Valencian Infertility Institute

IntroductionThe uterus exhibits dynamic peristaltic activity across the menstrual cycle, playing a critical role in reproductive processes such as sperm transport and embryo implantation. However, current imaging methods to assess this activity provide little information and are limited by subjectivity and lack of sensitivity. A recent pilot study has shown the potential of intracavitary electrohysterography (IC‐EHG) to study peristalsis in the uterine fundus. This study aimed to generalize previous results, compare peristalsis in other uterine regions, and study more peristaltic features.Material and MethodsThis prospective multicenter cohort study included 40 healthy women with proven fertility. IC‐EHG signals were recorded from different uterine sites for 30 min during three menstrual phases: mid‐follicular (MF), early luteal (EL), and late luteal (LL) using a custom‐designed multipolar catheter. Primary outcomes: contraction frequency (CT/min) and amplitude (μV); secondary outcomes: basal amplitude, contraction time percentage, contractility index and local organization index. Statistical comparisons between phases and regions were performed using Wilcoxon signed‐rank tests.ResultsA total of 95 fundal and 90 lower‐segment IC‐EHG recordings were analyzed. Contraction frequency peaked during the EL phase (fundus: 3.91 CT/min; lower segment: 4.01 CT/min) and was lowest during MF (fundus: 3.28 CT/min, p = 0.042; lower segment: 3.65 CT/min, p = 0.024). Fundal contraction amplitude decreased progressively from MF (16.27 μV) to LL phase (10.56 μV, p < 0.001). Basal amplitude, contraction time percentage and contractility index were also lowest in the LL phase for both uterine regions. Except for frequency, fundus peristaltic activity features were smaller than those of the lower segment, significantly during the MF phase. Local coordination index revealed lower local cell organization in the fundus across all phases, with maximum coordination during EL in both regions (p < 0.01).ConclusionsIC‐EHG technique enables objective, reproducible, and quantitative assessment of multiple aspects of uterine peristalsis, revealing distinct regional and cycle‐phase–dependent patterns. The decline in most contractile features during the LL phase supports the physiological uterine quiescence required for embryo implantation. The uterine fundus is more active during the MF phase. This study provided reference values for healthy, fertile conditions and could inform further investigation of alterations due to disorders or intervention strategies.

STUDY QUESTION:Which mechanisms of action and candidate drugs can be used to treat endometrial failure caused by molecular alterations rather than endometrial timing?SUMMARY ANSWER:Genistein, pioglitazone, alprostadil, flunisolide, and tenoxicam emerged as potential therapies to treat two molecular causes of endometrial failure not originating in endometrial timing.WHAT IS KNOWN ALREADY:Several studies have described molecular profiles of endometrial failure unrelated to endometrial timing and proposed diagnostic tools based on clinical and transcriptomic data, but effective therapeutic options remain lacking. Hence, there is a pressing need for tailored treatments to enable personalised medicine in endometrial-factor infertility.STUDY DESIGN, SIZE, DURATION:This multicentre prospective study, conducted at 5 fertility clinics in Spain between January 2019 and August 2022, included 192 patients undergoing in vitro fertilisation with hormone replacement therapy, whose endometrial biopsies were collected during the mid-secretory phase.PARTICIPANTS/MATERIALS, SETTING, METHODS:Of 291 endometrial biopsies, 192 met the quality criteria and 161 were classified according to clinical and transcriptomic data using a semi-supervised learning model for prognosis. Before classification, transcriptomic variation related to endometrial timing was corrected using our validated transcriptomic endometrial-dating model. Profiles were analysed using systems pharmacology approaches combining network analysis and reversal signature matching to identify therapeutic drugs capable of reversing molecular disruption. Candidate drugs were grouped by mechanism of action and prioritised by side-effect profile. Selected drugs were validated in endometrial cells through RT-PCR, F-actin staining, and enzyme-linked immunosorbent assays.MAIN RESULTS AND THE ROLE OF CHANCE:Four transcriptomic profiles were identified using artificial intelligence models, each with distinct clinical implications. Two profiles were associated with poor prognosis: clinical miscarriage-associated (CMA, n = 27) and biochemical miscarriage-associated (BMA, n = 16). CMA was characterised by upregulation of differentiation-related genes and BMA by upregulation of immune-related genes. The 4 profiles were homogeneous in demographic and embryological parameters (age, BMI, and embryo quality), reinforcing their biological relevance. Approved drugs capable of reversing these disrupted expression patterns were identified. Both BMA and CMA were linked to abnormal decidualisation, while BMA also showed immune dysregulation. Genistein and pioglitazone promoted decidualisation in vitro, whereas alprostadil, flunisolide, and tenoxicam inhibited immune responses in endometrial cell cultures, supporting their potential therapeutic role in endometrial failure not originating in endometrial timing.LIMITATIONS, REASONS FOR CAUTION:Although our artificial intelligence-based stratification model revealed clinical and functional differences among profiles, it was designed for drug repurposing rather than predictive diagnosis. A larger, specifically designed study would be required to validate predictive performance and generalisability. Further clinical trials are needed to evaluate the proposed drugs as personalised treatments for this condition.WIDER IMPLICATIONS OF THE FINDINGS:This is the first application of a systems-based drug repurposing strategy in IVF to develop tailored therapeutic interventions. We propose genistein, pioglitazone, alprostadil, flunisolide, and tenoxicam as approved, safe drugs identified through an evidence-based approach that could prevent loss of good-quality embryos and miscarriage due to maternal endometrial factors. These findings, supported by functional in vitro validation, pave the way for future clinical trials advancing personalised medicine in endometrial-factor infertility.TRIAL REGISTRATION NUMBER:Not applicable

To systematically review and quantify the impact of adenomyosis on maternal, neonatal, and obstetric outcomes. A comprehensive, unrestricted search was conducted in MEDLINE, Scopus, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, Scientific Electronic Library Online, Cochrane, ClinicalTrials.gov, Cumulative Index to Nursing and Allied Health Literature, Psychological Information Database, Allied and Complementary Medicine Database, and gray literature up to the present date. Studies were selected if they compared maternal, neonatal, and/or obstetric outcomes in women with adenomyosis compared to those without adenomyosis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to carry out meta-analyses using random-effects models reporting relative risks and 95% confidence intervals. The Risk Of Bias In Nonrandomized Studies-of Exposure tool and the Grading of Recommendations, Assessment, Development, and Evaluations methodology were used to rate the risk of bias and evidence certainty. Subgroup analysis was carried out by dividing studies according to the mode of conception. Thirty-nine studies (5,521,417 patients; 25,564 with adenomyosis) showed that adenomyosis was associated with increased risks of preeclampsia (relative risk, 2.24; 95% confidence interval, 1.34-3.75; I2=72.6%, low certainty), postpartum hemorrhage (relative risk, 1.73; 95% confidence interval, 1.2-2.49; I2=63.9%, low certainty), small for gestational age (relative risk, 1.79; 95% confidence interval, 1.34-2.39; I2=74.7%, low certainty), fetal malpresentation (relative risk, 1.95; 95% confidence interval, 1.29-2.93; I2=77.7%, low certainty), miscarriage (relative risk, 1.61; 95% confidence interval, 1.31-1.99; I2=82.99%, low certainty), preterm premature rupture of membranes (relative risk, 2.87; 95% confidence interval, 1.37-6.0; I2=35.2%, low certainty), placental malposition (relative risk, 3.26; 95% confidence interval, 2.76-3.86; I2=0%, low certainty), extreme preterm birth (relative risk, 3.71; 95% confidence interval, 1.75-7.88; I2=88.5%, low certainty), low birthweight (relative risk, 2.29; 95% confidence interval, 1.24-4.24; I2=91.5%, low certainty), and threatened preterm labor (relative risk, 1.54; 95% confidence interval, 1.37-1.73; very low certainty), although certainty of evidence was low to very low. No significant differences were observed for gestational diabetes, HELLP syndrome, uterine rupture, fetal growth restriction, fetal distress, intrauterine death, ectopic pregnancy, multiple pregnancy, premature rupture of membranes, Apgar <7, umbilical artery pH <7, or neonatal intensive care admission. Adenomyosis may be associated with increased risks of adverse maternal, obstetric, and neonatal outcomes; however, certainty of evidence was low to very low. While high-quality studies are needed to corroborate available findings, clinicians should be aware of these plausible increased risks to implement targeted prenatal surveillance, tailor pregnancy management, and optimize preconception counselling for women with adenomyosis.

BackgroundInfertility is an underrecognized disease which affects over 17% of the reproductive age population worldwide. However, availability of, and access to, assisted reproductive technology (ART) is variable across countries. There are significant challenges relating to awareness, financial and other barriers to care, cultural considerations, and the level of support provided to people undergoing care. Previous studies have explored these challenges, but less attention has been given to the policy implications. As the need for fertility care rises, we investigate the evidence that policy changes can be implemented to improve access to ART treatment.MethodsA review of literature was conducted on fertility policy challenges and developments, covering fertility recognition and awareness; cultural and religious considerations; and access to ART treatment, psycho-social care, and supplementary care. Nine medical and academic experts were invited to validate secondary research findings and provide their perspectives on policy implications. The experts covered different specialties and geographic expertise. Experts participated in individual 60-minute interviews, then a half-day Policy Forum discussion was held virtually in May 2023.ResultsLack of recognition of infertility as a disease, low financial coverage of fertility services, limited psychosocial support, and cultural considerations are substantial barriers to fertility services access. Some countries have limited reimbursement of services or offer only private care, significantly limiting treatment access. Others restrict reimbursement based on age, gender and family status, which creates access inequities. Policy action is needed to mitigate these challenges and to ensure timely and equitable access to fertility care. Decision-makers need to collectively recognize infertility as a disease, rather than just a social issue. Equity of access to infertility services should be ensured by expanding the availability of public funding, along with review and rationalisation of criteria for treatment reimbursement. To improve engagement in treatment and support through the fertility journey, access to psychosocial care should be expanded and included as a core service.ConclusionMajor obstacles to accessing ART treatment have been identified across regions globally, highlighting the urgent need for national policy action to enhance care quality by reviewing current legislation, improving patient and physician education, refining reimbursement procedures, and expanding psychosocial support services.