Abstract BACKGROUND The vaginal microbiome may influence the success of medically assisted reproduction (MAR), including IVF with or without ICSI, and IUI. However, findings across studies remain inconsistent, and previous meta-analyses have largely relied on binary microbiome classifications or pairwise comparisons. The relative associations between individual vaginal community state types (CSTs) and pregnancy outcomes therefore remain uncertain. OBJECTIVE AND RATIONALE To compare the associations between individual CSTs and pregnancy following MAR by integrating direct and indirect evidence in a systematic review and network meta-analysis (NMA) and to determine whether specific CSTs were associated with lower odds of pregnancy. SEARCH METHODS PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to 2 April 2026. Eligible longitudinal studies assessed vaginal microbiome composition using sequencing-based profiling before embryo transfer or IUI and reported pregnancy following MAR. Cross-sectional studies, studies without CST classification, or pregnancy outcome data, and studies based solely on post-treatment sampling were excluded. Two reviewers independently performed study selection and risk-of-bias assessment. Odds ratios (ORs) with 95% CIs were synthesized across CSTs using NMA. Twelve longitudinal studies including 2289 women met the inclusion criteria. The prospectively registered review was reported in accordance with PRISMA and the PRISMA extension for NMA. OUTCOMES The NMA allowed integration of direct and indirect evidence across six CST categories. Compared with Lactobacillus (L.) crispatus, Lactobacillus jensenii-dominated CSTs (OR 0.42, 95% CI 0.19–0.92), and low-lactobacillus community CSTs (OR 0.59, 95% CI 0.38–0.91) were associated with significantly lower odds of pregnancy. No statistically significant differences were observed for other lactobacilli, including Lactobacillus gasseri and Lactobacillus iners, compared with L. crispatus. Tests found no evidence of overall or loop inconsistency in the primary network. Subgroup analyses showed broadly similar patterns but were limited by sparse data, imprecision, and local inconsistency in some subgroup networks. Interpretation was further limited by clinical and methodological heterogeneity, observational study designs, residual confounding, and sparse evidence for several CST comparisons. Live-birth evidence was particularly limited: only five studies reported a total of 57 live births. Transitivity could not be formally assessed because potential effect modifiers were not consistently reported for individual CSTs. WIDER IMPLICATIONS The findings indicate that general assumption of Lactobacillus-dominated CSTs being beneficial to MAR-treatment effects should be regarded with caution, as these may differ in their associations with pregnancy, depending on the specific Lactobacillus dominance. However, the available evidence is insufficient to support clinical implementation of CST profiling. Larger, standardized prospective longitudinal studies with CST-specific reporting, adjusted estimates, repeated microbiome sampling, and live-birth outcomes are required to determine whether CST profiling has clinically useful prognostic value and whether microbiome-targeted interventions improve reproductive outcomes. REGISTRATION NUMBER PROSPERO CRD420251066092.
Abstract BACKGROUND Infertility is a prevalent reproductive health condition that affects one in six people worldwide. Despite recent increasing recognition of the global burden of infertility, a large fertility care gap remains, with limited understanding of the determinants of care-seeking among those who require infertility services to achieve their desired family size. OBJECTIVE AND RATIONALE To date, there has been no comprehensive global thematic synthesis specifically focused on the qualitative evidence regarding determinants of fertility care-seeking. This review aims to identify and to systematize these determinants across diverse populations, settings, and health systems, drawing on a candidacy-informed framework to support more equitable, person-centred fertility care. The research question focuses on what determinants shape care-seeking among people with infertility and how these can be utilized to guide interventions, services, and future research. SEARCH METHODS Seven databases were searched up to May 2026, complemented by citation tracking, to identify qualitative and mixed-methods studies documenting determinants of fertility care-seeking among affected individuals and couples. The quality of included studies was appraised using the Joanna Briggs Institute checklist; data were inductively coded and thematically synthesized, mapped to socio-ecological levels, and interpreted through a candidacy lens. Confidence of the evidence in each synthesized finding was assessed using GRADE-CERQual. OUTCOMES Twenty-seven studies from low-, middle-, and high-income countries involving users of biomedical, traditional, complementary, and cross-border fertility care were included. Determinants of care-seeking clustered into six domains: individual (e.g. personal fulfilment, fertility knowledge, age, psychological factors, gender norms); relational (e.g. couple dynamics, decision-making, negotiation, gendered power relations, masculinity norms); socio-cultural (e.g. stigma, social expectations, familial, and peer influences); socio-economic (e.g. financial barriers, health insurance coverage); health system and therapeutic (e.g. service quality, treatment costs, medical pluralism, public–private sector dynamics, availability of Medically Assisted Reproduction/ART, geographical accessibility, waiting times); and policy and political (e.g. infertility inclusion in national policies, regulatory frameworks, cross-border fertility care). Care pathways were typically non-linear, gendered, and diverse, characterized by delayed recognition of infertility as a health concern, medical pluralism, care interruptions, and re-engagement over time, often at considerable emotional and financial cost. WIDER IMPLICATIONS Multiple individual, relational, social, and structural determinants affect care-seeking for infertility. Multi-level policy, financing, and service delivery interventions are needed to address stigma, gendered norms, financial hardship, regulatory barriers, and often fragmented, pluralistic care pathways. This synthesis offers a candidacy-informed, multi-domain framework to guide context-sensitive interventions, including integrating infertility into universal health coverage, strengthening regulation of cross-border care, and embedding culturally competent, patient-centred fertility care within sexual and reproductive health programmes, and health systems. REGISTRATION NUMBER CRD420251163735.
Abstract BACKGROUND Women with polycystic ovary syndrome (PCOS) face an elevated long-term risk of type 2 diabetes and cardiovascular disease, largely driven by clustered cardiometabolic abnormalities. Although lifestyle interventions primarily involving exercise and dietary interventions have shown benefits, the optimal strategy remains uncertain. OBJECTIVE AND RATIONALE We aimed to systematically evaluate and compare multiple lifestyle interventions for cardiometabolic outcomes in women with PCOS, and explore potential dose–response relationships between intervention effects and key covariates such as exercise dose. Outcomes were grouped into five domains: anthropometry and body composition, glucose and insulin regulation, blood lipid profiles, inflammation, and blood pressure, together comprising 16 outcomes. This study was designed to address the limited comparative evidence across lifestyle interventions and the lack of quantitative evidence on factors that may modify intervention effects, with the aim of informing individualized lifestyle prescriptions and cardiometabolic risk management in women with PCOS. SEARCH METHODS A systematic search across five databases retrieved randomized controlled trials of lifestyle interventions in PCOS, spanning records from inception to 9 June 2026, including lifestyle interventions targeting cardiometabolic outcomes in women with PCOS. Studies involving pharmacological interventions or with an intervention duration of <2 weeks were excluded. An arm-based multilevel Bayesian random-effects network meta-analysis was used to synthesize arm-level change scores as mean differences (MD), with effects reported as MDs and 95% credible intervals (CrIs); treatments were ranked using the surface under the cumulative ranking curve (SUCRA). The risk of bias was assessed using the Cochrane Risk of Bias tool 2, and the confidence in each network estimate was evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework. OUTCOMES After exclusions, 43 studies with 2433 participants were included. Compared with the respective control condition, within the dietary network, the ketogenic diet reduced waist circumference (No (number of participants) = 86, k (number of study arms) = 2; MD = −5.74 cm, 95% CrIs −8.48 to −3.04) and body mass index (No = 86, k = 2; MD = −2.61 kg/m², −4.53 to −0.77). Meanwhile, within the exercise network, aerobic exercise ranked best for reducing waist to hip ratio (No = 141, k = 7; MD = −0.03, −0.04 to − 0.02), mind–body exercise ranked best for reducing insulin resistance assessed by the homeostatic model assessment of insulin resistance (HOMA-IR) (No = 72, k = 3; MD = −0.63, −1.06 to −0.24), fasting plasma glucose (No = 37, k = 2; MD = − 0.16 mmol/l, −0.31 to −0.03), triglycerides (No = 59, k = 2; MD = −0.28 mmol/l, −0.55 to −0.01), fasting insulin (No = 72, k = 3; MD = −6.26 pmol/l, −12.14 to −0.50) and low-density lipoprotein cholesterol (No = 59, k = 2; MD = −0.26 mmol/l, −0.42 to −0.14), and high-intensity interval training (HIIT) ranked best for improving high-density lipoprotein cholesterol (No = 117, k = 6; MD = 0.05 mmol/l, 0.01 to 0.10). Aerobic exercise also ranked best for reducing systolic blood pressure (No = 90, k = 4; MD = −3.49 mmHg; 95% CrI, −6.87 to −0.09). Overall, the certainty of evidence was generally rated as low or very low. An exercise dose of approximately 480–1012 metabolic equivalents of task (METs)·min/week was associated with the greatest overlap in predicted benefits across multiple cardiometabolic outcomes, and moderate-to-vigorous intensity exercise of 7.2–9.4 METs, 60 min/session, 3 sessions/week for 13–17 weeks was mainly associated with predicted favourable changes in lipid outcomes. WIDER IMPLICATIONS Collective evidence suggests that the ketogenic diet may reduce waist circumference and body mass index; HIIT and mind–body exercise appeared beneficial across multiple cardiometabolic outcomes. An exercise dose of approximately 480–1012 METs·min/week was associated with the greatest overlap in predicted benefits across outcomes. However, these findings should be interpreted cautiously because the certainty of evidence was generally low or very low, and some estimates were based on a limited number of studies. Nevertheless, this study provides a more targeted basis for exercise prescription and future research in PCOS. REGISTRATION NUMBER CRD420251079107.
Abstract BACKGROUND Ovarian aging is among the earliest functional declines in humans and acts as a pacemaker of female aging. It encompasses both physiological age-related ovarian decline and pathological accelerated aging, exemplified by premature ovarian insufficiency (POI). Increasing evidence positions the immune system as both a regulator of ovarian homeostasis and a driver of ovarian dysfunction. Age-related immunosenescence and chronic low-grade inflammation (inflammaging) coordinately drive ovarian aging through bidirectional crosstalk between systemic immunity and the ovarian immune microenvironment. POI frequently coexists with autoimmune disorders, reinforcing the central role of the immune-ovarian axis in reproductive aging. Elucidating this interplay may enable targeted immunomodulatory strategies to preserve reproductive longevity and mitigate systemic consequences of ovarian decline. OBJECTIVE AND RATIONALE The aim was to synthesize current evidence on (i) immune regulation of normal ovarian physiology; (ii) immune alterations in physiological ovarian aging, including systemic immunosenescence and ovarian immune microenvironment remodelling; (iii) autoimmune dysregulation in POI; and (iv) the translational potential of immunomodulatory interventions for mitigating ovarian aging. SEARCH METHODS Original articles published up to April 2026 were identified through PubMed using combinations of the terms ‘immune system’, ‘ovarian function’, ‘inflammation’, ‘immune cell’, ‘ovarian aging’, ‘menopause’, ‘primary ovarian insufficiency’, and ‘therapeutics’. OUTCOMES Immune cells and cytokine networks form a specialized regulatory axis that governs folliculogenesis, ovulation, and luteal dynamics. This review synthesizes emerging evidence showing that this immune–ovary axis undergoes profound remodelling during reproductive aging and that immune dysregulation is a causal driver of ovarian functional decline. Systemically, the menopausal transition accelerates immunosenescence and amplifies pro-inflammatory cytokine production. Locally, the aging ovary exhibits chronic inflammation, NLRP3 inflammasome activation, and accumulation of senescent cells with a senescence‑associated secretory phenotype. These changes coincide with a shift from tissue‑resident to monocyte‑derived macrophages and expansion of inflammatory γδ and double‑negative T cells. This progressive loss of immune homeostasis promotes follicular depletion, stromal fibrosis, and impaired steroidogenesis. POI represents a pathological extreme of this axis, characterized by autoimmune comorbidities, B cell-driven humoural abnormalities, T cell dysregulation, and genetic variants affecting immune pathways. Comparative analysis reveals both conserved inflammatory signatures shared with physiological aging and POI-specific immune features that reflect overt immune-mediated ovarian injury. By integrating systemic, local, and disease-specific immune mechanisms, this review reframes ovarian aging as a modifiable immunological process. Therapeutically, emerging immunomodulatory strategies range from molecular agents targeting inflammatory mediators and senescence programs, through cell-based immune reprogramming with stem cells, regulatory T cells, and senolytic immune effectors, to lifestyle-driven systemic immunomodulation. These strategies show promise in restoring ovarian immune homeostasis and extending the reproductive lifespan, with several of these approaches now advancing toward early-phase clinical evaluation. WIDER IMPLICATIONS Collectively, the current evidence positions immune dysregulation as a mechanistic driver, rather than a secondary correlate, of ovarian aging. Integrating immune biomarkers into predictive frameworks and designing stratified immunomodulatory trials may shift ovarian aging management from symptomatic hormone replacement toward mechanism-based intervention. Reframing ovarian aging as a modifiable immune-mediated process offers new opportunities to extend female reproductive longevity and the female health span. REGISTRATION NUMBER N/A
BACKGROUND:In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE:The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS:A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES:Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS:Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER:N/A.
