Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

The Burden of Pelvic Pain Associated With Endometriosis Among Women in Selected European Countries and the United States: A Restricted Systematic Review.

OBJECTIVE: To evaluate the burden of endometriosis-associated pelvic pain (EAPP) on health-related quality of life (HRQoL) among women living in similar socio-economic conditions. DATA SOURCES: Searches were performed in PubMed and Embase on September 26, 2022. The review was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocol (PRISMA-P) and was registered on PROSPERO (ID: CRD42023370363). METHODS OF STUDY SELECTION: Due to the high volume of eligible publications following initial review, inclusion criteria were restricted to studies undertaken in France, Germany, Italy, Spain, the United Kingdom, and the United States. This restriction was applied before screening as these countries have broad social and economic similarities, and previous studies in the literature suggest pain reporting and experience are influenced by numerous socio-cultural factors. Eligible studies were those published between 2013 and 2022 and include a sample size of ≥50 participants. The search strategy identified all relevant publications relating to the burden of illness due to EAPP. A variety of terms are used in the literature to describe pain associated with endometriosis, and this was considered in the design of the search strategy and screening procedure. TABULATION, INTEGRATION, AND RESULTS: The database searches resulted in a total of 6139 records. After removal of duplicates, 3855 records were assessed further. A total of 27 publications were identified as eligible. Fourteen (52%) were from Italy, 5 (19%) were multinational studies, 4 (15%) were from the United States, 3 (11%) were from Spain, and 1 (4%) was from Germany. Most studies were cross-sectional (n = 15; 56%); 7 (26%) were case-control studies; 3 (11%) were cohort studies; and 2 (7%) were longitudinal studies. These publications collectively highlighted an association between EAPP and reduced HRQoL. Several studies showed that EAPP was associated with lower HRQoL when compared with endometriosis without pain and potentially with chronic pelvic pain caused by other conditions, although the evidence is limited in this case. Moreover, the studies reported detrimental effects on general HRQoL, mental health functioning, and sexual functioning, culminating in reduced work productivity and difficulties in performing everyday activities. The associations were generally similar across study populations, including adolescents, as well as younger and older women. Results were consistent across the range of different patient-reported outcome tools used to assess HRQoL. CONCLUSION: The existing literature suggests that, among women in selected European countries and the United States, EAPP is associated with reduced HRQoL, including impaired mental and sexual functioning, as well as reduced work performance and productivity; each of which may contribute to the societal burden of endometriosis.

Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use.

Introduction: Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods: The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2-ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results: In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67-0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion: The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.

Subgroups of pelvic pain are differentially associated with endometriosis and inflammatory comorbidities: a latent class analysis.

ABSTRACT: Chronic pelvic pain is heterogeneous with potentially clinically informative subgroups. We aimed to identify subgroups of pelvic pain based on symptom patterns and investigate their associations with inflammatory and chronic pain-related comorbidities. Latent class analysis (LCA) identified subgroups of participants (n = 1255) from the Adolescence to Adulthood (A2A) cohort. Six participant characteristics were included in the LCA: severity, frequency, and impact on daily activities of both menstruation-associated (cyclic) and non-menstruation-associated (acyclic) pelvic pain. Three-step LCA quantified associations between LC subgroups, demographic and clinical variables, and 18 comorbidities (10 with prevalence ≥10%). Five subgroups were identified: none or minimal (23%), moderate cyclic only (28%), severe cyclic only (20%), moderate or severe acyclic plus moderate cyclic (9%), and severe acyclic plus severe cyclic (21%). Endometriosis prevalence within these 5 LCA-pelvic pain-defined subgroups ranged in size from 4% in "none or minimal pelvic pain" to 24%, 72%, 70%, and 94%, respectively, in the 4 pain subgroups, with statistically significant odds of membership only for the latter 3 subgroups. Migraines were associated with significant odds of membership in all 4 pelvic pain subgroups relative to those with no pelvic pain (adjusted odds ratios = 2.92-7.78), whereas back, joint, or leg pain each had significantly greater odds of membership in the latter 3 subgroups. Asthma or allergies had three times the odds of membership in the most severe pain group. Subgroups with elevated levels of cyclic or acyclic pain are associated with greater frequency of chronic overlapping pain conditions, suggesting an important role for central inflammatory and immunological mechanisms.

Pelvic pain symptoms and endometriosis characteristics in relation to oxidative stress among adolescents and adults with and without surgically-confirmed endometriosis.

Background: While the majority of reproductive-aged females will experience pelvic pain during their lives, biological mechanisms underlying pelvic pain are not well understood. We investigated associations between pelvic pain symptoms and oxidative stress among people with and without surgically-confirmed endometriosis. Methods: Using an enzyme-linked immunosorbent assay, we measured 8-Hydroxy-2'-deoxyguanosine (8-OHdG) in urine samples and corrected for creatinine levels in 434 surgically-confirmed endometriosis participants compared to 605 participants never diagnosed with endometriosis. At enrollment, participants reported details of their pelvic pain symptoms. Linear regression was used to compute geometric mean (GM) creatinine-corrected 8-OHdG levels with 95% confidence intervals (CI) among all participants and those with and without endometriosis separately, adjusting for potential confounders. Interactions by surgically-confirmed endometriosis status were tested by Wald statistics. Results: No trends in 8-OHdG were observed among those with or without endometriosis for severity or frequency of dysmenorrhea, acyclic pelvic pain, dyspareunia or pain with bowel movements. Among endometriosis participants, lower 8-OHdG levels were observed for participants with any white, blue/black, or brown lesions (GM=76.7 versus 82.9 ng/mg; p=0.10), which was primarily driven by lower levels of 8-OHdG for any blue/black lesions (GM=72.8 versus 81.6 ng/mg; p=0.05). Conclusion: While no associations were observed between 8-OHdG and pelvic pain symptoms, future research is needed to assess how other pathways of oxidative damage, e.g. through proteins or lipids, may affect endometriosis-associated symptoms. Additionally, further research is needed to understand differences in oxidative stress among endometriosis lesion sub-phenotypes.

Quantitative somatosensory testing of the abdomen: establishing initial reference values across developmental age and biological sex.

ABSTRACT: Abdominal pain is a common symptom of several debilitating conditions (eg, inflammatory bowel disease, irritable bowel syndrome, and endometriosis) and affects individuals throughout their lifespan. Quantitative sensory testing (QST) reference values exist for many body sites but not the abdomen. Using a QST battery adapted from the German Research Network on Neuropathic Pain, we collected QST data on the upper and lower abdomen in 181 pain-free participants, ages 12 to 50 years, to establish reference values by age and biological sex. The normative values are presented as medians for each QST measure by sex (male, n = 63; female, n = 118) and across 3 age categories (adolescents: 12-19 years, n = 48; young adults: 20-30 years, n = 87; and adults: 31-50 years, n = 46). Evaluating the sensory functioning of the abdomen and characterizing ranges of QST measures is an essential first step in understanding and monitoring the clinical course of sensory abnormalities in patients with underlying diseases affecting the abdomen and pelvis. The impact of age and development on sensory functioning is necessary, given age-related changes in pain perception and modulation.

Estimated Ovulatory Years Prior to Menopause and Postmenopausal Endogenous Hormone Levels.

BACKGROUND: Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones. METHODS: Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses' Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated. RESULTS: Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI. CONCLUSIONS: This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone. IMPACT: A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.

Endogenous Steroid Hormone Concentrations and Risk of Endometriosis in Nurses' Health Study II.

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.

Trends in pelvic pain symptoms over 2 years of follow-up among adolescents and young adults with and without endometriosis.

ABSTRACT: 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.

Differences in characteristics and use of complementary and alternative methods for coping with endometriosis-associated acyclic pelvic pain across adolescence and adulthood.

Introduction: Over four million women in the US alone have been diagnosed with endometriosis. For those living with this disease, surgery and hormonal treatment reduce associated pelvic pain in some, while others continue to experience life impacting pain. Therefore, identification of accessible and cost-effective methods of pain reduction to compliment current treatment is urgently needed. Our objective was to quantify the prevalence of complementary and alternative methods used to manage acyclic pelvic pain and their reported benefit among women of different age groups living with endometriosis. Methods: We used baseline questionnaire data from laparoscopically-confirmed endometriosis cases who completed a WERF EPHect compliant questionnaire in the longitudinal cohort of The Women's Health Study: From Adolescence to Adulthood (A2A). Participants with acyclic pelvic pain were asked to indicate specific methods or activities that either helped or worsened their pelvic/lower abdominal pain. Differences among age groups [adolescent (<18 years), young adult (18-25 years), and adult (>25 years)] were assessed using Fisher's exact test. Results: Of the 357 participants included in analysis, sleep for coping was reported more frequently among adolescents (n = 59, 57.3%) compared to young adults (n = 40, 44.0%) and adults (n = 19, 31.1%; p = 0.004). Adolescents also reported more frequent use of music (n = 29, 21.2%) than young adults (n = 10, 7.0%) and adults (n = 7, 9.1%; p = 0.001). Exercise worsened pain most commonly among adolescents (n = 82, 59.9%), followed by younger adults (n = 67, 46.9%), and adults (n = 27, 35.1%; p = 0.002). Discussion: Our analysis of participants in the A2A cohort showed that the prevalence of complementary and alternative methods used for coping with endometriosis-associated acyclic pelvic pain varied by age group. Future studies should aim to provide information that will further inform decisions in making care plans for managing endometriosis-associated pain that is effective, accessible, and tailored to the preferences of the patient.

Visualized peritoneal fluid variation in adolescents and young adults with endometriosis: is there more to it?

Background: Peritoneal fluid is a medium for endometriosis-associated biomarker discovery from which the local peritoneal environment and pathophysiologic pathways are often inferred. Therefore, we evaluated the associations between peritoneal fluid color and volume at time of endometriosis-related laparoscopic surgery with patient characteristics, endometriosis type and lesion location in adolescents and young adults with endometriosis. Methods: We conducted a cross-sectional analysis among 545 patients undergoing surgery for endometriosis who enrolled in the Women's Health Study: from Adolescence to Adulthood cohort study. Patient characteristics, surgically visualized endometriosis phenotypes, and gross characteristics of peritoneal fluid were collected in compliance with World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (EPHect) tools. Chi-square or Fisher's exact tests were applied to test for differences across categories. Results: Most of the patients were adolescents or young adults (86% age <25 years) of white race (89%), with only superficial peritoneal lesions and rASRM stage = I/II observed at surgery (both 95%). We observed variation in peritoneal fluid color across different menstrual cycle phases at time of surgery (p = 0.006). Among those who were cycling at time of surgery, endometriosis patients with red peritoneal fluid were most likely to be in the proliferative phase (49%) compared to the secretory phase (27%), while those with yellow or orange peritoneal fluid were most likely to be in the secretory phase (57% and 86% respectively). Yellow color was significantly less common in those taking combined oral contraceptives but much more common with progesterone only formulation exposure (p = 0.002). Peritoneal fluid volume did not differ by cycle phase but was more likely to be low (≤6 ml) for those exposed to hormones at time of surgery (p = 0.01). Those with acyclic pelvic pain were less likely to have red peritoneal fluid (p = 0.001) but had greater volume (p = 0.02) compared to those without. Conclusion: Our findings highlight the importance of accounting for menstrual cycle phase and hormonal exposures when designing research using peritoneal fluid samples and inferring from biomarker results intended to advance our understanding of endometriosis and associated symptom pathophysiology.

Cohort profile: The Endometriosis pain QUality aftEr Surgical Treatment (EndoQUEST) Study.

Endometriosis affects reproductive-aged females and varies considerably in terms of symptom presentation, morphologic features, and treatment response. Most studies investigating symptom recurrence after an endometriosis-related surgery have been conducted among adults. The Endometriosis pain QUality aftEr Surgical Treatment (EndoQUEST) Study was established to assess characteristics and biomarkers that are associated with pain remediation and improved quality of life after an endometriosis-related surgery among adolescents and young adults. This paper describes the EndoQUEST methodology, summarizes baseline descriptive factors, and compares characteristics by participant retention status. We enrolled 100 surgically-confirmed endometriosis participants aged 12-23 years who provided questionnaire data on reproductive and behavioral factors, pain characteristics and quality of life at three time points; before surgery, 6 weeks to 26 weeks after surgery, and 1 year after surgery. Among these 100 participants, 88 provided blood and/or saliva at all three time points, while 12 provided blood and/or saliva samples only before surgery and 6 to 26 weeks after surgery. There was little evidence of lost to follow-up at 1 year after surgery due to pain symptoms, as pain and quality of life characteristics were similar between participants who completed the questionnaire 1 year after surgery and those who did not. Analyses utilizing these longitudinal data will advance personalized treatment decision making for adolescents and young adults with endometriosis.

Association Between Laparoscopically Confirmed Endometriosis and Risk of Early Natural Menopause.

Importance: Early natural menopause (ENM) has been associated with reduced reproductive span, cardiovascular disease risk, and early mortality. The potential adverse implications of endometrioma surgery for ovarian reserve are known, yet the association of endometriosis with menopausal timing remains understudied. Objective: To investigate the association between endometriosis and risk for ENM. Design, Setting, and Participants: This large, population-based cohort study analyzed data from the Nurses' Health Study II cohort questionnaires from the 1989 to 2015 questionnaire cycles. The sample included premenopausal women aged 25 to 42 years at baseline or enrollment in 1989. Cumulative follow-up rate was greater than 90%, and participants continued follow-up until the onset of ENM, age 45 years, hysterectomy, oophorectomy, cancer diagnosis, death, loss to follow-up, or end of follow-up in May 2017, whichever occurred first. Data analyses were conducted from October 26, 2020, to April 27, 2021. Exposures: Endometriosis diagnosis status was queried in the biennial questionnaires, with participants reporting physician diagnosis and whether the diagnosis was laparoscopically confirmed. Main Outcomes and Measures: Natural menopause before age 45 years. Menopause status was assessed every 2 years. Results: The study included 106 633 premenopausal women with a mean (SD) age of 34.8 (4.3) years at baseline, of whom 3921 reported a laparoscopically confirmed endometriosis diagnosis. During 1 508 462 person-years of follow-up, 6640 participants reported being diagnosed with endometriosis, 99 993 never reported endometriosis, and 2542 reported experiencing ENM. In the age- and calendar time-adjusted model, laparoscopically confirmed endometriosis was associated with a 50% greater risk for ENM (hazard ratio [HR], 1.51; 95% CI, 1.30-1.74). A similar risk was observed after adjusting for race and ethnicity and time-varying anthropometric and behavioral factors (HR, 1.46; 95% CI, 1.26-1.69). With additional adjustment for reproductive factors, the HR of ENM was attenuated but significant (HR, 1.28; 95% CI, 1.10-1.48). A greater risk of ENM was observed among women who were nulliparous after stratifying by parity (nulliparous vs parous: HR, 1.46 [95% CI, 1.15-1.86] vs 1.14 [95% CI, 0.94-1.39]; P for heterogeneity = .05) or who never used oral contraceptives when stratifying by oral contraceptive use (never vs ever: HR, 2.03 [95% CI, 1.34-3.06] vs 1.20 [95% CI, 1.02-1.42]; P for heterogeneity = .02). No significant differences were observed in the association between endometriosis and ENM when stratifying by body mass index (calculated as weight in kilograms divided by height in meters squared; <25 vs ≥25: HR, 1.20 [95% CI, 0.99-1.45] vs 1.43 [95% CI, 1.11-1.83; P for heterogeneity = .34), cigarette smoking status (never vs ever: HR, 1.36 [95% CI, 1.13-1.65] vs 1.11 [95% CI, 0.87-1.42]; P for heterogeneity = .57), or history of infertility attributed to ovulatory disorder (no vs yes: HR, 1.28 [95% CI, 1.08-1.51] vs 1.28 [95% CI, 0.90-1.82]; P for heterogeneity = .86). Conclusions and Relevance: This cohort study found a risk for ENM in women with laparoscopically confirmed endometriosis. These women compared with those without endometriosis may be at a higher risk for shortened reproductive duration, particularly those who were nulliparous or never used oral contraceptives.

Oral contraceptive use by formulation and breast cancer risk by subtype in the Nurses' Health Study II: a prospective cohort study.

BACKGROUND: Oral contraceptive use has been associated with a higher breast cancer risk; however, evidence for the associations between different oral contraceptive formulations and breast cancer risk, especially by disease subtype, is limited. OBJECTIVE: This study aimed to evaluate the associations between oral contraceptive use by formulation and breast cancer risk by disease subtype. STUDY DESIGN: This prospective cohort study included 113,187 women from the Nurses' Health Study II with recalled information on oral contraceptive usage from 13 years of age to baseline (1989) and updated data on usage until 2009 collected via biennial questionnaires. A total of 5799 breast cancer cases were identified until the end of 2017. Multivariable Cox proportional hazards models estimated hazard ratios and 95% confidence intervals for the associations between oral contraceptive use and breast cancer risk overall and by estrogen and progesterone receptor and human epidermal growth factor receptor 2 status. Oral contraceptive use was evaluated by status of use (current, former, and never), duration of and time since last use independently and cross-classified, and formulation (ie, estrogen and progestin type). RESULTS: Current oral contraceptive use was associated with a higher risk for invasive breast cancer (hazard ratio, 1.31; 95% confidence interval, 1.09-1.58) when compared with never use, with stronger associations observed for longer durations of current use (>5 years: hazard ratio, 1.56; 95% confidence interval, 1.23-1.99; ≤5 years: hazard ratio, 1.19; 95% confidence interval, 0.95-1.49). Among former users with >5 years since cessation, the risk was similar to that of never users (eg, >5 to 10 years since cessation: hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). Associations did not differ significantly by tumor subtype. In analyses by formulation, current use of formulations containing levonorgestrel in triphasic (hazard ratio, 2.83; 95% confidence interval, 1.98-4.03) and extended cycle regimens (hazard ratio, 3.49; 95% confidence interval, 1.28-9.53) and norgestrel in monophasic regimens (hazard ratio, 1.91; 95% confidence interval, 1.19-3.06), all combined with ethinyl estradiol, was associated with a higher breast cancer risk when compared with never oral contraceptive use. No association was observed for current use of the other progestin types evaluated (norethindrone, norethindrone acetate, ethynodiol diacetate, desogestrel, norgestimate, and drospirenone), however, sample sizes were relatively small for some of the subgroups, limiting these analyses. CONCLUSION: Current oral contraceptive use was associated with a higher risk for invasive breast cancer regardless of disease subtype, however, the risk in former users was comparable with never users 5 years after cessation. In analyses by progestin type, associations were observed for select formulations containing levonorgestrel and norgestrel. Assessment of the associations for newer progestin types (desogestrel, norgestimate, drospirenone) was limited by sample size, and further research on more recently introduced progestins is warranted.

Pelvic floor, abdominal and uterine tenderness in relation to pressure pain sensitivity among women with endometriosis and chronic pelvic pain.

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).

Co-occurrence of immune-mediated conditions and endometriosis among adolescents and adult women.

PROBLEM: Associations between immune dysfunction conditions (eg, systemic lupus erythematous, rheumatoid arthritis) and endometriosis have been observed in adult women, but not assessed among a younger population. We investigated the association between immune-mediated conditions and endometriosis among young women. METHOD OF STUDY: This cross-sectional analysis in the Women's Health Study: From Adolescence to Adulthood included 551 participants with surgically diagnosed endometriosis (median age=19) and 652 controls without endometriosis (median age=24). Participants completed an expanded Endometriosis Phenome and Biobanking Harmonization Project questionnaire. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the associations between autoimmune/inflammatory, atopic, chronic pain/fatigue, and endocrine disorders with endometriosis, adjusting for confounders. RESULTS: Participants with any autoimmune and/or inflammatory condition had an increased odds of co-occurring endometriosis (OR: 1.87; CI: 0.92-3.80), as did participants with allergies (OR: 1.76; CI: 1.32-2.36), asthma (OR: 1.35; CI: 0.97-1.88), chronic fatigue syndrome and/or fibromyalgia (OR: 5.81; CI: 1.89-17.9), or previous mononucleosis (OR: 1.75; CI: 1.14-2.68). Odds of endometriosis were lower among participants with eczema (OR: 0.68; CI: 0.44-1.04). We observed a positive trend between the number of immune-mediated conditions and the odds of endometriosis (p-trend=0.0002). Endocrine disorders were not associated with endometriosis. CONCLUSIONS: Among this population of adolescents and adult women, endometriosis was more likely among participants with autoimmune and/or inflammatory diseases, allergies, asthma, previous mononucleosis infection, and chronic fatigue and/or fibromyalgia. We observed that an increasing number of immune-mediated conditions were positively associated with endometriosis risk. It is important for clinicians who care for adolescents and women with these conditions to consider endometriosis as a comorbidity.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947-1964: The Nurses' Health Study II, a prospective cohort study.

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses' Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65-0.91]; >10 years of use, 0.43 [0.32-0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41-0.67]) and second-generation progestins (0.43 [0.30-0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50-0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49-0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Mosaic fungal individuals have the potential to evolve within a single generation.

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space.

Estrogen Receptor-ß Expression of Ovarian Tumors and Its Association with Ovarian Cancer Risk Factors.

BACKGROUND: Differential associations between ovarian cancer risk factors and estrogen receptor-α (ERα) ovarian tumor expression have been noted; however, no research has assessed estrogen receptor-ß (ERß) expression. Thus, in exploratory analyses, we assessed the association of several factors with ovarian cancer risk by ERß tumor status. METHODS: We conducted a nested case-control study within the prospective Nurses' Health Study cohorts (NHS/NHSII), with exposures collected through biennial questionnaires. Paraffin-embedded tumor blocks were requested for cases diagnosed from 1976 to 2006 (NHS) and 1989 to 2005 (NHSII) and tissue microarrays were stained for nuclear ERß (ERß-nuc) and cytoplasmic ERß (ERß-cyto), with any staining considered positive (+). We obtained odds ratios (OR) and 95% confidence intervals (CI) using multivariate polytomous logistic regression. RESULTS: We included 245 cases [43% ERß-cyto (+) and 71% ERß-nuc (+)] and 1,050 matched controls. An inverse association was observed between parity and risk of ERß-nuc (+) (OR, parous vs. nulliparous: 0.46; 95% CI, 0.26-0.81), but not ERß-nuc (-) tumors (OR, parous vs. nulliparous: 1.51; 95% CI, 0.45-5.04; P heterogeneity = 0.04). Conversely, parity was inversely associated with ERß-cyto (-) tumors (OR, parous vs. nulliparous: 0.42; 95% CI, 0.23-0.78), but was not associated with ERß-cyto (+) tumors (OR, parous vs. nulliparous: 1.08; 95% CI, 0.45-2.63; P heterogeneity = 0.05). Associations for other exposures, including hormone therapy, did not differ by ERß-nuc or ERß-cyto status. CONCLUSIONS: Our results suggest that parity may influence ovarian cancer risk, in part, through alterations in ERß localization within tumor cells. IMPACT: Alterations in ERß expression and localization appear to be important for ovarian cancer etiology. Future research should confirm our results and assess potential biologic mechanisms for the observed associations.

Evaluation of CA125 in relation to pain symptoms among adolescents and young adult women with and without surgically-confirmed endometriosis.

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