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Background: Prior research suggests that women with endometriosis are at greater risk of coronary heart disease. Therefore, our objective was to prospectively investigate the association between laparoscopically confirmed endometriosis and risk of incident stroke during 28 years of follow-up. Methods: Participants in the NHSII cohort study (Nurses’ Health Study II) were followed from 1989 when they were between the ages of 25 to 42 until 2017 for development of incident stroke (ischemic and hemorrhagic). Cox proportional hazard models were used to calculate hazard ratios and 95% CI, with adjustment for potential confounding variables (alcohol intake, body mass index at age 18, current body mass index, age at menarche, menstrual cycle pattern in adolescence, current menstrual cycle pattern, parity, oral contraceptive use history, smoking history, diet quality, physical activity, NSAID use, aspirin use, race/ethnicity, and income). We estimated the proportion of the total association mediated by history of hypertension, hypercholesterolemia, hysterectomy/oophorectomy, and hormone therapy. We also tested for effect modification by age (≥ 50 years), infertility history, body mass index (≥ 25 kg/m 2 ), and menopausal status. Results: We documented 893 incident cases of stroke during 2 770 152 person-years of follow-up. Women with laparoscopically confirmed endometriosis had a 34% greater risk of stroke in multivariable-adjusted models (hazard ratio, 1.34 [95% CI, 1.10–1.62]), compared to those without a history of endometriosis. Of the total association of endometriosis with risk of stroke, the largest proportion was attributed to hysterectomy/oophorectomy (39% mediated [95% CI, 14%–71%]) and hormone therapy (16% mediated [95% CI, 5%–40%]). We observed no differences in the relationship between endometriosis and stroke by age, infertility history, body mass index, or menopausal status. Conclusions: We observed that women with endometriosis were at elevated risk of stroke. Women and their health care providers should be aware of endometriosis history, maximize primary cardiovascular prevention, and discuss signs and symptoms of cardiovascular disease.

Few studies have assessed the association between endogenous steroid hormone levels and a subsequent diagnosis of endometriosis. We prospectively evaluated premenopausal plasma sex hormone levels and the risk of laparoscopically confirmed endometriosis in a nested case-control study within Nurses’ Health Study II. Between blood collection (1996–1999) and 2009, we ascertained 446 women with incident endometriosis and matched them to 878 controls through risk-set sampling. We conducted multivariable conditional logistic regression accounting for matching and confounders to estimate relative risks (RRs) and 95% confidence intervals (CIs). Women with greater early follicular-phase total or free estradiol levels had a nonlinear increased risk of endometriosis (early follicular total estradiol: second quartile vs. first, RR = 2.23 (95% CI: 1.44, 3.47); third quartile, RR = 1.83 (95% CI: 1.16, 2.88); fourth quartile, RR = 1.68 (95% CI: 1.05, 2.68); early follicular free estradiol: second quartile vs. first, RR = 1.63 (95% CI: 1.05, 2.54); third quartile, RR = 2.02 (95% CI: 1.31, 3.12); fourth quartile, RR = 1.04 (95% CI: 0.66, 1.65)). Free testosterone assessed in quartile categories was not associated with endometriosis, although a threshold effect was observed, with a positive association among women in the top 2% of free testosterone levels. Levels of mid–luteal-phase total and free estradiol, follicular and luteal estrone, total testosterone, progesterone, and sex hormone binding globulin were not associated with endometriosis risk. These results support the role of sex steroids in endometriosis etiology, although the relationships suggest complex threshold effects.

To examine the association between the intake of fruits and vegetables with high- vs. low-pesticide residue burden and diagnosis of laparoscopically confirmed endometriosis. The etiology of endometriosis is not well understood, but dietary factors may influence the risk. Pesticides may act as endocrine disruptors, and the intake of pesticide-contaminated food is a common exposure pathway.Prospective cohort study. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox proportional hazard models to evaluate the intake of fruits and vegetables with high- and low-pesticide residues in relation to the diagnosis of laparoscopically confirmed endometriosis.Not applicable.Premenopausal US women (N = 52,053) of the Nurses' Health Study II, aged 34-53 years at study baseline (1999), were followed until 2013. The diet was assessed every 4 years using a validated food frequency questionnaire. A previously developed and validated pesticide residue burden score (PRBS), on the basis of the US Department of Agriculture Pesticide Data Program, was used to assign fruits and vegetables to pesticide residue groups (high/low).Not applicable.Cases of laparoscopically confirmed endometriosis were identified from self-reports to validated questionnaires.During 14 years of follow-up, 956 incidences of laparoscopically confirmed endometriosis were reported. No association was observed between the intake of high- or low-PRBS fruit and vegetable intake and endometriosis (hazard ratio for 5th vs. 1st quintile: high-PRBS intake = 0.94, 95% confidence interval = 0.73-1.23; low-PRBS intake = 1.07, 95% confidence interval = 0.82-1.40). No associations were observed for high- or low-PRBS fruit and vegetable intake by fertility status.No clear associations were observed between high- or low-PRBS fruit and vegetable intake and endometriosis risk among premenopausal women. To our knowledge, this is the first study to evaluate the association between dietary pesticide residue intake and endometriosis. Further research is needed, particularly to evaluate this association among a younger population of women (adolescence or early adulthood) and assess the dietary exposure to specific pesticides or chemical families.

Numerous studies have demonstrated that assisted reproductive technology (ART: defined here as including only

STUDY QUESTION Do women with polycystic ovary syndrome (PCOS) have a greater risk of adverse pregnancy complications (gestational diabetes, preeclampsia, cesarean section, placental abnormalities) and neonatal outcomes (preterm birth, small for gestational age, prolonged delivery hospitalization) compared to women without a PCOS diagnosis and does this risk vary by BMI, subfertility and fertility treatment utilization? SUMMARY ANSWER Deliveries to women with a history of PCOS were at greater risk of complications associated with cardiometabolic function, including gestational diabetes and preeclampsia, as well as preterm birth and prolonged length of delivery hospitalization. WHAT IS KNOWN ALREADY Prior research has suggested that women with PCOS may be at increased risk of adverse pregnancy outcomes. However, findings have been inconsistent possibly due to lack of consistent adjustment for confounding factors, small samples size and other sources of bias. STUDY DESIGN, SIZE, DURATION Massachusetts deliveries among women ≥18 years old during 2013–2017 from state vital records linked to hospital discharges, observational stays and emergency department visits were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and the Massachusetts All-Payers Claims Database (APCD). PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS was identified by ICD9 and ICD10 codes in APCD prior to index delivery. Relative risks (RRs) and 95% CI for pregnancy and delivery complications were modeled using generalized estimating equations with a log link and a Poisson distribution to take multiple cycles into account and were adjusted a priori for maternal age, BMI, race/ethnicity, education, plurality, birth year, chronic hypertension and chronic diabetes. Tests for homogeneity investigated differences between maternal pre-pregnancy BMI categories ( MAIN RESULTS AND THE ROLE OF CHANCE Among 91 825 deliveries, 3.9% had a history of PCOS. Women with a history of PCOS had a 51% greater risk of gestational diabetes (CI: 1.38–1.65) and a 25% greater risk of preeclampsia (CI: 1.15–1.35) compared to women without a diagnosis of PCOS. Neonates born to women with a history of PCOS were more likely to be born preterm (RR: 1.17, CI: 1.06–1.29) and more likely to have a prolonged delivery hospitalization after additionally adjusting for gestational age (RR: 1.23, CI: 1.09–1.40) compared to those of women without a diagnosis of PCOS. The risk for gestational diabetes for women with PCOS was greater among women with a pre-pregnancy BMI LIMITATIONS, REASONS FOR CAUTION PCOS was defined by ICD documentation prior to delivery so there may be women with undiagnosed PCOS or PCOS diagnosed after delivery included in the unexposed group. The study population is limited to deliveries within Massachusetts among most private insurance payers and inpatient or observational hospitalization in Massachusetts during the follow-up window, therefore there may be diagnoses and or deliveries outside of the state or outside of our sample that were not captured. WIDER IMPLICATIONS OF THE FINDINGS In this population-based study, women with a history of PCOS were at greater risk of pregnancy complications associated with cardiometabolic function and preterm birth. Obstetricians should be aware of patients’ PCOS status and closely monitor for potential pregnancy complications to improve maternal and infant perinatal health outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the NIH (R01HD067270). S.A.M. receives grant funding from NIH, AbbVie and the Marriot Family Foundation; payment/honoraria from the University of British Columbia, World Endometriosis Research Foundation and Huilun Shanghai; travel support for attending meetings for ESHRE 2019, IASP 2019, National Endometriosis Network UK meeting 2019; SRI 2022, ESHRE 2022; participates on the data safety monitoring board/advisory board for AbbVie, Roche, Frontiers in Reproductive Health; and has a leadership role in the Society for Women’s Health Research, World Endometriosis Research Foundation, World Endometriosis Society, American Society for Reproductive Medicine and ESHRE. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

BACKGROUND: The etiology of endometriosis is not well understood. Limited evidence suggests that dietary factors influence risk, but prospective data related to carbohydrate, fiber, and gluten consumption are scarce. Despite this, recommendations concerning fiber, gluten intake, and endometriosis are pervasive in the lay literature. OBJECTIVES: We aimed to investigate the associations of carbohydrate quality [glycemic index (GI) and glycemic load (GL)], fiber intake (total, legume, vegetable, cruciferous vegetable, fruit, cereal), and gluten intake with incident laparoscopically confirmed endometriosis. METHODS: This was a prospective cohort study using data collected from 81,961 premenopausal women in the Nurses’ Health Study II (mean age = 36 y in 1991). Diet was assessed with a validated FFQ every 4 y. Cox proportional hazards models were used to calculate rate ratios (RRs) and 95% CIs. RESULTS: A total of 3810 incident cases of laparoscopically confirmed endometriosis were reported over 24 y of follow-up. Women in the highest quintile of GI had 12% (95% CI: 1.01, 1.23; P(trend) = 0.03) higher risk of endometriosis diagnosis than those in the lowest quintile. Total vegetable and cruciferous vegetable fiber intakes were also associated with higher risk (highest compared with lowest quintile RR: 1.13; 95% CI: 1.02, 1.24; P(trend) = 0.004 and RR: 1.17; 95% CI: 1.06, 1.29; P(trend) = 0.02, respectively). Higher intake of fruit fiber was associated with lower risk of endometriosis but the association was not significant after adjusting for the Alternative Healthy Eating Index. Gluten intake was also associated with lower risk (highest compared with lowest quintile RR: 0.91; 95% CI: 0.80, 1.02; P(trend) = 0.01), but these results were not consistent in direction nor statistical significance across sensitivity analyses. No association was observed for GL or total, legume, or cereal fiber intake. CONCLUSIONS: Our findings suggest that carbohydrate quality and specific types of fiber—total vegetable and cruciferous vegetable fiber—are associated with endometriosis diagnosis in premenopausal women. These results also indicate it is unlikely that gluten intake is a strong factor in the etiology or symptomatology of endometriosis.

We described trends in pelvic pain characteristics over 2 years of follow-up among adolescents and adults with and without endometriosis participating in the longitudinal observational cohort of the Women's Health Study: From Adolescence to Adulthood, using data reported at baseline and at years 1 and 2 of follow-up. Participants completed a questionnaire at baseline (between November 2012 and May 2019) and annually thereafter that included validated measures of severity, frequency, and life interference of dysmenorrhea, acyclic pelvic pain, and dyspareunia. Our study population included 620 participants with surgically confirmed endometriosis (rASRM stage I/II = 95%) and 671 community-based and hospital-based controls, with median age = 19 and 24 years, respectively. The proportion reporting hormone use varied across the 3 years ranging from 88% to 92% for cases and 56% to 58% for controls. At baseline, endometriosis cases were more likely to report severe, frequent, and life-interfering dysmenorrhea, acyclic pelvic pain, and dyspareunia compared with controls. Among cases, frequency and severity of dysmenorrhea and dyspareunia were relatively static across 2 years. However, acyclic pelvic pain improved. Severe acyclic pain decreased from 69% at baseline to 46% at year 2. Daily pain decreased from 28% to 14%, and life interference from 68% to 38%. Trends among controls remained fairly stable across 2 years. Among endometriosis cases who completed the questionnaire at all 3 time points, 18% reported persistent, severe acyclic pelvic pain at all 3 time points. Over time, different trends were observed by pelvic pain type among endometriosis cases and controls, supporting the importance of assessing multidimensional features of pelvic pain.

STUDY QUESTION What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value WHAT IS KNOWN ALREADY Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women’s Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS We measured 1305 plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P MAIN RESULTS AND THE ROLE OF CHANCE Average age at blood draw was 18 years for endometriosis cases and 22 years for controls. We identified 63 proteins associated with endometriosis with type-I error set at 0.05, and absolute fold change >1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value LIMITATIONS, REASONS FOR CAUTION Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Department of Defense (W81XWH1910318) and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD94842). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all Ptrend ≥ 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (Ptrend = 0.04) and estrone sulfate (Ptrend = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (Ptrend = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (Ptrend = 0.001), free estradiol (Ptrend = 0.01), estrone sulfate (Ptrend = 0.03), and the ratio of estradiol to testosterone (Ptrend = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users. Cancer Epidemiol Biomarkers Prev; 19(4); 1033–41. ©2010 AACR.

Supplementary Table 1 from Analgesic Use and Sex Steroid Hormone Concentrations in Postmenopausal Women

Supplementary Table 2 from Analgesic Use and Sex Steroid Hormone Concentrations in Postmenopausal Women

To determine if women with endometriosis experience lower urinary tract symptoms (LUTSs) more often than those without.Cross-sectional analysis at enrollment in a longitudinal cohort.Enrollment at 2 academic hospitals and from the local community.This analysis included 1,161 women with (n = 520) and without (n = 641) surgically confirmed endometriosis who were enrolled in the Women's Health Study: from Adolescence to Adulthood between 2012 and 2018.Not applicable.Prevalence of LUTSs, including stress incontinence, urgency and frequency, straining with urination, incomplete bladder emptying, hematuria, dysuria, and bladder pain using standardized questionnaires.The primary outcomes were that women with endometriosis reported the following more often than those without: difficulty passing urine (7.9% vs. 2%; crude odds ratio [OR], 4.14 [95% confidence interval {CI}, 2.19-7.80]; adjusted OR [aOR], 4.31 [95% CI, 2.07-8.95]); still feeling full after urination (18.8% vs. 4.7%; crude OR, 4.73 [95% CI, 3.08-7.25]; aOR, 4.67 [95% CI, 2.88-7.56]); having to urinate again within minutes of urinating (33.1% vs. 17.0%; crude OR, 2.41 [95% CI, 1.83-3.18]; aOR, 2.49 [95% CI, 1.81-3.43]), dysuria (11.7% vs. 4.9%; crude OR, 2.55 [95% CI, 1.62-4.01]; aOR, 2.38 [95% CI, 1.40-4.02]); and pain when the bladder is full (23.0% vs. 4.9%; crude OR, 5.79 [95% CI, 3.82-8.78]; aOR, 6.04 [95% CI, 3.74-9.76]). For the secondary outcomes, among female participants with endometriosis, we observed that the odds of LUTS did not differ by the revised American Society for Reproductive Medicine stage (I/II vs. III/IV) or duration of endometriosis-associated symptoms.Women with surgically confirmed endometriosis were more likely to report LUTS than those without.

OBJECTIVE: To investigate hospitalizations up to 8 years after livebirth among women who utilized ART or who were subfertile, compared to women who conceived naturally. DESIGN: Retrospective cohort SETTING: Massachusetts deliveries among privately insured women ≥18 years old between 2004–2017 from state vital records were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), and hospital observational/inpatient stays. PATIENTS: We compared patients with ART, medically assisted reproduction, and unassisted subfertile delivery to fertile delivery. INTERVENTION: NA MAIN OUTCOME MEASURED: Post-delivery hospitalization information was derived from ICD codes for discharges and were combined by type. The relative risks (RR) and 95% confidence intervals (CI) of hospitalization for up to the first 8 years post-delivery were modeled. RESULTS: Among 492,515 deliveries, 5.6% used ART, 1.6% used medically assisted reproduction, and 1.8% were unassisted subfertile. Compared to fertile deliveries, deliveries that utilized ART, medically assisted reproduction or were unassisted subfertile were more likely to have hospital utilization (inpatient or observational stay) for any reason for up to 8 years of follow-up (unassisted subfertile aRR:1.18 (1.12–1.25); medically assisted reproduction:1.20 (1.13–1.27); ART aRR:1.29 (1.25–1.34)). ART deliveries had an increased risk of hospitalization for conditions of the cardiovascular system(aRR: 1.31 (1.20–1.41)), overweight/obesity(aRR:1.30 (1.17–1.44)), diabetes(aRR:1.25 (1.05–1.49)), reproductive tract(aRR:1.62 (1.47–1.79)), digestive tract(aRR:1.39 (1.30–1.49), thyroid(aRR:2.02 (1.80–2.26)), respiratory system(aRR: 1.13 (1.03–1.24)), and cancer(aRR:1.40 (1.18–1.65)) up to 8 years after delivery. Deliveries with medically assisted reproduction and subfertility had similar patterns of hospitalization as ART deliveries. CONCLUSION: Women who conceived through fertility treatment or who experienced subfertility were at an increased risk for subsequent hospitalization resulting from a variety of chronic and acute conditions. FUNDING: NIH R01HD067270

Endometriosis, affecting 5-10% of reproductive-age women, is a common contributor to dysmenorrhea and chronic pelvic pain. Diagnosis requires laparoscopic tissue biopsy, but careful pelvic examination, and/or imaging with either ultrasound or MRI, may identify patients who should receive empiric first-line therapy. The presence of dyschezia, particularly with cyclical exacerbation, should raise suspicion for bowel or rectovaginal septum involvement, and a greater need for surgical management. Treatment of dysmenorrhea includes hormonal suppression of the menstrual cycle, and/or analgesics; more severe cases with strong pain and disability may require earlier surgical intervention to excise disease while preserving fertility desires.

To investigate whether there is an association between season, temperature, and day length at oocyte retrieval and/or embryo transfer (ET) and clinical outcomes in frozen ET cycles.Retrospective cohort study.Large academically affiliated research hospital.A total of 3,004 frozen ET cycles from 1,937 different women with oocyte retrieval and transfer between 2012 and 2017.None.Implantation, clinical pregnancy, spontaneous abortion, and live birth.Frozen ETs with oocyte retrieval dates in summer had 45% greater odds of clinical pregnancy (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.15-1.82) and 42% greater odds of live birth (OR, 1.42; 95% CI, 1.13-1.79) compared with those with oocyte retrieval dates in winter. A 41% greater odds of clinical pregnancy (OR, 1.41; 95% CI, 1.16-1.71) and 34% greater odds of live birth (OR, 1.34; 95% CI, 1.10-1.62) were observed among transfers with an average temperature at oocyte retrieval in the highest tertile (17.2-33.3 °C) compared with those in the lowest tertile (-17.2-6.7 °C). There were no consistent associations between clinical outcomes and day length at oocyte retrieval or between season, day length, or temperature at transfer of thawed embryos.Warmer temperatures at oocyte retrieval are associated with higher odds of clinical pregnancy and live birth among frozen ET cycles. The consistent associations seen with oocyte retrieval dates and the lack of associations observed with ET dates suggest that any seasonality effects on in vitro fertilization success are related to ovarian function and not uterine receptivity.

STUDY QUESTIONAre menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk?SUMMARY ANSWERIrregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers.WHAT IS KNOWN ALREADYLong and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear.STUDY DESIGN, SIZE, DURATIONProspective cohort study. Prospective follow-up of 78 943 women participating in the Nurses’ Health Study II between 1989 and 2015.PARTICIPANTS/MATERIALS, SETTING, METHODSWe followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14–17, 18–22 and 29–46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence.MAIN RESULTS AND THE ROLE OF CHANCEWe documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29–46 years had an 11% (95% CI: 2–21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9–39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09–1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14–17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02–1.81).LIMITATIONS, REASONS FOR CAUTIONOur study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White.WIDER IMPLICATIONS OF THE FINDINGSWomen with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood.STUDY FUNDING/COMPETING INTERESTThis work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBERN/A.

Endometriosis 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.

Objective Pelvic floor pain, abdominal wall pain, and central nervous system pain amplification can be contributing factors in chronic pelvic pain (CPP), however; limited research has investigated the association of pelvic floor, abdominal, and uterine tenderness with central nervous system pain amplification. We assessed whether pressure pain thresholds on the non-dominant thumbnail, a marker of central nervous system pain amplification, were associated with pelvic floor, abdominal, and uterine tenderness among women with endometriosis or CPP. Study design We conducted a cross-sectional study among 88 females with endometriosis and/or CPP. Abdominal (6 locations), pelvic floor (6 locations) and uterine (1 location) tenderness were assessed via a standardized physical exam. Participants reported their pain levels (0–10 scale) with application of 2 kg of pressure at each area, with a pain rating of ≥4 on the 0–10 scale considered moderate to severe pain. Pain sensitivity was measured on the non-dominant thumbnail by applying discrete pressure stimuli using a previously validated protocol. Results Overall, 50% (44/88), 42% (37/88), and 58% (51/88) of participants reported high pelvic floor, abdominal, and uterine tenderness, respectively. Pressure intensities needed to elicit ‘faint’ and ‘mild’ pain were lower for participants with high vs. low pelvic floor tenderness (median intensity for ‘faint’ pain = 0.50 kgf/cm2(min–max:0.25–3.25) vs. 1.06(0.25–3.00), p-value = 0.006; median intensity for ‘mild’ pain = 2.00(0.63–4.88) vs. 2.63(0.75–6.00), p-value = 0.03). No association was observed between pressure pain sensitivity and abdominal or uterine tenderness (p > 0.11). Participants with endometriosis without pain were less likely to have high pelvic floor (22.2%), abdominal (11.1%), and uterine (25.9%) tenderness compared to participants with endometriosis with pain (63.0%, 50%, 65.2%, respectively) and participants with chronic pelvic pain (60%, 73.3%, 93.3%, respectively). Conclusions These results suggest that high pelvic floor tenderness among women with endometriosis/CPP may be a marker of heightened pain sensitivity suggestive of central nervous system pain amplification and may impact treatment response. Future research should examine whether this clinical phenotype predicts response to medical and behavioral treatments (e.g, anti-convulsants, behavioral therapy, Physical Therapy).

ImportanceMenstrual cycle characteristics may be associated with an increased risk of cardiovascular disease (CVD). However, existing studies are limited, and few have explored the mediating role of established CVD risk factors.ObjectiveTo explore the associations of menstrual cycle characteristics across the reproductive lifespan with the risk of CVD and to what extent these associations were mediated by hypercholesterolemia, chronic hypertension, and type 2 diabetes.Design, Setting, and ParticipantsThis cohort study prospectively followed Nurses’ Health Study II participants between 1993 and 2017 who reported menstrual cycle regularity and length for ages 14 to 17 years and 18 to 22 years at enrollment in 1989 and updated current cycle characteristics in 1993 (at ages 29 to 46 years). Data analysis was performed from October 1, 2019, to January 1, 2022.ExposuresMenstrual cycle regularity and length across the reproductive lifespan.Main Outcomes and MeasuresIncident CVD events of interest, including fatal and nonfatal coronary heart disease (CHD; myocardial infarction [MI] or coronary revascularization) and stroke.ResultsA total of 80 630 Nurses’ Health Study II participants were included in the analysis, with a mean (SD) age of 37.7 (4.6) years and body mass index of 25.1 (5.6) at baseline. Over 24 years of prospective follow-up, 1816 women developed their first CVD event. Multivariable Cox proportional hazards models showed that, compared with women reporting very regular cycles at the same ages, women who had irregular cycles or no periods at ages 14 to 17, 18 to 22, or 29 to 46 years had hazard ratios for CVD of 1.15 (95% CI, 0.99-1.34), 1.36 (95% CI, 1.06-1.75), and 1.40 (95% CI, 1.14-1.71), respectively. Similarly, compared with women reporting a cycle length of 26 to 31 days, women reporting a cycle length 40 days or more or a cycle too irregular to estimate from ages 18 to 22 or 29 to 46 years had hazard ratios for CVD of 1.44 (95% CI, 1.13-1.84) and 1.30 (95% CI, 1.09-1.57), respectively. Mediation analyses showed that subsequent development of hypercholesteremia, chronic hypertension, and type 2 diabetes only explained 5.4% to 13.5% of the observed associations.Conclusions and RelevanceIn this cohort study, both irregular and long menstrual cycles were associated with increased rates of CVD, which persisted even after accounting for subsequently established CVD risk factors.

To examine the association between the consumption of fruits and vegetables and pesticide residue intake from consumption of fruits and vegetables and risk of ultrasound or hysterectomy-confirmed fibroids. Only a few studies have evaluated the association of fruit and vegetable intake with uterine fibroids with inconsistent results. No studies have examined pesticide exposure through fruits and vegetables with fibroid risk.Prospective cohort study. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).Not applicable.81,782 premenopausal participants from the Nurses' Health Study II cohort were followed from 1991-2009 for the fruits and vegetable analysis, and 49,927 participants were followed from 1999-2009 for the pesticide residue burden analysis. Diet was assessed every four years with a food frequency questionnaire. Fruits and vegetables were classified into high- or low-pesticide-residues using a validated method based on surveillance data from the U.S. Department of Agriculture.Not applicable MAIN OUTCOME MEASURE(S): Cases of ultrasound or hysterectomy-confirmed fibroids were identified from self-reports to validated questionnaires.From 1991-2009, 9,706 incident cases of ultrasound or hysterectomy-confirmed fibroids were reported, and 4,195 incident cases were identified from 1999-2009. No association was observed between total fruit and vegetable consumption and uterine fibroid risk. Participants who consumed the highest intake of total fruits (≥4/day) were 10% less likely to develop uterine fibroids compared to participants who consumed1/day (95% CI=0.80-1.01; pOur findings suggest that pesticide residues on fruits and vegetables are not associated with a higher risk of uterine fibroids. Further, our results suggest that intake of fruits may be associated with a lower risk of fibroids. Future research in this area should focus on dietary exposures across the life course as well as assessment of class-specific pesticides.

Objective To explore associations between early life physical and sexual abuse and subsequent risk of premature mortality (death before age 70 years). Design Prospective cohort study. Setting The Nurses’ Health Study II (2001-19). Participants 67 726 female nurses aged 37-54 years when completing a violence victimization questionnaire in 2001. Main outcome measures Hazard ratios and 95% confidence intervals for total and cause specific premature mortality by childhood or adolescent physical and sexual abuse, estimated by multivariable Cox proportional hazard models. Results 2410 premature deaths were identified over 18 years of follow-up. Nurses who experienced severe physical abuse or forced sexual activity in childhood and adolescence had a higher crude premature mortality rate than nurses without such abuse in childhood or adolescence (3.15 v 1.83 and 4.00 v 1.90 per 1000 person years, respectively). The corresponding age adjusted hazard ratios for premature deaths were 1.65 (95% confidence interval 1.45 to 1.87) and 2.04 (1.71 to 2.44), respectively, which were materially unchanged after further adjusting for personal characteristics and early life socioeconomic status (1.53, 1.35 to 1.74, and 1.80, 1.50 to 2.15, respectively). Cause specific analyses indicated that severe physical abuse was associated with a greater risk of mortality due to external causes of injury and poisoning (multivariable adjusted hazard ratio 2.81, 95% confidence interval 1.62 to 4.89), suicide (3.05, 1.41 to 6.60), and diseases of the digestive system (2.40, 1.01 to 5.68). Forced sexual activity as a child and adolescent was associated with greater risk of mortality due to cardiovascular disease (2.48, 1.37 to 4.46), external injury or poisoning (3.25, 1.53 to 6.91), suicide (4.30, 1.74 to 10.61), respiratory disease (3.74, 1.40 to 9.99), and diseases of the digestive system (4.83, 1.77 to 13.21). The association of sexual abuse with premature mortality was stronger among women who smoked or had higher levels of anxiety during adulthood. Smoking, low physical activity, anxiety, and depression each explained 3.9-22.4% of the association between early life abuse and premature mortality. Conclusion Early life physical and sexual abuse could be associated with a greater risk of adult premature mortality.

Background The prevalence of adenomyosis is underestimated due to lack of a specific diagnostic code and diagnostic delays given most diagnoses occur at hysterectomy. Objectives To identify women with adenomyosis using indicators derived from natural language processing (NLP) of clinical notes in the Optum Electronic Health Record database (2014-2018), and to estimate the prevalence of potentially undiagnosed adenomyosis. Methods An NLP algorithm identified mentions of adenomyosis in clinical notes that were highly likely to represent a diagnosis. The anchor date was date of first affirmed adenomyosis mention; baseline characteristics were assessed in the 12 months prior to this date. Characteristics common to adenomyosis cases were used to select a suitable pool of women from the underlying population, among whom undiagnosed adenomyosis might exist. A random sample of this pool was selected to form the comparator cohort. Logistic regression was used to compare adenomyosis cases to comparators; the predictive probability (PP) of being an adenomyosis case was assessed. Comparators having a PP ≥ 0.1 were considered potentially undiagnosed adenomyosis and were used to calculate the prevalence of potentially undiagnosed adenomyosis in the underlying population. Results Among 11 456 347 women aged 18-55 years in the underlying population, 19 503 were adenomyosis cases. Among 332 583 comparators, 22 696 women were potentially undiagnosed adenomyosis cases. The prevalence of adenomyosis and potentially undiagnosed adenomyosis was 1.70 and 19.1 per 1000 women aged 18-55 years, respectively. Conclusions Considering potentially undiagnosed adenomyosis, the prevalence of adenomyosis may be 10x higher than prior estimates based on histologically confirmed adenomyosis cases only.

OBJECTIVE: Inadequate communication about endometriosis symptom burden between women and healthcare providers is a barrier for optimal treatment. This study describes the development of the EndoWheel, a patient-reported assessment tool that visualizes the multi-dimensional burden of endometriosis to facilitate patient-provider communication. METHODS: Assessment questions for the tool were developed using an iterative Delphi consensus process. A consensus phase included additional practitioners and specialists to broaden perspectives and select revised statements. Semi-structured qualitative interviews were conducted with 13 women with endometriosis to assess the scoring and content of the measures. RESULTS: Symptoms included in the tool were pelvic pain, vaginal bleeding, bowel/bladder symptoms, energy levels, fertility, impact on activities, emotional and sexual well-being, and self-perceived global health. Additional life impact areas included relationships, social and occupational activity, and self-perception. The 13 interviewees completed the tool in approximately 5-6 minutes (range 4.0-7.5 minutes). Most participants (92%) perceived that the tool would enable better patient-provider communication, including addressing symptoms and areas of impact not normally discussed during office visits. CONCLUSION: Similar to visual circular tools used in burden assessment of other chronic diseases, the tool may facilitate improved patient dialogue with providers around endometriosis treatment goals and options.

ObjectivesChronic pelvic pain is common, poorly understood, and many women suffer for years without proper diagnosis and effective treatment. The Translational Research in Pelvic Pain (TRiPP) project takes a phenotyping approach, with a particular focus on endometriosis-associated pain (EAP) and bladder pain syndrome (IC/BPS), to improve our fundamental understanding of chronic pelvic pain. We believe that reconceptualising these conditions in the context of the multisystem dysfunction known for other chronic pain conditions rather than as end-organ pathologies has the potential to improve our understanding of the conditions. Our approach combines clinical, biological, physiological and psychological data to establish perturbations in the functions of pain-relevant systems that are specific to EAP and IC/BPS, and those that overlap both conditions and chronic pelvic pain more generally and associated quantitative biomarker profiles.DiscussionWe believe that TRiPP’s novel methodological approach will produce clinical data to aid our understanding of pelvic pain and identify underlying pathways for the development of refined animal models and targeted therapeutic treatments.

Background Sexual minority (lesbian, bisexual, mostly heterosexual) young women face many sexual and reproductive health disparities, but there is scant information on their experiences of chronic pelvic pain, including an absence of information on prevalence, treatment, and outcomes. Aim The purpose of this study was to describe the characteristics of chronic pelvic pain experiences of young women by sexual orientation identity and gender of sexual partners. Methods The analytical sample consisted of a nationwide sample of 6,150 U.S. young women (mean age = 23 years) from the Growing Up Today Study who completed cross-sectional questionnaires from 1996 to 2007. Outcomes Age-adjusted regression analyses were used to examine groups categorized by sexual orientation identity (completely heterosexual [ref.], mostly heterosexual, bisexual, lesbian) and gender of sexual partner (only men [ref.], no partners, both men, and women). We examined differences in lifetime and past-year chronic pelvic pain symptoms, diagnosis, treatment, and quality of life outcomes. Sensitivity analyses also examined the role of pelvic/gynecologic exam history and hormonal contraceptive use as potential effect modifiers. Results Around half of all women reported ever experiencing chronic pelvic pain, among whom nearly 90% had past-year chronic pelvic pain. Compared to completely heterosexual women, there was greater risk of lifetime chronic pelvic pain among mostly heterosexual (risk ratio [RR] = 1.30, 95% confidence interval [CI]: 1.22–1.38), bisexual (RR = 1.30, 95% CI: 1.10–1.52), and lesbian (RR = 1.23, 95% CI: 1.00–1.52) young women. Additionally, compared to young women with only past male sexual partners, young women who had both men and women as past sexual partners were more likely to report chronic pelvic pain interfered with their social activities (b = 0.63, 95% CI: 0.25–1.02), work/school (b = 0.55, 95% CI: 0.17–0.93), and sex (b = 0.53, 95% CI: 0.05–1.00). Clinical Implications Healthcare providers, medical education, and field-wide standards of care should be attentive to the way sexual orientation-based healthcare disparities can manifest into differential prognosis and quality of life outcomes for women with chronic pelvic pain (particularly bisexual women). Strengths & Limitations Our study is the first to examine a variety of chronic pelvic pain outcomes in a nationwide U.S. sample across different outcomes (ie, past-year and lifetime). Though limited by sample homogeneity in terms of age, race, ethnicity, and gender, findings from this article provide foundational insights about chronic pelvic pain experiences of sexual minority young women. Conclusion Our key finding is that sexual minority women were commonly affected by chronic pelvic pain, and bisexual women face pain-related quality of life disparities.

Purpose We previously developed a subfertile comparison group with which to compare outcomes of assisted reproductive technology (ART) treatment. In this study, we evaluated whether insurance claims data in the Massachusetts All Payers Claims Database (APCD) defined a more appropriate comparison group. Methods We used Massachusetts vital records of women who delivered between 2013 and 2017 on whom APCD data were available. ART deliveries were those linked to a national ART database. Deliveries were subfertile if fertility treatment was marked on the birth certificate, had prior hospitalization with ICD code for infertility, or prior fertility treatment. An infertile group included women with an APCD outpatient or inpatient ICD 9/10 infertility code prior to delivery. Fertile deliveries were none of the above. Demographics, health risks, and obstetric outcomes were compared among groups. Multivariable generalized estimating equations were used to calculate adjusted relative risk (aRR) and 95% confidence intervals (CI). Results There were 70,726 fertile, 4,763 subfertile, 11,970 infertile, and 7,689 ART-treated deliveries. Only 3,297 deliveries were identified as both subfertile and infertile. Both subfertile and infertile were older, and had more education, chronic hypertension, and diabetes than the fertile group and less than the ART-treated group. Prematurity (aRR = 1.15–1.17) and birthweight (aRR = 1.10–1.21) were increased in all groups compared with the fertile group. Conclusion Although the APCD allowed identification of more women than the previously defined subfertile categorization and allowed us to remove previously unidentified infertile women from the fertile group, it is not clear that it offered a clinically significantly improved comparison group.

STUDY QUESTION How accurately do women report a diagnosis of endometriosis on self-administered questionnaires? SUMMARY ANSWER Based on the analysis of four international cohorts, women self-report endometriosis fairly accurately with a > 70% confirmation for clinical and surgical records. WHAT IS KNOWN ALREADY The study of complex diseases requires large, diverse population-based samples, and endometriosis is no exception. Due to the difficulty of obtaining medical records for a condition that may have been diagnosed years earlier and for which there is no standardized documentation, reliance on self-report is necessary. Only a few studies have assessed the validity of self-reported endometriosis compared with medical records, with the observed confirmation ranging from 32% to 89%. STUDY DESIGN, SIZE, DURATION We compared questionnaire-reported endometriosis with medical record notation among participants from the Black Women’s Health Study (BWHS; 1995-2013), Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale (E3N; 1990-2006), Growing Up Today Study (GUTS; 2005–2016), and Nurses’ Health Study II (NHSII; 1989–1993 first wave, 1995–2007 second wave). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants who had reported endometriosis on self-administered questionnaires gave permission to procure and review their clinical, surgical, and pathology medical records, yielding records for 827 women: 225 (BWHS), 168 (E3N), 85 (GUTS), 132 (NHSII first wave), and 217 (NHSII second wave). We abstracted diagnosis confirmation as well as American Fertility Society (AFS) or revised American Society of Reproductive Medicine (rASRM) stage and visualized macro-presentation (e.g. superficial peritoneal, deep endometriosis, endometrioma). For each cohort, we calculated clinical reference to endometriosis, and surgical- and pathologic-confirmation proportions. MAIN RESULTS AND THE ROLE OF CHANCE Confirmation was high—84% overall when combining clinical, surgical, and pathology records (ranging from 72% for BWHS to 95% for GUTS), suggesting that women accurately report if they are told by a physician that they have endometriosis. Among women with self-reported laparoscopic confirmation of their endometriosis diagnosis, confirmation of medical records was extremely high (97% overall, ranging from 95% for NHSII second wave to 100% for NHSII first wave). Importantly, only 42% of medical records included pathology reports, among which histologic confirmation ranged from 76% (GUTS) to 100% (NHSII first wave). Documentation of visualized endometriosis presentation was often absent, and details recorded were inconsistent. AFS or rASRM stage was documented in 44% of NHSII first wave, 13% of NHSII second wave, and 24% of GUTS surgical records. The presence/absence of deep endometriosis was rarely noted in the medical records. LIMITATIONS, REASONS FOR CAUTION Medical record abstraction was conducted separately by cohort-specific investigators, potentially introducing misclassification due to variation in abstraction protocols and interpretation. Additionally, information on the presence/absence of AFS/rASRM stage, deep endometriosis, and histologic findings were not available for all four cohort studies. WIDER IMPLICATIONS OF THE FINDINGS Variation in access to care and differences in disease phenotypes and risk factor distributions among patients with endometriosis necessitates the use of large, diverse population samples to subdivide patients for risk factor, treatment response and discovery of long-term outcomes. Women self-report endometriosis with reasonable accuracy (>70%) and with exceptional accuracy when women are restricted to those who report that their endometriosis had been confirmed by laparoscopic surgery (>94%). Thus, relying on self-reported endometriosis in order to use larger sample sizes of patients with endometriosis appears to be valid, particularly when self-report of laparoscopic confirmation is used as the case definition. However, the paucity of data on histologic findings, AFS/rASRM stage, and endometriosis phenotypic characteristics suggests that a universal requirement for harmonized clinical and surgical data documentation is needed if we hope to obtain the relevant details for subgrouping patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by Eunice Kennedy Shriver National Institute of Child Health and Development grants HD48544, HD52473, HD57210, and HD94842, National Cancer Institute grants CA50385, R01CA058420, UM1CA164974, and U01CA176726, and National Heart, Lung, and Blood Institute grant U01HL154386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. AS, SM, and KT were additionally supported by the J. Willard and Alice S. Marriott Foundation. MK was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. LA Wise has served as a fibroid consultant for AbbVie, Inc for the last three years and has received in-kind donations (e.g. home pregnancy tests) from Swiss Precision Diagnostics, Sandstone Diagnostics, Kindara.com, and FertilityFriend.com for the PRESTO cohort. SA Missmer serves as an advisory board member for AbbVie and a single working group service for Roche; neither are related to this study. No other authors have a conflict of interest to report. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. TRIAL REGISTRATION NUMBER N/A.