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ABSTRACTEndometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.

Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

Endometriosis is a common inflammatory disease characterized by the presence of tissue outside the uterus that resembles endometrium, mainly on pelvic organs and tissues. It affects ~5–10% of women in their reproductive years — translating to 176 million women worldwide — and is associated with pelvic pain and infertility. Diagnosis is reliably established only through surgical visualization with histological verification, although ovarian endometrioma and deep nodular forms of disease can be detected through ultrasonography and MRI. Retrograde menstruation is regarded as an important origin of the endometrial deposits, but other factors are involved, including a favourable endocrine and metabolic environment, epithelial–mesenchymal transition and altered immunity and inflammatory responses in genetically susceptible women. Current treatments are dictated by the primary indication (infertility or pelvic pain) and are limited to surgery and hormonal treatments and analgesics with many adverse effects that rarely provide long-term relief. Endometriosis substantially affects the quality of life of women and their families and imposes costs on society similar to those of other chronic conditions such as type 2 diabetes mellitus, Crohn’s disease and rheumatoid arthritis. Future research must focus on understanding the pathogenesis, identifying disease subtypes, developing non-invasive diagnostic methods and targeting non-hormonal treatments that are acceptable to women who wish to conceive. Endometriosis is a common inflammatory disease associated with pelvic pain and infertility and is characterized by the presence of tissue outside the uterus that resembles endometrium. This Primer describes the pathogenesis of the condition and the current outlook for future research.

AbstractObjectiveTo evaluate whether irregular or long menstrual cycles throughout the life course are associated with all cause and cause specific premature mortality (age <70 years).DesignProspective cohort study.SettingNurses’ Health Study II (1993-2017).Participants79 505 premenopausal women without a history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages 14-17 years, 18-22 years, and 29-46 years.Main outcome measuresHazard ratios and 95% confidence intervals for all cause and cause specific premature mortality (death before age 70 years) were estimated from multivariable Cox proportional hazards models.ResultsDuring 24 years of follow-up, 1975 premature deaths were documented, including 894 from cancer and 172 from cardiovascular disease. Women who reported always having irregular menstrual cycles experienced higher mortality rates during follow-up than women who reported very regular cycles in the same age ranges. The crude mortality rate per 1000 person years of follow-up for women reporting very regular cycles and women reporting always irregular cycles were 1.05 and 1.23 for cycle characteristics at ages 14-17 years, 1.00 and 1.37 for cycle characteristics at ages 18-22 years, and 1.00 and 1.68 for cycle characteristics at ages 29-46 years. The corresponding multivariable adjusted hazard ratios for premature death during follow-up were 1.18 (95% confidence interval 1.02 to 1.37), 1.37 (1.09 to 1.73), and 1.39 (1.14 to 1.70), respectively. Similarly, women who reported that their usual cycle length was 40 days or more at ages 18-22 years and 29-46 years were more likely to die prematurely than women who reported a usual cycle length of 26-31 days in the same age ranges (1.34, 1.06 to 1.69; and 1.40, 1.17 to 1.68, respectively). These relations were strongest for deaths related to cardiovascular disease. The higher mortality associated with long and irregular menstrual cycles was slightly stronger among current smokers.ConclusionsIrregular and long menstrual cycles in adolescence and adulthood are associated with a greater risk of premature mortality (age <70 years). This relation is slightly stronger among women who smoke.

BackgroundCardiovascular disease is the leading cause of death globally. Non-malignant gynaecological diseases (NMGD) significantly affect patient health and well-being and may be associated with cardiovascular or cerebrovascular disease (C/CVD).MethodsSeven databases were searched for relevant studies up to 21 April 2024. Observational studies reporting risk estimates and 95% CIs for the association between NMGD and C/CVD were included. Data were extracted by two independent reviewers. Random effects models were used to calculate summary relative risk (SRR) with 95% CI. Composite C/CVD outcome was defined as a combination of ischaemic heart disease, cerebrovascular disease, heart failure, and peripheral vascular disease. The ROBINS-I tool defined study quality and risk of bias.ResultsWe screened 6639 studies, of which 59 were eligible for full-text review and 28 were included in our analysis, comprising a total of 3 271 242 individuals. The majority (53.5%) of the studies were scored as having a ‘serious’/‘critical’ risk of bias. Overall, individuals with an NMGD had a significantly greater risk of composite C/CVD with low heterogeneity among contributing studies (SRR 1.28, 95% CI 1.20 to 1.37; n=16 studies, I2=65.3%), ischaemic heart disease (SRR 1.41, 95% CI 1.31 to 1.51; n=21 studies, I2=73.7%), and cerebrovascular disease (SRR 1.33, 95% CI 1.18 to 1.51; n=16 studies, I2=91.5%). In NMGD-specific analyses, the risk of C/CVD and its components was greater among those with a history of endometriosis or polycystic ovary syndrome.ConclusionsWe found an overall association between NMGD and C/CVD across all studies. However, estimates from individual studies varied substantially.

ObjectivesThe aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between endometriosis and SLE or RA. We sought to investigate the association between laparoscopically confirmed endometriosis and subsequently diagnosed SLE and RA.MethodsWe analysed data from the Nurses’ Health Study II (n=114 453 women) over a 22-year follow-up period. Multivariable, time-varying Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between laparoscopically confirmed endometriosis and confirmed incident SLE or RA.ResultsFrom 1989 to 2011, 103 incident cases of SLE and 390 cases of RA were confirmed. Laparoscopically confirmed endometriosis was significantly associated with subsequent SLE diagnosis (HR=2.03; CI 1.17 to 3.51) and RA diagnosis (HR=1.41; CI 1.05 to 1.89). These associations were robust to adjustment for SLE or RA risk factors and for potential confounders; however, adjustment for hysterectomy and oophorectomy attenuated both relations such that they were no longer significant. No significant differences by infertility status or age (<45 years) were observed.ConclusionsOur findings suggest an association between endometriosis and risk of SLE and RA. It remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to risk of SLE or RA.

Endometriosis is a painful gynecologic disease affecting one in ten reproductive aged women worldwide. Few studies have correlated this symptomatology with biomarker levels among women with and without endometriosis, and no studies correlating pain with biomarker levels have been performed in young patient populations. The purpose of this study was to examine whether CA125 correlates with different types and severity of pain among adolescents and young women with and without endometriosis and assess its performance as an endometriosis biomarker among those presenting with dysmenorrhea in this young population. Reproductive-aged women with laparoscopically-confirmed endometriosis (n = 282) and controls (n = 293) who participated in The Women's Health Study: From Adolescence to Adulthood (A2A), a cohort of adolescents and young women enrolled from 2012-2018, were included in this cross-sectional analysis. Plasma CA125 values were measured using WERF EPHect compliant blood samples collected at enrollment. Average CA125 were calculated by self-reported pain type (i.e. dysmenorrhea, non-cyclic/general pelvic pain, dyspareunia), severity, and frequency in endometriosis cases and controls. Median age at blood draw was 24 years in controls and 17 years in cases, with 68% and 89% non-Hispanic white, respectively. Most endometriosis cases (95%) were rASRM stage I/II. Average CA125 values were 12.5 U/mL in controls and 12.1 U/mL in cases adjusted for age. CA125 did not differ by pain type, its severity, or frequency in endometriosis cases or controls. Among participants who reported dysmenorrhea, CA125 did not discriminate endometriosis cases from controls using cutoff of 35 U/mL (AUC = 0.51, 95%CI = 0.50-0.53). Among adolescents and young adult women, CA125 did not correlate with pain type. CA125 did not efficiently discriminate endometriosis cases from controls even when accounting for pain symptomatology. Average CA125 values were low in adolescents and young women in both endometriosis cases and controls, suggesting cautious interpretation may be needed when measuring CA125 in this population.

About 10% of reproductive-age women have endometriosis. Symptoms can include severe pain, dysmenorrhea, dyspareunia, dysuria, infertility, and fatigue. The pathogenesis is unclear. Hormonal therapy controls symptoms in some women; others require surgery, which may not be effective.

Purpose Endometriosis is associated with ovarian cancer, but the relation with endometrial cancer is unclear. Prior studies generally were retrospective and had potential limitations, including use of self-reported endometriosis, failure to account for delays between symptom onset and endometriosis diagnosis, and changes in risk factors post-endometriosis diagnosis. We evaluated whether these limitations obscured a weak association with endometrial cancer and the extent to which these limitations impacted associations with ovarian cancer. Methods Cox proportional hazards regression models were used to assess associations between endometriosis and cancer risk, evaluating the impacts of self-reported vs. laparoscopically confirmed endometriosis, delayed diagnosis, and post-endometriosis diagnosis changes in risk factor exposures on relative risk estimates. Results Over 18 years of follow-up, we identified 228 ovarian and 166 endometrial cancers among 102,025 and 97,109 eligible women, respectively. Self-reported endometriosis was associated with ovarian cancer [relative risk (RR): 1.81; 95% confidence interval (CI): 1.26–2.58]; this association was stronger for laparoscopically confirmed endometriosis (HR: 2.14; 95% CI 1.45–3.15). No association was observed with endometrial cancer (self-report RR: 0.78; 95% CI 0.42–1.44; laparoscopic-confirmation RR: 0.76; 95% CI 0.35–1.64). Accounting for diagnosis delays or post-endometriosis diagnosis changes in risk factors had a little impact. Conclusions This study adds to the evidence that endometriosis is not strongly linked to endometrial cancer risk and that the association with ovarian cancer is robust to misclassification, diagnostic delay, and changes in exposures post-endometriosis diagnosis. Our analysis suggests that confounding and misclassification do not obscure a weak association for endometrial cancer risk, although our results should be replicated.

Dale Nyholt and colleagues report a genome-wide association meta-analysis of endometriosis in individuals of Japanese and European ancestry. They report a new susceptibility locus at 12q22 and establish an association at 2p25.1. We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese 1 and European 2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese ( P = 3.6 × 10 −3 ), and we confirm association of rs7521902 at 1p36.12 near WNT4 . In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10 −8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent ( P = 8.8 × 10 −11 ), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.