. Our findings in a relevant model support the translational potential of combining IL1 blockade with antibiotics for infection-associated preterm labor. One sentence summary: Recombinant human IL1 receptor antagonist (anakinra) decreased E. coli infection induced preterm labor and partially decreased intrauterine inflammation in a non-human primate model of inflammation mediated preterm labor.

Around 10% of global births are preterm (before 37 weeks of gestation), posing a significant challenge to maternal and neonatal health. Preterm infants face an increased risk of mortality and long-term health complications, impacting their survival and development across all life stages. Despite decades (~ 80 years) of research, effective methods to predict and prevent idiopathic or spontaneous preterm birth remain limited. Therefore, a deeper understanding of the pathophysiology of spontaneous preterm birth is warranted. This review explores some aspects of recent progress in unravelling the complex pathophysiology of both normal and preterm human birth. We present parturition as an inflammatory event, triggered by stressors affecting the uterine reproductive tissues (myometrium, decidua, and cervix), and involving multiple endocrine and paracrine pathways. These pathways, along with signals from fetal membrane senescence and the vaginal microbiome, contribute to labor induction. Proposed perspectives in parturition research include using mathematical modeling and machine learning (artificial intelligence) to map pregnancy trajectories and identify patient phenotypes associated with preterm birth risk. Additionally, incorporating preterm birth history into routine life course medical surveillance for affected individuals and their offspring is recommended. Finally, increased investment and prioritization from national funding bodies, along with greater support for international collaborations, are essential to identify the causes of preterm birth across multiple populations and develop new, effective treatments.

Parturition is a complex physiological process that must occur in a reliable manner and at an appropriate gestation stage to ensure a healthy newborn and mother. To this end, hormones that affect the function of the gravid uterus, especially progesterone (P4), 17β-estradiol (E₂), oxytocin (OT), and prostaglandins (PGs), play pivotal roles. P4 via the nuclear P4 receptor (PR) promotes uterine quiescence and for most of pregnancy exerts a dominant block to labor. Loss of the P4 block to parturition in association with a gain in prolabor actions of E₂ are key transitions in the hormonal cascade leading to parturition. P4 withdrawal can occur through various mechanisms depending on species and physiological context. Parturition in most species involves inflammation within the uterine tissues and especially at the maternal-fetal interface. Local PGs and other inflammatory mediators may initiate parturition by inducing P4 withdrawal. Withdrawal of the P4 block is coordinated with increased E₂ actions to enhance uterotonic signals mediated by OT and PGs to promote uterine contractions, cervix softening, and membrane rupture, i.e., labor. This review examines recent advances in research to understand the hormonal control of parturition, with focus on the roles of P4, E₂, PGs, OT, inflammatory cytokines, and placental peptide hormones together with evolutionary biology of and implications for clinical management of human parturition.

Although published studies have demonstrated that IFN-ε has a crucial role in regulating protective immunity in the mouse female reproductive tract, expression and regulation of IFN-ε in the human female reproductive tract (hFRT) have not been characterized to our knowledge. We obtained hFRT samples from a well-characterized cohort of women to enable us to comprehensively assess ex vivo IFN-ε expression in the hFRT at various stages of the menstrual cycle. We found that among the various types of IFNs, IFN-ε was uniquely, selectively, and constitutively expressed in the hFRT epithelium. It had distinct expression patterns in the surface and glandular epithelia of the upper hFRT compared with basal layers of the stratified squamous epithelia of the lower hFRT. There was cyclical variation of IFN-ε expression in the endometrial epithelium of the upper hFRT and not in the distal FRT, consistent with selective endometrial expression of the progesterone receptor and regulation of the IFNE promoter by progesterone. Because we showed IFN-ε stimulated important protective IFN-regulated genes in FRT epithelium, this characterization is a key element in understanding the mechanisms of hormonal control of mucosal immunity.