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IntroductionMenstrual health is a key patient-reported outcome beyond its importance as a general indicator of health and fertility. However, menstrual function was not measured in the clinical trials of COVID-19 vaccines. The purpose of this review was to synthesise the existing literature on the relationship between COVID-19 vaccination and menstrual health outcomes.MethodsA PubMed search to 31 October 2023 identified a total of 53 publications: 11 prospective cohort studies, 11 retrospective cohort studies or registry-based cohort studies, and 31 cross-sectional or retrospective case–control studies.ResultsIdentified studies were generally at moderate-to-high risk of bias due to retrospective design, interviewer bias, and failure to include a non-vaccinated control group. Nonetheless, the bulk of the literature demonstrates that COVID-19 vaccine is associated with temporary changes in menstrual characteristics (cycle length and flow) and menstrual pain. Follicular phase (at the time of vaccination) is associated with greater increases in cycle length. Evidence suggests temporary post-vaccine menstrual changes in adolescents, abnormal vaginal bleeding in postmenopausal individuals, and a potential protective effect of using hormonal contraception.ConclusionsIn this review we found evidence supporting an association between the COVID-19 vaccine and menstrual health outcomes. Given the importance of menstrual function to overall health, we recommend that all future vaccine trials include menstruation as a study outcome. Future vaccine studies should include rigorous assessment of the menstrual cycle as an outcome variable to limit sources of bias, identify biological mechanisms, and elucidate the impact of stress.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSNand NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

To examine the association between 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.

Assisted reproductive technology (ART, defined here as including only in vitro fertilization and related technologies) is associated with increased adverse pregnancy, neonatal, and childhood developmental outcomes, even in singletons. The comparison group for many of these studies has often been a fertile population that conceived without assistance. The Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART) was initiated to define a subfertile population with which to compare ART outcomes. Over >10 years, we have used the MOSART database to not only study pregnancy abnormalities and delivery complications but also evaluate ongoing health of women, infants, and children. This article will review studies from the MOSART in the context of how they compare with those of other investigations. We will present MOSART studies that identified the influence of ART and subfertility/infertility on adverse pregnancy (pregnancy hypertensive disorder, gestational diabetes, and placental abnormality) and delivery (preterm birth and low birth weight) outcomes as well as on maternal and child hospitalizations. We will provide evidence that although subfertility/infertility increases the risk of adverse outcomes, there is additional risk associated with the use of ART. Studies exploring the contribution of placental abnormalities as a factor adding to this increased ART-associated risk will be described.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ijlp.2009.06.006 Byline: Elizabeth Reed (a), Anita Raj (b), Gilliatt Falbo (c), Fatima Caminha (c), Michele R. Decker (d), Deborah C. Kaliel (d), Stacey A. Missmer (e), Beth E. Molnar (d), Jay G. Silverman (d) Keywords: Violence against women; Incarceration; Substance use; Depression Abstract: To assess the prevalence and different types of violence experienced by women prisoners in Brazil and the effects of violence on women's depression and illicit drug use. Author Affiliation: (a) Duke University Global Health Institute, Duke University, Durham, NC, United States (b) Social Behavioral Sciences Department, Boston University School of Public Health; Boston, MA, United States (c) Grupo de Estudos da Violencia, Instituto Materno Infantil de Professor Fernando Figueira (IMIP); Recife, Pernambuco, Brazil (d) Department for Society, Human Development, and Health; Harvard University School of Public Health; Boston, MA, United States (e) Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

Background: Higher levels of endogenous sex steroid hormones are associated with increased risks of breast cancer in postmenopausal women. Data for premenopausal women are sparse, in part because of the complexity of measuring hormone levels that vary cyclically. We prospectively evaluated associations between plasma sex hormone levels and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II. Methods: From 1996 to 1999, blood samples were collected from 18 521 premenopausal women during the early follicular and mid-luteal phases of their menstrual cycles. A total of 197 cases of breast cancer were diagnosed among these women after blood collection and before June 1, 2003; these case subjects were matched to 394 control subjects. Logistic regression models, controlling for breast cancer risk factors, were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Women in the highest (versus the lowest) quartiles of follicular total and free estradiol levels had statistically significantly increased risks of breast cancer (RR = 2.1 [95% CI = 1.1 to 4.1], [P.sub.trend] = .08, and RR = 2.4 [95% CI = 1.3 to 4.5], [P.sub.trend] = .01, respectively); the associations were stronger for invasive breast cancer and for estrogen and progesterone receptor-positive (ER+/PR+) tumors. Luteal estradiol levels were not associated with breast cancer risk. Higher levels of total and free testosterone and androstenedione in both menstrual cycle phases were associated with modest, non-statistically significant increases in overall risk of breast cancer and with stronger, statistically significant increases in risks of invasive and ER+/PR+ cancers (e.g., RR of invasive cancers for the top [versus bottom] quartile of luteal total testosterone levels = 2.0 [95% CI = 1.1 to 3.6], [P.sub.trend] = .05, and RR of ER+/PR+ cancers = 2.9 [95% CI = 1.4 to 6.0], [P.sub.trend] = .02). Levels of estrone, estrone sulfate, progesterone, and sex hormone-binding globulin were not associated with breast cancer risk. The absolute number of cases observed over 3 years were 30 among women in the lowest 25% of follicular total estradiol levels and 50 among women in the highest 25%. Conclusions: Levels of circulating estrogens and androgens may be important in the etiology of premenopausal breast cancer.

Background: Sex hormone concentrations are associated with breast cancer risk among women not using postmenopausal hormones (PMH); however, whether a relationship exists among PMH users is unknown. Therefore, we conducted a prospective, nested case--control study within the Nurses' Health Study (NHS) cohort to examine the association between plasma sex hormone concentrations and postmenopausal breast cancer among women using PMH at blood collection. Methods: Blood samples were collected from 1989 to 1990. During follow-up through May 31, 2000, 446 women developed breast cancer and were matched by age, date and time of day of blood collection, and fasting status to 459 control subjects (PMH users) who did not develop cancer. We used conditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). We compared hormone concentrations of the 459 control subjects with those of 363 postmenopausal NHS participants not taking PMH. All statistical tests were two-sided. Results: PMH users had statistically significantly higher estradiol, free estradiol, sex hormone--binding globulin, and testosterone, and lower free testosterone concentrations than non-PMH users. Among PMH users, we found modest associations with breast cancer risk when comparing the highest versus lowest quartiles of free estradiol (RR = 1.7, 95% CI = 1.1 to 2.7; [P.sub.trend] = .06), free testosterone (RR = 1.6, 95% CI = 1.1 to 2.4; [P.sub.trend] = .03), and sex hormone--binding globulin (RR = 0.7, 95% CI = 0.5 to 1.1; [P.sub.trend] = .04), but not of estradiol or of testosterone. However, estradiol and free estradiol were statistically significantly positively associated with breast cancer risk among women older than 60 years (RR = 2.8, 95% CI = 1.5 to 5.0; [P.sub.trend] = .002 and 2.6, 95% CI = 1.4 to 4.7; [P.sub.trend] = .001, respectively) and among women with a body mass index of less than 25 kg/[m.sup.2] (RR = 1.8, 95% CI = 1.1 to 3.1, [P.sub.trend] = .01 and 2.4, 95% CI = 1.4 to 4.0, [P.sub.trend] = .003, respectively). Conclusion: Although women using PMH have a different hormonal profile than those not using PMH, plasma sex hormone concentrations appear to be associated with breast cancer risk among PMH users. [J Natl Cancer Inst 2005;97:595-602]

Background: Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopausal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study. Methods: Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [E[R.sup.+]/P[R.sup.+]], and 39 ER-negative and PR-negative [E[R.sup.-]/P[R.sup.-]] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors. Results: We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with E[R.sup.+]/P[R.sup.+] tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease. Conclusion: Circulating levels of sex steroid hormones may be most strongly associated with risk of E[R.sup.+]/ P[R.sup.+] breast tumors.

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.

Endometriosis is generally histopathologically defined as the presence of at least 2 of the following: endometrial stroma, Müllerian epithelium, and/or hemosiderin-laden macrophages (HLM). Despite clinically evident endometriotic lesions, biopsies are frequently nondiagnostic. In this study, we conducted a large-scale review of biopsies of lesions clinically thought to represent endometriosis and correlate the histologic findings with clinical appearance to expand sensitivity of the pathologic definition of endometriosis, particularly in patients on hormonal therapy. In all, 112 biopsies from 78 patients (mean age=25, range 18–39 yr) were reviewed for histopathologic features suggestive of or diagnostic for endometriosis including the presence of endometrial stroma, Müllerian epithelium, dystrophic calcifications, HLM, chronic inflammation, adhesions, and vascular proliferation. Endometriosis was confirmed by pathologic criteria in 37 of 78 patients (47%). Biopsies from patients on hormonal therapy (n=62, 80%) were significantly less likely to meet pathologic criteria for endometriosis (P=0.01). Nondiagnostic biopsies (70/112; 63%) frequently displayed HLM (20%), chronic inflammation (29%), dystrophic calcifications (26%), vascular proliferation (20%), or adhesions (20%) and were significantly more likely to have a vascular clinical appearance (P=0.01). Diagnostic biopsies (42/112; 38%) were more likely to have a blue/black clinical appearance (P=0.03), demonstrate HLM (P=0.004), and display pseudodecidualization (P=0.05). Patients with a high clinical suspicion of endometriosis have a range of histologic findings, with less than half meeting the current histopathologic criteria for diagnosing endometriosis. Given the heterogeneous histopathologic appearance, revision of the histologic criteria may be warranted with further exploration, particularly for lesions with predominantly vascular features.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2007.05.033 Byline: Kathryn L. Terry (a)(b)(c), Stacey A. Missmer (a)(b)(c), Susan E. Hankinson (a)(c), Walter C. Willett (a)(c)(d), Immaculata De Vivo (a)(c) Keywords: carotenoids; fibroids; uterine leiomyoma Abstract: Carotenoids have antioxidant properties and have been associated with reduced risks of some cancers. We hypothesized that carotenoid intake may reduce the risk of diagnosed uterine leiomyoma (UL). Author Affiliation: (a) Channing Laboratory, the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (b) Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (c) Department of Epidemiology, Harvard School of Public Health, Boston, MA (d) Department of Nutrition, Harvard School of Public Health, Boston, MA. Article History: Received 28 November 2006; Revised 6 March 2007; Accepted 23 May 2007 Article Note: (footnote) Cite this article as: Terry KL, Missmer SA, Hankinson SE, et al. Lycopene and other carotenoid intake in relation to risk of uterine leiomyomata. Am J Obstet Gynecol 2008;198:37.e1-37.e8. This work was supported in part by DSM Nutritional Products Inc, Parsippany, NJ; National Cancer Institute Grants CA50385, CA67262, and T32 CA009001 (to K.L.T.); and American Cancer Society Research Scholar Grant RSG-00-061-04-CCE (to I.D.V.).

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women, affecting approximately 6% to 15% of reproductive-aged women. Polycystic ovarian syndrome is associated with obesity, metabolic syndrome, impaired glucose tolerance, insulin resistance, adverse pregnancy outcomes, and infertility. Previous meta-analyses and reviews have suggested that women with PCOS are at an increased risk of pregnancy complications, although many of the studies included are small and may not be generalizable.This population-based study aimed to investigate whether women with a previous history of PCOS had greater risk of adverse maternal and pregnancy outcomes compared with women without a diagnosis of PCOS accounting for potential confounding factors. Data were obtained from 3 sources: the Massachusetts Pregnancy to Early Life Longitudinal Data System, the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, and the Massachusetts All-Payers Claims Database. Maternal outcomes investigated included gestational diabetes, hypertensive disorders of pregnancy, cesarean delivery, and placental abnormalities. Neonatal outcomes investigated were size for gestational age, low birth weight, prematurity, prolonged delivery, and hospital stay. Infant conditions and diagnoses during the first year of life were also investigated. Deliveries were classified into groups of noninfertile, subfertile/infertile, or assisted reproductive technology. The relative risks (RRs) and 95% confidence intervals (CIs) of adverse outcomes were estimated with a log-link and Poisson distribution, and multivariable models were a priori adjusted for potential confounding factors.A total of 3552 deliveries to women with a history of PCOS and 88,273 deliveries to women without a diagnosis of PCOS were included. When adjusting for maternal age, prepregnancy body mass index (BMI), education, race/ethnicity, plurality, birth year, and history of hypertension and diabetes, women with a history of PCOS had a 51% greater risk of gestational diabetes (RR, 1.51; 95% CI, 1.38–1.65). Women with a history of PCOS were also at a greater risk of pregnancy-induced hypertension, preeclampsia, and eclampsia (RR, 1.25; 95% CI, 1.15–1.35) and higher risk of cesarean delivery (RR, 1.07; 95% CI, 1.02–1.11). Women with a history of PCOS were more likely to deliver prematurely (RR, 1.17; 95% CI, 1.06–1.29), and infants born to mothers with a history of PCOS were more likely to have a prolonged neonatal hospital stay (RR, 1.23; 95% CI, 1.01–1.19). Among women with a BMI <30 kg/m2, PCOS was associated with a greater risk of gestational diabetes (RR, 1.60; 95% CI, 1.42–1.80) than among those with a BMI >30 kg/m2(gestational diabetes: RR, 1.37; 95% CI, 1.21–1.57).The results of this study demonstrate that women with a history of PCOS were more likely to experience gestational diabetes, hypertensive disorders of pregnancy, and cesarean delivery, and their neonates were more likely to be born premature and have a prolonged neonatal hospital stay.

We examined the association between pregnancy and life-course lipid trajectories. Linked data from the Nord-Trøndelag Health Study and the Medical Birth Registry of Norway yielded 19,987 parous and 1,625 nulliparous women. Using mixed-effects spline models, we estimated differences in nonfasting lipid levels from before to after first birth in parous women and between parous and nulliparous women. HDL cholesterol (HDL-C) dropped by −4.2 mg/dl (95% CI: −5.0, −3.3) from before to after first birth in adjusted models, a 7% change, and the total cholesterol (TC) to HDL-C ratio increased by 0.18 (95% CI: 0.11, 0.25), with no change in non-HDL-C or triglycerides. Changes in HDL-C and the TC/HDL-C ratio associated with pregnancy persisted for decades, leading to altered life-course lipid trajectories. For example, parous women had a lower HDL-C than nulliparous women at the age of 50 years (−1.4 mg/dl; 95% CI: −2.3, −0.4). Adverse changes in lipids were greatest after first birth, with small changes after subsequent births, and were larger in women who did not breastfeed. Findings suggest that pregnancy is associated with long-lasting adverse changes in HDL-C, potentially setting parous women on a more atherogenic trajectory than prior to pregnancy.

Letter to the Editor

Introduction The levonorgestrel (LNG)-intrauterine device (IUD) is effective for many, but not all, women with endometriosis in managing pelvic pain. The aim of this study was to explore the characteristics associated with recurrent endometriosis pain within 12 months after operative laparoscopy and LNG-IUD placement.Methods This retrospective case series was performed at a university-affiliated infertility and reproductive surgery practice and included women who underwent operative laparoscopy and LNG-IUD placement by a single surgeon from January 1, 2012 to October 7, 2015 (n = 32). Within 12 months post-operatively, the primary surgeon assessed pain reported by the patient and prescribed adjunctive oral hormonal therapy for recurrent pain symptoms. Data were collected using the patients’ electronic medical records. The main outcome was the presence of recurrent endometriosis pain within 12 months after operative laparoscopy with LNG-IUD placement.Results Of the 32 women who underwent laparoscopy and LNG-IUD placement, 26 presented for follow-up (81.2%) within 12 months, 15 of whom (57.7%) reported recurrent pain. The odds of poor pain control were higher among the women who were obese, among those who had undergone prior laparoscopy, and among those with a history of asthma, depression, or headaches.Conclusions The optimal management of endometriosis-related pain is highly patient-specific, and poor response to LNG-IUD may be associated with having had a prior laparoscopy, obesity, and certain medical comorbidities.

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The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

ObjectiveTo explore associations between early life physical and sexual abuse and subsequent risk of premature mortality (death before age 70 years).DesignProspective cohort study.SettingThe Nurses’ Health Study II (2001-19).Participants67 726 female nurses aged 37-54 years when completing a violence victimization questionnaire in 2001.Main outcome measuresHazard 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.Results2410 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 v1.83 and 4.00 v1.90 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.ConclusionEarly life physical and sexual abuse could be associated with a greater risk of adult premature mortality.

Air pollution, particularly from vehicle exhaust, has been shown to influence hormonal activity. However, it is unknown whether air pollution exposure is associated with the occurrence of uterine leiomyomata, a hormonally sensitive tumor of the uterus.

The prevalence of peanut (PN) and tree nut (TN) allergy in children has tripled in the past decade. Prenatal exposures, including maternal diet and medications, may account for some of this increase. In the United States, progesterone for luteal support in assisted reproduction is commonly formulated in PN or sesame seed (SS) oil.

Purpose Diet is a potentially modifiable risk factor for endometriosis. It has been hypothesized that vitamins C, E, and the B vitamins may influence factors involved in the pathogenesis of endometriosis, such as oxidative stress and steroid hormone metabolism. In this large, prospective cohort study, we examined the relation between intake of vitamins C, E, the B vitamins, and the use of multivitamin supplements and diagnosis of endometriosis.Methods Data were collected from women in the Nurses' Health Study II between 1991 and 2005. Diet was assessed via food frequency questionnaire. Incidence rate ratios (RR) and 95% confidence intervals (CI) were estimated using time-varying Cox proportional hazards models.Results A total of 1383 incident cases of laparoscopically-confirmed endometriosis were observed among 70,617 women during 735,286 person years of follow-up. Intakes of thiamine (B1) (RR = 0.84, CI = 0.72-0.99; P-value, test for linear trend[P] = 0.04), folate (B9) (RR = 0.79, CI = 0.66-0.93; P = 0.003), vitamin C (RR = 0.81, CI = 0.68-0.95; P = 0.02), and vitamin E (RR = 0.70, CI = 0.59-0.83; P<0.0001) solely from food sources were inversely related to endometriosis diagnosis. However, intakes of these nutrients from supplements alone were unrelated to endometriosis.Conclusion Thiamine, folate, vitamin C, and vitamin E from food sources are inversely related to endometriosis risk. Our results suggest that the protective mechanism may not be related to the nutrients themselves but rather other components of foods rich in these micronutrients or factors correlated with diets high in these vitamin-rich foods.

The number of in vitro fertilization (IVF) cycles in the United States increased from fewer than 46,000 in 1995 to more than 120,000 in 2005. IVF and other assisted reproductive technology (ART) data are routinely collected and used to identify outcome predictors. However, researchers do not always make full use of the data due to their complexity. Design approaches have included restriction to first-cycle attempts only, which reduces power and identifies effects only of those factors associated with initial success. Many statistical techniques have been used or proposed for analysis of IVF data, ranging from simple ttests to sophisticated models designed specifically for IVF. We applied several of these methods to data from a prospective cohort of 2687 couples undergoing ART from 1994 through 2003. Results across methods are compared and the appropriateness of the various methods is discussed with the intent to illustrate methodologic validity. We observed a remarkable similarity of coefficient estimates across models. However, each method for dealing with multiple cycle data relies on assumptions that may or may not be expected to hold in a given IVF study. The robustness and reported magnitude of effect for individual predictors of IVF success may be inflated or attenuated due to violation of statistical assumptions, and should always be critically interpreted. Given that risk factors associated with IVF success may also advance our understanding of the physiologic processes underlying conception, implantation, and gestation, the application of valid methods to these complex data is critical.

Regular exercise has been associated with a 40%–80% reduction in risk for endometriosis in several case-control studies. However, women experiencing symptoms prior to their diagnosis may be less likely to exercise than healthy controls, thus biasing the observed association.

Background In the one study examining the relationship, adolescent physical activity was not associated with risk for endometriosis. Case-control studies have shown 40–80% reductions in risk for adult activity, while only an 11% reduction in endometriosis risk was observed in a recent prospective analysis.Methods Using data collected from the Nurses’ Health Study II, a prospective cohort study of premenopausal US nurses that began in 1989, we have attempted to clarify this relation. Data are updated every 2 yrs with follow-up for these analyses through to 2001. Women reported the average amount of time per week spent in moderate and strenuous recreational activity during three age periods: ages 12–13, ages 14–17, and ages 18–22. A metabolic equivalent (MET) score was assigned to each activity and these were summed to estimate total activity.Results During 637,747 person-years of follow-up, 1,481 cases of laparoscopically confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, birth weight, age at menarche, parity, oral contraceptive use, and body mass index (BMI), we observed a 16% increase in the risk for endometriosis comparing the greatest amount of activity (≥80 MET-h/wk) with the least (<20 MET-h/wk) during ages 12–13 (RR=1.16, 95% CI=0.98–1.37, p-value test for trend=0.02), and no associations for ages 14–17 or ages 18–22. In analyses of the individual activity types within each time period, only strenuous activity during ages 12–13 was associated with endometriosis.Conclusions We did not find evidence of a beneficial association between adolescent physical activity and laparoscopically confirmed endometriosis, but in fact found a small increase in risk.

To examine the association between intake of fruits and vegetables with high versus low pesticide residue burden and diagnosis of laparoscopically-confirmed endometriosis. The etiology of endometriosis is not well understood, but dietary factors may influence risk. Pesticides may act as endocrine disruptors and intake of pesticide contaminated food is a common exposure pathway.

To investigate barriers in accessing care for infertility in Mexico, because little is known about this issue for low and middle-income countries, which comprise 80% of the world’s population.

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.

The etiology of uterine leiomyoma (or fibroids) is poorly understood. Sex steroid hormones and growth factors have been hypothesized to play a role in their development, and anthropometric characteristics may influence uterine leiomyoma risk.

Most research treats endometriosis as a single entity, potentially obscuring informative subtype-specific associations with risk factors, biomarkers and treatment responses. A 2020 study raises the hypothesis that deep endometriosis oestrogen receptor-α expression might be associated with progestin treatment and the degree of post-surgical excision pain.

Insulin-like growth factor-1 (IGF-I), a potent mitogen, is hypothesized to influence breast cancer risk. In 3 previous studies, a polymorphism in the IGF-1 gene (sequence repeat length) was associated with plasma IGF-I level. We evaluated prospectively the relationships among a (CA)n repeat polymorphism in the IGF-1 gene, IGF-I level and breast cancer risk in a nested case-control study conducted within the Nurses' Health Study. Blood samples were collected in 1989–1990; up to June 1994, we identified 463 cases of breast cancer. One to 2 controls were selected per case, matched by age, menopausal status, postmenopausal hormone use, month and time of day of blood collection and fasting status, for a total of 622 controls. Although no significant trend was observed, plasma IGF-I levels were significantly lower among controls, with no copy of the 19 allele, compared with those homozygous for the 19 (CA)n repeat length (146 and 173 ng/ml, respectively; p-value for pairwise mean comparison = 0.005). In conditional logistic regression, controlling for established breast cancer risk factors, we observed no significant association between (CA)n repeat length genotype and risk of breast cancer [compared with repeat genotype 19/19—18/19 genotype relative risk (RR) = 0.96, 95% confidence interval (CI) = 0.56–1.64; 18/20 genotype RR = 0.92, 95% CI = 0.39–2.19; 19/20 genotype RR = 1.16, 95% CI = 0.82–1.64; 19/21 genotype RR = 0.69, 95% CI = 0.42–1.14; 20/20 genotype RR = 0.55, 95% CI = 0.28–1.10; 20/21 genotype RR = 0.72, 95% CI = 0.29–1.79]. Results did not vary substantially when evaluated according to menopausal status, tumor receptor status or category of other breast cancer risk factors. Although a modest association cannot be excluded, our data do not support an important relation between this IGF-1 gene polymorphism and breast cancer risk. © 2002 Wiley-Liss, Inc.

Two major methodological problems that impact clinical research in endometriosis are the absence of a low-cost, highly reliable method for diagnosing endometriosis and the possibility that endometriosis is actually multiple different diseases that we have not yet been able to differentiate. Animal models of endometriosis clearly demonstrate that advanced endometriosis causes reduced fertility. In humans, endometriosis and infertility are commonly associated. However, few data from high-quality clinical trials demonstrate that endometriosis causes infertility in humans. Future research should focus on the implications of the observation that, in ovarian endometriosis cysts, the epithelium is monoclonal. This observation suggests that nonrandom somatic mutations cause ovarian endometriosis cysts. If somatic mutations cause ovarian endometriosis cysts, it is likely that a small number of genes can be identified that play a central role in pathogenesis of this disease.

Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodologic problems related to disease definition and control selection. Nevertheless, a better picture of the epidemiology of endometriosis has emerged over the past few decades. Prevalence estimates of the disease in clinic populations vary from about a 4 occurrence of largely asymptomatic endometriosis found in women undergoing tubal ligation to 50 of teenagers with intractable dysmenorrhea. General population incidence during the 1970s in this country has been suggested to be 1.6 per 1000 white females aged 15-49, while a more current study based upon hospital discharges finds endometriosis as a first listed diagnosis in 1.3 per 1000 discharges in women aged 15-44. There is a clinical impression that blacks have lower rates of endometriosis and Orientals have higher rates than whites. A variety of personal risk factors for endometriosis have also been described. Women with endometriosis may be taller and thinner. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. There is support for the idea that lifestyle exposures that might raise or lower estrogen levels could affect risk, including a decreased risk associated with smoking and exercise and an increased risk associated with caffeine or alcohol use. These risk factors appear to be compatible with the central importance of retrograde menstruation influenced by outflow obstruction that might affect its amount, immune factors that might affect its ability to be cleared, or hormonal stimuli that might affect its growth. In this model, dysmenorrhea could be either a disease symptom or a manifestation of outflow obstruction. Nulliparity could be either a consequence of disease or a cause since nulliparous women would not have the benefit of cervical dilation associated with labor and delivery. Since there is evidence that family history is a risk factor for disease, a challenge is how to integrate genetic factors into the model. The genetics of endometriosis might be advanced if we could identify an "endometriosis phenotype". We propose that this may consist of early menarche, short cycles, painful periods, subfertility, and possibly tall stature that could be explained by genetic factors that predispose to poor endowment of germ cells and canalization defects of the cervix. The value of establishing an "endometriosis phenotype" is that, as candidates for genetic markers are identified, particular genotypes can be correlated with these factors even if a formal diagnosis of endometriosis has not been made. Additional well-designed case-control and cohort studies will be necessary to test theories related to pathogenesis, establish the precise relationship between reproductive morbidity and endometriosis, identify specific genetic factors, and establish long-term risks.

More than 20 studies have investigated the relation between meat and dairy food consumption and breast cancer risk with conflicting results. Our objective was to evaluate the risk of breast cancer associated with meat and dairy food consumption and to assess whether non-dietary risk factors modify the relation.

Debilitating abdominal and pelvic pain conditions are highly prevalent in adults and adolescents. Assessing sensory functioning among people with painful conditions is important in understanding the disease. Reference values for Quantitative Sensory Testing (QST), used to assess sensory perception, are well established for other regions but not the abdomen. The aim of this study was to establish QST reference values for the abdomen in a diverse group of males and female adults and adolescents. In this cross-sectional study, 181 healthy, pain-free males and females from age 12-50 years completed a comprehensive QST battery in upper and lower abdomen and a control site. The QST battery consisted of: Dynamic Mechanical Touch (DMT), Light Touch Detection (LTD), Sharp Prick Detection (SPD), Pressure Pain Threshold (PPT), Temporal Summation of Pain (TSP), Cool and Warmth Detection Thresholds (CDT, WDT), and Cold and Heat Pain Thresholds (CPT, HPT). Participants also answered pain-related questionnaires including the Pain Catastrophizing Scale, 36-Item Short Form Survey, Pain Sensitivity Questionnaire (PSQ). Mean and standard deviation values were calculated for each QST sub-test and separated by age, sex, and body site (upper and lower abdomen, and control site). Results of RMANOVAs indicated that pain sensitivity differed by site and modality, with no consistent pattern indicating one area was generally more sensitive than others. There were also effects of sex with males experienced less sensitivity to pressure and cold pain than females. Self-reported pain sensitivity (PSQ) was associated with greater abdominal sensitivity to punctate, cold, and heat pain. This paper successfully established reference QST values for the upper and lower abdominal sites for healthy, pain-free male and female adolescents and adults which will be critical in understanding somatosensory nervous system function among patients with abdominal and pelvic pain. These data will be critical in understanding nociceptive processing in the abdominal region. Boston Center for Endometriosis/Marriott Family Foundation Investigator Grant Office of Faculty Developtment at Boston Children's Hospital.

Infertility has been associated with common chronic non-communicable diseases. However, the association of infertility with long-term mortality is unclear.

ObjectiveTo investigate the association of spontaneous abortion with the risk of all cause and cause specific premature mortality (death before the age of 70).DesignProspective cohort study.SettingThe Nurses’ Health Study II (1993-2017), United States.Participants101 681 ever gravid female nurses participating in the Nurses’ Health Study II.Main outcomes measuresLifetime occurrence of spontaneous abortion in pregnancies lasting less than 6 months, determined by biennial questionnaires. Hazard ratios and 95% confidence intervals for all cause and cause specific premature death according to the occurrence of spontaneous abortion, estimated with time dependent Cox proportional hazards models.ResultsDuring 24 years of follow-up, 2936 premature deaths were recorded, including 1346 deaths from cancer and 269 from cardiovascular disease. Crude all cause mortality rates were comparable for women with and without a history of spontaneous abortion (1.24 per 1000 person years in both groups) but were higher for women experiencing three or more spontaneous abortions (1.47 per 1000 person years) and for women reporting their first spontaneous abortion before the age of 24 (1.69 per 1000 person years). The corresponding age adjusted hazard ratios for all cause premature death during follow-up were 1.02 (95% confidence interval 0.94 to 1.11), 1.39 (1.03 to 1.86), and 1.27 (1.11 to 1.46), respectively. After adjusting for confounding factors and updated dietary and lifestyle factors, the occurrence of spontaneous abortion was associated with a hazard ratio of 1.19 (95% confidence interval 1.08 to 1.30) for premature mortality during follow-up. The association was stronger for recurrent spontaneous abortions (hazard ratio 1.59, 95% confidence interval 1.17 to 2.15 for three or more spontaneous abortions; 1.23, 1.00 to 1.50 for two; and 1.16, 1.05 to 1.28 for one compared with none), and for spontaneous abortions occurring early in a woman’s reproductive life (1.32, 1.14 to 1.53 for age ≤23; 1.16, 1.01 to 1.33 for ages 24-29; and 1.12, 0.98 to 1.28 for age ≥30 compared with none). When cause specific mortality was evaluated, the association of spontaneous abortion with premature death was strongest for deaths from cardiovascular disease (1.48, 1.09 to 1.99). Spontaneous abortion was not related to premature death from cancer (1.08, 0.94 to 1.24).ConclusionsSpontaneous abortion was associated with an increased risk of premature mortality, particularly death from cardiovascular disease.

IMPORTANCE: Menstrual cycle dysfunction is associated with insulin resistance, a key feature early in the pathogenesis of type 2 diabetes. However, the evidence linking irregular and long menstrual cycles with type 2 diabetes is scarce and inconsistent. OBJECTIVES: To evaluate the associations between menstrual cycle characteristics at different points throughout a woman’s reproductive life span and risk of type 2 diabetes and the extent to which this association is modified by lifestyle factors. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 75?546 premenopausal US female nurses participating in the Nurses’ Health Study II from 1993 to June 30, 2017. Data analysis was performed from February 1 to December 30, 2019. EXPOSURES: Self-reported usual length and regularity of menstrual cycles at the age ranges of 14 to 17 years, 18 to 22 years, and 29 to 46 years. MAIN OUTCOMES AND MEASURES: Incident type 2 diabetes identified through self-report and confirmed by validated supplemental questionnaires. RESULTS: Among the 75?546 women in the study at baseline, the mean (SD) age was 37.9 (4.6) years (range, 29.0-46.0 years). A total of 5608 participants (7.4%) had documented new cases of type 2 diabetes during 1?639?485 person-years of follow-up. After adjustment for potential confounders, women reporting always having irregular menstrual cycles between the age ranges of 14 to 17 years, 18 to 22 years, and 29 to 46 years were, respectively, 32% (95% CI, 22%-44%), 41% (95% CI, 23%-62%), and 66% (95% CI, 49%-84%) more likely to develop type 2 diabetes than women reporting very regular cycles (within 3-4 days of expected period) in the same age range. Similarly, women reporting a usual cycle length of 40 days or more between the age ranges of 18 to 22 years and 29 to 46 years were, respectively, 37% (95% CI, 19%-57%) and 50% (95% CI, 36%-65%) more likely to develop type 2 diabetes during follow-up compared with women reporting a usual cycle length of 26 to 31 days in the same age ranges. These associations appeared to be stronger among women with overweight or obesity, a low-quality diet, and low levels of physical activity. The relative excess risk of type 2 diabetes due to the interaction between irregular and long menstrual cycles and the overall unhealthy lifestyle score was 0.73 (95% CI, 0.57-0.89) and 0.68 (95% CI, 0.54-0.83), respectively. CONCLUSIONS AND RELEVANCE: In this cohort study of US female nurses participating in the Nurses’ Health Study II, irregular and long menstrual cycles throughout life were associated with a greater risk of type 2 diabetes, particularly among women with overweight or obesity, a low-quality diet, and low levels of physical activity.

Endometriosis affects 1 in 10 women and is characterized by the presence of abnormal endometrium at ectopic sites. ARID1Amutations are observed in deeply invasive forms of the disease, often correlating with malignancy. To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium. We show that super-enhancers marked by high H3K27 acetylation are strongly associated with ARID1A binding. ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation. ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1Amutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1Amutant endometrial invasion. Broadly, our findings provide rationale for therapeutic strategies targeting super-enhancers in ARID1Amutant endometrium.

Endometriosis affects 6% to 10% of women of reproductive age. Previous studies have demonstrated that risk of this disease is influenced by genetic factors; the estimated heritability is about 51%. Genome-wide association studies have investigated genetic variations in the DNA of women that predispose them to develop endometriosis, but have not addressed the genetic burden for different stages of disease severity.

Introduction:Women with a history of hypertensive disorders in pregnancy (HDP; gestational hypertension [GHTN] or preeclampsia) have an increased risk of CVD risk factors and events compared to women with normotensive pregnancies. However, the extent to which the relationship between HDP and CVD events is mediated by established CVD risk factors is less clear.Hypothesis:We hypothesized that a large proportion of the HDP-CVD relationship would be mediated by subsequent CVD risk factors — chronic hypertension (CHTN), type 2 diabetes (T2D), hypercholesterolemia, and BMI.Methods:Parous women free of prior CVD events, CHTN, T2D, and hypercholesterolemia at first birth in the Nurses’ Health Study II comprised the analytic sample (n=57,974). Pregnancy history was retrospectively reported in 2009. Women were followed for confirmed CVD events (coronary heart disease [non-fatal or fatal MI, fatal CHD] or stroke [non-fatal or fatal]) from first birth through 2015. Potential mediators were self-reported on biennial questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HDP in first pregnancy (preeclampsia or GHTN vs. normotension [ref]) and CVD, adjusting for age, race/ethnicity, parental education, family history of CVD before age 60, and pre-pregnancy risk factors (e.g., smoking, diet, and BMI). To evaluate the proportion of the HDP-CVD association that was jointly mediated by the CVD risk factors we used the difference method, comparing a model including these four factors to a model without them.Results:Nine percent of women (n=5,306) had a history of HDP in first pregnancy (preeclampsia: 6.3%; GHTN: 2.9%). CVD events occurred in 650 women with normotension in first pregnancy, 30 with GHTN, and 81 with preeclampsia. Adjusting for pre-pregnancy confounders, women with HDP in first pregnancy had a 63% higher rate of incident CVD (CI: 1.33-2.00) compared to women with normotension in first pregnancy; in particular, the strongest association was observed between preeclampsia and CHD (HR=2.18, CI: 1.62-2.93). The overall HDP-CVD association was largely mediated by the group of four CVD risk factors (HDP: proportion mediation [PM]=65%, CI: 35-87; preeclampsia: PM=57%, CI: 21-87; GHTN: PM=99%, CI: inestimable). All CVD risk factors contributed to mediation, but chronic hypertension accounted for the largest proportion.Conclusions:While approximately 40% of the association between preeclampsia and CVD remained unexplained, almost all the increased risk of CVD conferred by a history of GHTN was jointly accounted for by the development of established risk factors postpartum. Screening for CHTN, T2D, hypercholesterolemia, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.

ObjectiveTo 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.

In view of increased attention to limiting multiple gestations resulting from assisted reproductive techniques, outcomes were assessed by analyzing data reported to the Centers for Disease Control and Prevention from 1995 to 2001 by U.S. fertility clinics. In addition, data on twin births and triplet or higher-order multiple births were taken from the National Center for Health Statistics. Each year, approximately 5% to 9% of fertility clinics failed to submit data or lacked verification that reported success rates were correct.