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Progestin-based therapy is the first-line treatment for managing endometriosis-associated pain. However, response to progestins is currently variable and unpredictable. Predictive markers for response to progestin-based therapy would allow for a personalized approach to endometriosis treatment. We hypothesize that progesterone receptor (PR) levels in endometriotic lesions determine response to progestin-based therapy. Retrospective cohort study. Academic center. Fifty-two subjects with histologically confirmed endometriosis and a previous documented response to hormonal therapy were included. Immunohistochemistry was performed on sections of endometriotic lesions using a rabbit polyclonal IgG for detection of PR-A/B. The Histo (H)-score was used for quantifying PR status. Response to progestin-based therapies was determined from review of the electronic medical record. H-score was higher in responders compared with nonresponders. Subjects were categorized into three groups: high (H-score > 80, n = 7), medium (H-score 6 to 80, n = 28), and low (H-score ≤ 5, n = 17) PR status. The threshold of PR > 80 was associated with a 100% positive predictive value. The threshold of PR < 5 was associated with a 94% negative predictive value. PR status is strongly associated with response to progestin-based therapy. Receptor status in endometriosis could be used to tailor hormonal-based regimens after surgery, and negate trialing progestin-based therapy to determine resistance. Ascertainment of PR status may allow for a novel, targeted, precision-based approach to treating endometriosis.

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools. Boretto et al. demonstrate that organoids derived from patients with various types of endometrial pathologies can model disease traits and diversity, and can be used as a drug-screening tool.

Successful pregnancy requires the establishment of a complex dialogue between the implanting embryo and the endometrium. Knowledge regarding molecular candidates involved in this early communication process is inadequate due to limited access to primary human endometrial epithelial cells (EEC). Since pseudo-pregnancy in rodents can be induced by mechanical scratching of an appropriately primed uterus, this study aimed to investigate the expression of mechanosensitive ion channels in EEC. Poking of EEC provoked a robust calcium influx and induced an increase in current densities, which could be blocked by an inhibitor of mechanosensitive ion channels. Interestingly, RNA expression studies showed high expression of PIEZO1 in EEC of mouse and human. Additional analysis provided further evidence for the functional expression of PIEZO1 since stimulation with Yoda1, a chemical agonist of PIEZO1, induced increases in intracellular calcium concentrations and current densities in EEC. Moreover, the ion channel profile of human endometrial organoids (EMO) was validated as a representative model for endometrial epithelial cells. Mechanical and chemical stimulation of EMO induced strong calcium responses supporting the hypothesis of mechanosensitive ion channel expression in endometrial epithelial cells. In conclusion, EEC and EMO functionally express the mechanosensitive PIEZO1 channel that could act as a potential target for the development of novel treatments to further improve successful implantation processes.

Endometriosis-associated pain has debilitating effects on the quality of life of patients. Despite its high prevalence in reproductive-aged women, the pathophysiology is still unknown, impeding the development of targeted treatment approaches. The prospective ExPAND study proposes the neurosteroids pregnenolone sulphate (PS) and dehydroepiandrosterone sulphate (DHEAS) as potential contributors to endometriosis-associated pain, due to their agonistic action at the pain-related ion channel TRPM3. To this end, endometrium, deep endometriosis lesions, and peritoneal fluid were prospectively collected in four demarcated patient groups, which were characterised based on their pain symptoms, as scored via the WERF-EPHect questionnaire, i.e., (1) control (n = 44), (2) endometriosis patients with no pain symptoms (n = 24), (3) with only severe dysmenorrhea (n = 54), or (4) with both severe dysmenorrhea and non-cyclic pelvic pain (n = 78). Tissue mRNA expression levels of steroidogenic enzymes were investigated and showed significantly increased levels of CYP17A1 in the endometrium of patients with severe pain symptoms compared to control tissue. In addition, liquid chromatography with tandem mass spectrometry (LC-MS/MS) was performed to investigate neurosteroid concentrations in the peritoneal fluid. Both neurosteroids PS and DHEAS were present in the peritoneal fluid at concentrations that are known to stimulate TRPM3 activity in vitro. Finally, using microfluorimetric Ca2+ imaging, we demonstrate that both DHEAS and PS stimulate human stem-cell-derived sensory neurons in a TRPM3-dependent manner. Taken together, these data indicate a potential contribution of steroidogenesis and TRPM3 in endometriosis-associated pain.

Background Endurance exercise has the potential to affect reproductive function, with amenorrhea in female athletes. However, most studies focus on women. Evidence on the association between endurance exercise and male fertility is limited. Objective To synthesise existing literature on exercise-induced alterations in semen parameters and to assess the clinical impact on male fertility. Methods Studies reporting on the association between semen parameters and endurance exercise in healthy men were eligible. Men attending fertility clinics were excluded. We searched MEDLINE (PubMed), Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) from their inception to May 28th 2022. JBI Critical Appraisal Tool was used to assess the potential risk of bias. Results Thirteen studies met inclusion criteria, reporting on 280 subjects. Eight articles reported on endurance runners, three on cyclists and four on triathletes. Four studies did not find any statistically significant sperm alterations. Five reported significant changes in semen parameters, but these were not clinically relevant, as semen parameters remained well above World Health Organisation (WHO) thresholds. Four articles reported a decrease in semen quality with potential clinical consequences as they found a reduced number of sperm cells exhibiting normal morphology in cyclists and triathletes and a greater amount of DNA fragmentation in triathletes. Conclusion Endurance exercise can have a negative effect on semen quality, although rarely with a clinically relevant impact on male fertility. Evidence is however limited, with poor quality of the included studies. Registration : PROSPERO International prospective register of systematic reviews (CRD42022336753). Key Points Results suggest that endurance exercise can decrease semen quality, although without a clinically relevant impact on male fertility potential. The available evidence is limited and lacks comparability due to poor methodology. High quality studies are necessary to further assess the relationship between endurance exercise and semen quality.

The aim of this systematic review is to assess the power of circulating miRNAs as biomarkers as a diagnostic tool in endometriosis. In endometriosis-suspected women with uncertain imaging, the only way to confirm or exclude endometriosis with certainty is currently laparoscopy. This creates a need for non-invasive diagnostics. We searched the literature through the PubMed database using the Mesh terms ‘endometriosis’ and ‘miRNAs’. Some, but limited, overlap was found between the 32 articles included, with a total of 20 miRNAs reported as dysregulated in endometriosis in two or more studies. MiR-17-5p was reported as dysregulated in six studies, followed by miR-451a and let-7b-5p in four studies and miR-20a-5p, miR-143-3p, miR-199a-5p and miR-3613-5p in three studies. Furthermore, a possible impact of the menstrual phase on miRNA expression was noted in five studies, while no influence of hormonal intake was observed in any included study. The modest reproducibility between studies may be attributable to biological variability as well as to the lack of universal protocols, resulting in pre- and analytical variability. Despite the identification of several suitable candidate biomarkers among the miRNAs, the need for high-quality studies with larger and well-defined population cohorts and the use of standardized protocols lingers.

Endometriosis is a common gynecological disease that is characterized by the presence of functional endometrial-like lesions in the abdominal cavity. Aside from epithelial cells, these lesions consist of stromal cells that have the capacity to migrate, adhere, proliferate, and induce neuro- and lymphangiogenesis, which allows them to survive at ectopic locations. However, the exact underlying mechanisms that regulate these changes are yet to be elucidated. The common ground of these processes, however, is the second messenger, calcium. In this regard, members of the superfamily of transient receptor potential (TRP) ion channels, which are known to be calcium-permeable and expressed in the endometrium, have emerged as key regulators. Here, we assessed the molecular and functional expression of TRP channels in stromal cells isolated from the eutopic endometrium of endometriosis patients and controls. Using RT-qPCR, high mRNA levels of TRPV2, TRPV4, TRPM4, TRPM7, TRPC1, TRPC3, TRPC4, and TRPC6 were observed in the whole endometrium throughout the menstrual cycle. Additionally, and in line with previous reports of control patients, TRPV2, TRPV4, TRPC1/4, and TRPC6 were present in human endometrial stromal cells (hESC) from endometriosis patients both at the molecular and functional level. Moreover, proliferation and migration assays illustrated that these parameters were not affected in stromal cells from endometriosis patients. Furthermore, comparison between eutopic and ectopic endometrial samples revealed that the RNA expression pattern of TRP channels did not differ significantly. Collectively, although a functional expression of specific ion channels in hESCs was found, their expression did not correlate with endometriosis.

Endometriosis is an important gynecological disease, affecting 10% of reproductive age women, and associated with pain, infertility, reduced quality of life, and high health economic cost. Except for ultrasound detection of ovarian endometriotic cysts, the gold standard for diagnosis is laparoscopy, leading to diagnostic delays of 5–10 years. Accurate noninvasive biomarkers are needed, especially for symptomatic women with a normal gynecological ultrasound, to triage them towards medical or surgical treatment and to monitor their treatment outcome. Such biomarkers are not available today, largely because the research focus has been on discovery, not on reproducibility and validation. Academia/industry partnerships can move this field forward by validation of promising markers, consensus on endometriosis phenotypes/controls and desirable accuracy (sensitivity/specificity). Such partnerships should increase the quality and reproducibility of target discovery work and foster global consensus on the use of relevant preclinical/animal models, if they are managed with complete (financial) transparency and with the aim to translate innovation into products benefiting patients. It is essential that mutual objectives are clarified between industry and academia partners including intellectual property policy, critical decision points, funding agreements, milestones and timelines, with a clear strategy for project termination/change of strategy, a restriction on publications till new discoveries have been patented, considering that a minority of novel findings can be translated into new therapeutic targets, diagnostics, or marketed products. Summary Sentence Academia–industry partnerships are needed to translate innovation via validation to robust noninvasive biomarker assays for the diagnosis of endometriosis.