Large Cohort Of Women Research Articles

Lack of oral involvement in a large cohort of women with vulvar lichen sclerosus - a multicenter prospective study.

We assessed the prevalence of oral lichen sclerosus in a cohort of women affected with vulvar lichen sclerosus (VLS). This prospective, observational study included adult female patients with a histologically proven VLS who attended the Vulva Clinics of three Dermatology Units from January 2020 to July 2023. During this period, all VLS patients were asked to be examined in their oral cavities in order to detect any possible sign of oral diseases, which were then biopsied. Three hundred women (mean age 64.5 ±13.0years) were included, of whom 21 (7%) had a concurrent extragenital LS. In six (2%) patients, white, non-removable lesions were found at oral inspection and biopsied. All cases were histologically lichen planus. No other clinically relevant oral lesions were found. The six women with histologically proven oral lichen planus had more frequent periodontal and autoimmune diseases than the other included subjects. Our findings confirm the absolute rarity of oral involvement in patients with VLS. They suggest that the oral mucosa, unlike the genitals, is a setting which weakly leads to development of LS, also in predisposed subjects.

7497 Association between Plasma Prolactin Levels and Menopausal Vasomotor Symptoms

Abstract Disclosure: F. Galbiati: None. J. Kang: None. D.J. Cote: None. J.E. Manson: None. U.B. Kaiser: None. Background: High prolactin (PRL) levels inhibit gonadotropin-releasing hormone (GnRH), causing hypogonadism. GnRH release is regulated by neurokinin B (NKB) and kisspeptin. NKB antagonists are used in treatment of menopausal hot flashes and vasomotor symptoms (VMS). In mice and humans with hyperprolactinemic anovulation, kisspeptin restored ovarian cyclicity and LH pulsatility. However, the interplay between kisspeptin and PRL is not fully understood. In two menopausal women with hyperprolactinemia and central hypogonadism, treatment with bromocriptine led to PRL normalization and new-onset VMS, suggesting that hyperprolactinemia inhibited VMS associated with hypogonadism. We aimed to investigate the association between PRL and menopausal VMS in women from the Nurses’ Health Study I and II (NHS, NHSII). We hypothesized that women with higher PRL levels would have a lower frequency/severity of menopausal VMS. Methods: We conducted a cohort study of 2618 females enrolled in NHS (n=1692) and NHSII (n=926) in whom blood samples were collected between 1989-99, were not pregnant or on hormonal therapy, and were either pre or post-menopausal as of blood draw. Subjects were free of breast, ovarian and other cancers, and provided complete data on VMS at menopause as well as in the past 4 weeks (assessed in 2008 in NHS and 2009, 2013, 2017 in NHSII). Plasma PRL was measured as part of 28 case-control studies of various health outcomes. We evaluated the presence and severity of VMS at menopause and 4 weeks prior to the questionnaire, as well as duration (in years) of VMS. We used multiple logistic regression, adjusting for covariates to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs). Results: Women were aged 33-65 years at blood draw; range for years from blood draw to menopause was -10 to 10 (median=1.8) years; range for years from blood draw to report of VMS (both at menopause and current VMS) was 9.8 to 22 years. Mean PRL (SD; range) was 14.7ng/mL (10.1; 0.08-246). Women with the highest PRL levels were likely to be younger and less likely to be current smokers or obese. 77.4% of women reported VMS at menopause and 47.6% in recent 4 weeks; 52.3% reported moderate-to-severe VMS at menopause and 32.0% reported VMS in recent 4 weeks. Overall, PRL was not associated with duration of VMS or moderate-to-severe VMS at menopause or in the past 4 weeks; compared to the lowest quintile (≤8.0ng/mL), those in the highest PRL quintile (≥18.2ng/mL) had MVRR of 1.23(95%CI=0.94,1.60) for moderate-to-severe menopausal VMS and 1.03(95%CI=0.67,1.59) for recent VMS. Menopausal status did not affect the association between prolactin levels and VMS. Conclusion: PRL levels were not associated with occurrence, severity, or duration of menopausal VMS in a large cohort of women. Presentation: 6/1/2024

Fitness consequences of depressive symptoms vary between generations: Evidence from a large cohort of women across the 20th century.

Depression has strong negative impacts on how individuals function, leading to the assumption that there is strong negative selection on this trait that should deplete genetic variation and decrease its prevalence in human populations. Yet, depressive symptoms remain common. While there has been a large body of work trying to resolve this paradox by mapping genetic variation of this complex trait, there have been few direct empirical tests of the core assumption that there is consistent negative selection on depression in human populations. Here, we use a unique long-term dataset from the National Health and Nutrition Examination Survey that spans four generational cohorts (Silent Generation: 1928-1945, Baby Boomers: 1946-1964, Generation X: 1965-1980, and Millenials: 1981-1996) to measure both depression scores and fitness components (lifetime sexual partners, pregnancies, and live births) of women from the United States born between 1938-1994. We not only assess fitness consequences of depression across multiple generations to determine whether the strength and direction of selection on depression has changed over time, but we also pair these fitness measurements with mixed models to assess how several important covariates, including age, body mass, education, race/ethnicity, and income might influence this relationship. We found that, overall, selection on depression was positive and the strength of selection changed over time-women reporting higher depression had relatively more sexual partners, pregnancies, and births except during the Silent Generation when selection coefficients neared zero. We also found that depression scores and fitness components differed among generations-Baby Boomers showed the highest severity of depression and the most sexual partners. These results were not changed by the inclusion of covariates in our models. A limitation of this study is that for the Millenials, reproduction has not completed and data for this generation is interrupted by right censoring. Most importantly, our results undermine the common belief that there is consistent negative selection on depression and demonstrate that the relationship between depression and fitness changes between generations, which may explain its maintenance in human populations.

Migraine and Risk of Parkinson Disease in Women: A Cohort Study.

Migraine and Parkinson disease (PD) are common neurologic disorders, which are hypothesized to share some pathophysiologic mechanisms. However, data on the association between migraine and risk of developing PD are sparse. We estimate the effect of migraine, migraine subtypes, and migraine episode frequency on the risk of developing PD in middle-aged and older women. We used data from the Women's Health Study, a United States-based cohort of women in health professions aged 45 years and older at baseline (1992-1995). Only women with complete self-reported information on migraine and headache and no history of PD were included. Participants were followed up for self-reported physician-diagnosed PD through December 31, 2021. We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and corresponding 95% CIs of the association between migraine, migraine subtypes, and migraine episode frequency and the risk of developing PD. A total of 39,312 women were included in the analyses. Among those, 7,321 women (18.6%) reported any migraine at baseline, of whom 2,153 (5.5%) reported a history of migraine, 2,057 (5.2%) reported migraine with aura, and 3,111 (7.9%) reported migraine without aura. During a mean follow-up of 22.0 years, 685 PD cases were reported. Of those, 128 (18.7%) were reported by women who also reported any migraine and 557 (81.3%) by women without any migraine. After adjusting for confounding, the HR for the association of any migraine on the risk of PD was 1.07 (0.88-1.29). Compared with women without migraine, the HRs (95% CI) for PD were 0.87 (0.59-1.27) for migraine with aura, 1.21 (0.93-1.58) for migraine without aura, and 1.05 (0.76-1.45) for history of migraine. Compared with those with a migraine frequency of less than monthly, the HRs were 1.09 (0.64-1.87) for a monthly frequency and 1.10 (0.44-2.75) for a weekly or greater frequency. In this large cohort of women, the risk of developing PD was not elevated among those experiencing migraine, irrespective of migraine subtypes or the frequency of migraine. The generalizability of our findings to other populations, such as men, should be further investigated. ClinicalTrials.gov Identifier: NCT00000479.

O-193 Age-related normograms of AMH in women with polycystic ovary syndrome using three different assays

Abstract Study question To develop an age-specific percentile distribution of anti-Müllerian hormone (AMH) in patients with polycystic ovary syndrome (PCOS) measured by three different assays. Summary answer Our age-related normograms may help to interpret AMH levels in PCOS patients and facilitate the use of AMH as a diagnostic tool across age ranges. What is known already In the last years, AMH assessment has gained widespread use in the clinical settings of several conditions. However, several challenges still exist to adopt the AMH as a marker of polycystic ovary morphology (PCOM), as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the last years, these studies have mainly been conducted in normo-ovulatory or infertile women and little is known about the higher range of AMH levels, especially in women with PCOS. Study design, size, duration Retrospective single-center cross-sectional study, including 2,725 women with PCOS who consulted the Reproductive Endocrinology and Infertility Clinic of the Erasmus University Medical Center, Rotterdam, The Netherlands. Participants/materials, setting, methods A total of 2,725 women aged 20 to 40 years with PCOS were included. PCOS was diagnosed according to the Rotterdam Criteria. Serum AMH levels were measured using the following AMH assays: (1) Gen II AMH ELISA, 2) picoAMH assay, and 3) Elecsys AMH plus assay. Age-specific centile curves were constructed using the LMS method. The correlations between AMH with clinical, endocrine, and ultrasound features were also evaluated. Main results and the role of chance To our knowledge, this is the first study with real-world data reporting AMH age-specific percentile nomograms in a large population of PCOS women using three different assays. The 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were calculated according to a population/based approach per age (years) for the Gen II, the picoAMH, and the Elecsys assays. We also considered the age-percentile values of AMH in PCOS patients for the Gen II, the picoAMH and the Elecsys assays according to the cut-offs previously proposed in literature for each specific assay. Interestingly, in our population, a high percentage of women with polycystic ovarian morphology (PCOM) showed AMH levels lower than the cut-offs proposed. Serum AMH levels were significantly higher in patients with phenotype A compared to all other phenotypes for all three assays. For all three assays, we found a statistically significant positive correlation between AMH levels and LH, LH/FSH ratio, testosterone, androstenedione, FAI, mean follicular number, and mean ovarian volume. In contrast, AMH levels were negatively correlated with BMI in all groups. Limitations, reasons for caution This is a retrospective cross-sectional study. Longitudinal studies with a large cohort of women that could be followed for many years are needed to validate our nomogram. Wider implications of the findings AMH threshold levels can be influenced by several variables, making it difficult to identify a general cut-off to diagnose PCOM. Further research should overcome the concept of a single cut-off value. The results of the present study may help clinicians interpret AMH levels in PCOS patients across age ranges. Trial registration number In this retrospective cross-sectional study, 2,725 women who consulted the Reproductive Endocrinology and Infertility Clinic of the Erasmus University Medical Center, Rotterdam, The Netherlands, were included. The Medical Ethical Review Board of the Erasmus University Medical Center Rotterdam approved retrospective studies within this patient population, which includes women with ovulatory dysfunction (MEC-2020-0534).

Colposcopically Directed Biopsy Before Ablative Treatment Versus Direct Ablative Treatment in Patients With Cervical Oncogenic HPV.

In the past, the standard of care for women with abnormal cervical cytology has been the performance of colposcopically guided biopsy, followed by conization or large loop excision of the transition zone (LLETZ) where biopsy revealed pre-cancerous or cancerous areas. More straightforward protocols are emerging which advocate performing LLETZ in all women with highly suspicious cytology, suspicious colposcopic impression, or the presence of high-risk oncogenic human papilloma virus (HPV) strains in their cervical swabs. This, theoretically, would reduce the rate of false-negative diagnoses, but at the price of overtreating a significant number of healthy women. We retrospectively analyzed cervical cancer screening protocols in two large cohorts of women with high-risk HPV. The study compared outcomes between patients undergoing a colposcopically directed biopsy before LLETZ (n=683) and those proceeding directly to LLETZ without a biopsy (n=136). The primary focus was to assess whether intervening biopsies would reduce unnecessary ablative procedures without compromising the detection of high-grade lesions. The biopsy group had a high false-negative rate, with several high-grade lesions (CIN3) and a case of invasive cancer initially underdiagnosed. Conversely, the direct-to-LLETZ approach, while ensuring no high-grade lesions were missed, led to overtreatment of lower grade lesions. These findings raise concern about the reliance on biopsy results for treatment decisions. Neither protocol was entirely satisfactory, although the more aggressive one avoided the potentially life-threatening consequence of false-negative results. Further research is mandatory to accurately diagnose all cases requiring aggressive treatment, without subjecting healthy women to ablative treatments they do not need.

Abstract PO1-27-11: Survival Benefit of Adjuvant Endocrine Therapy in Patients with Estrogen Receptor Low-Positive Breast Cancer

Abstract Background: Estrogen receptor (ER) low-positive (1–10%) breast cancer is a very rare subtype that accounts for only 2–5% of all breast cancer cases and was introduced as a new category in the 2020 American Society of Clinical Oncology/College of American Pathologist Guidelines. There are limited data on the overall benefit of endocrine therapy for patients with ER low-positive cancers. The objective of this study was to analyze the clinicopathological characteristics and treatment patterns in patients with ER low-positive breast cancer and to compare disease-free survival (DFS) between patients who received and did not receive endocrine therapy. Methods: A retrospective search of the prospectively maintained database of our institution identified consecutive women with ER low-positive (1–10%) primary invasive breast cancer who underwent curative surgery at Seoul National University Hospital (Seoul, Korea) between January 2010 and April 2021. Standard immunohistochemical staining techniques were used to assess the level of ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, and semiquantitative scores (0–100%) were reported for ER and PR. DFS was defined as the time from surgery to the development of any recurrence and was compared between women who received and did not receive adjuvant endocrine therapy using univariable and multivariable Cox proportional hazards regression. Results: A total of 721 women (median age, 51 years; range, 24–83 years) with ER low-positive cancer were included in the analysis. Overall, 28% (203/721) had AJCC stage I, 42% (304/721) had stage II, and 30% (214/721) had stage III. PR expression was negative (< 1%) in 79% (571/721), low-positive (1–10%) in 12% (90/721), and high-positive ( >10%) in 8% (60/721). HER2 expression was negative in 54% (390/721) and positive in 46% (331/721). Most women (88% [634/721]) received adjuvant endocrine therapy, including all women with PR expression >10%. Of the 661 women with PR expression ≤10%, 87 (13%) did not receive adjuvant endocrine therapy. HER2-targeted therapy was performed in 81% (268/331) of women with HER2-positive cancer. During a median follow-up of 5.7 years, 98 (14%) had recurrence (25 locoregional/contralateral and 73 distant metastases). AJCC stage III (HR, 3.6; 95% CI: 2.4, 5.4; P < .001) and receiving total mastectomy (HR, 1.8; 95% CI: 1.2, 2.8; P = .004) were associated with worse DFS. Receiving adjuvant endocrine therapy was independently associated with better DFS in the entire cohort (HR, 0.46; 95% CI: 0.28, 0.76; P = .002) and in the HER2-negative subgroup (HR, 0.40; 95% CI: 0.22, 0.75; P = .004). In the HER2-positive subgroup, receiving adjuvant endocrine therapy was not significantly associated with better DFS (HR, 0.55; 95% CI: 0.23, 1.32; P = .18). Conclusion: In this large cohort of women with ER low-positive breast cancers, adjuvant endocrine therapy was administered in the majority of cases, including those with PR >10% expression. Receiving adjuvant endocrine therapy was associated with better DFS, especially when HER2 expression was negative. Citation Format: Su Hyun Lee, Han Suk Ryu, Myoung-jin Jang, Kyung-Hun Lee, Han-Byoel Lee. Survival Benefit of Adjuvant Endocrine Therapy in Patients with Estrogen Receptor Low-Positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-11.

Abstract 780: Normal breast tissues harbor rare populations of aneuploid epithelial cells

Abstract Although aneuploidy is a hallmark of invasive breast cancers, the presence of aneuploid cells in breast tissues of disease-free women is poorly understood. Furthermore, the expansion of aneuploid cells and the specific copy number events that they harbor, as well as their relationship to invasive breast cancers has not been characterized in large cohorts of women. In this study, we obtained viable cell suspensions from 31 disease-free women that underwent reduction mammoplasty surgeries and fresh tissue collection in the HBCA project along with the collection of clinical metadata. The viable cell suspensions from 31 women were enriched for epithelial cells and used to perform high-thoughput nanowell scDNA-seq. In total, 55,321 cells were analyzed. The normal breast tissue samples were also embedded into OCT and frozen to perform Spatial Transcriptomics (Visium 10X Genomics) profiling and embedded into FFPE to perform histopathological analysis. Our data shows that all women harbored rare populations of aneuploid epithelial cells (mean 4.3%) that increased in frequency and their number of copy number aberrations with age. Many aneuploid epithelial cells (mean 79%) in normal breast tissues underwent clonal expansions of their genomes and harbored chromosomal aberrations detected in invasive breast cancers (gain of 1q and loss of 7q, 10q, 16q). Spatial mapping showed that aneuploid cells are localized in focal regions of ductal and lobular epithelial structures with normal histopathological features. Collectively, these data show that aneuploid epithelial cells exist in the normal breast tissues of disease-free women and increase with age. In many women, the aneuploid cells expand and harbor CNA events associated with invasive breast cancer. Citation Format: Yiyun Lin, Junke Wang, Kaile Wang, Shanshan Bai, Aatish Thennavan, Runmin Wei, Yun Yan, Jianzhuo Li, Heba Elgamal, Emi Sei, Anna Casasent, Mitchell Rao, Chenling Tang, Jessica Montalvan, Chandandeep Nagi, Sebastrian Winocour, Bora Lim, Alastair Thompson, Nicholas Navin. Normal breast tissues harbor rare populations of aneuploid epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 780.

Rheumatoid arthritis and cancer risk in the Million Women Study.

Most previous studies of rheumatoid arthritis (RA) and cancer risk have lacked information on potential confounding factors. We investigated RA-associated cancer risks in a large cohort of women in the UK, taking account of shared risk factors. In 1996-2001, women aged 50-64, who were invited for routine breast screening at 66 National Health Service (NHS) screening centres in England and Scotland, were also invited to take part in the Million Women Study. Participants provided information on sociodemographic, lifestyle and health-related factors, including RA, and were followed up for cancers and deaths. Cox regression yielded RA-associated hazard ratios (HRs) of 20 cancers, adjusted for 10 characteristics including smoking status and adiposity. Around 1.3 million women (half of those invited) were recruited into the study. In minimally adjusted analyses, RA was associated with the risk of 13 of the 20 cancers. After additional adjustment for lifestyle factors, many of these associations were attenuated but there remained robust evidence of RA-associated increases in the risk of lung (HR 1.21, 95% confidence interval 1.15-1.26), lymphoid (1.25, 1.18-1.33), myeloid (1.12, 1.01-1.25), cervical (1.39, 1.11-1.75) and oropharyngeal (1.40, 1.21-1.61) cancers, and decreases in the risk of endometrial (0.84, 0.77-0.91) and colorectal (0.82, 0.77-0.87) cancers. After taking account of shared risk factors, RA is positively associated with lung and certain blood and infection-related cancers, and inversely associated with colorectal cancer. These findings are consistent with existing hypotheses around immune response, susceptibility to infections, and chronic inflammation. The inverse association observed for endometrial cancer merits further investigation.

Gynaecological follow-up for women of reproductive age with multiple sclerosis: The GYNESEP study

BackgroundThe gynaecological care of women with Multiple Sclerosis has received little attention; most reports focussed on pregnancy or sexuality. The objective of the present study was to evaluate if gynaecological follow-up for women of reproductive age with Multiple Sclerosis was adequate. MethodsWe performed a cross-sectional study on a large cohort of women with Multiple Sclerosis aged 18–40 years. All participants completed online questionnaires on general health status, gynaecological follow-up, and sexuality. Expanded Disability Status Scale (EDSS) scores were extracted from medical records. The study was registered in clinicaltrials.gov with the number NCT05248438, and in the European database ID-RCB with the number 2021-A02912–39. ResultsOf the 192 patients who completed questionnaires, 157 (82.2%) reported gynaecological follow-up. Of the 155 patients on immunosuppressive treatments, only 31 (20%) underwent annual cervical screening. Of the 140 patients who met the French papillomavirus vaccination age recommendations, only 50 (35.7%) were vaccinated. A total of 128 (66.7%) patients used contraception. However, 16 (8.3%) patients reported unplanned pregnancies since the time of diagnosis. ConclusionWomen with Multiple Sclerosis require more information on reproductive health and prevention of cancer. Better contraceptive advice would reduce the number of unplanned pregnancies and avoid foetal exposure to potentially teratogenic treatment.

Comparison of Minimally Invasive Surgery with Open Surgery for Type II Endometrial Cancer: An Analysis of the National Cancer Database.

Prior studies comparing minimally invasive surgery with open surgery among patients with endometrial cancer have reported similar survival outcomes and improved perioperative outcomes with minimally invasive surgery (MIS). However, patients with Type II endometrial cancer were underrepresented in these studies. We sought to compare the overall survival and surgical outcomes between open surgery and MIS in a large cohort of women with Type II endometrial cancer. Using data from the National Cancer Database, we identified a cohort of women who underwent hysterectomy for type II endometrial cancer (serous, clear cell, and carcinosarcoma) between January 2010 and December 2014. The primary outcome was a comparison of the overall survival for MIS with that for the open approach. The secondary outcomes included a comparison of the length of hospital stay, readmission within 30 days of discharge, and 30- and 90-day mortality. Outcomes were compared between the cohorts using the Mann-Whitney U test, Pearson's chi-square test, or Fisher's exact test. Multivariable logistic regression with inverse propensity weighting was used to determine clinical characteristics that were statistically significant predictors of outcomes. p values < 0.05 were considered significant. We identified 12,905 patients with Type II, Stage I-III endometrial cancer that underwent a hysterectomy. In total, 7123 of these women (55.2%) underwent MIS. The rate of MIS increased from 39% to 64% over four years. Women who underwent MIS were more often White, privately insured, older, and had a higher income. The laparotomy group had a higher rate of carcinosarcoma histology (30.9% vs. 23.6%, p < 0.001), stage III disease (38.4% vs. 27.4%, p < 0.001), and larger primary tumors (59 vs. 45 mm, p < 0.001). Lymph node dissection was more commonly performed in the MIS group (89.6% vs. 85.4%, p < 0.001). With regard to adjuvant therapy, subjection to postoperative radiation was more common in the MIS group (37% vs. 40.1%, p < 0.001), while chemotherapy was more common in the laparotomy group (37.6% vs. 33.9%, p < 0.001). The time interval between surgery and the initiation of chemotherapy was shorter in the MIS group (39 vs. 42 days, p < 0.001). According to the results of propensity-score-weighted analysis, MIS was associated with superior overall survival (101.7 vs. 86.7 months, p = 0.0003 determined using the long-rank test), which corresponded to a 10% decreased risk of all-cause mortality (HR 0.9; CI 0.857-0.954, p = 0.0002). The survival benefit was uniform across all three histology types and stages. MIS was associated with superior perioperative outcomes, including shorter length of stay (1 vs. 4 days, p < 0.001), lower 30-day readmission rates (2.5% vs. 5%), and lower 30- and 90-day postoperative mortality (0.5% vs. 1.3% and 1.5% vs. 3.6%, respectively; p < 0.001 for both). The increased adoption of MIS from 2010 to 2014 corresponds to a decrease in 90-day postoperative mortality (2.8% to 2.2%, r = -0.89; p = 0.04) and overall mortality (51% to 38%, r = -0.95; p = 0.006). In a large cohort of patients from the National Cancer Database, MIS was associated with improved overall survival and superior perioperative outcomes compared to open surgery among women with Type II endometrial cancer. A decrease in postoperative mortality and a shorter interval between surgery and the initiation of chemotherapy may contribute to the survival benefit of MIS. A racial and economic disparity in the surgical management of Type II endometrial cancer was identified, and further investigation is warranted to narrow this gap and improve patient outcomes.

Smoking and Alcohol Consumption and Risk of Incident Diverticulitis in Women

Much of what is known about the effects of alcohol and tobacco use on diverticular disease derives from studies of asymptomatic diverticulosis or complicated diverticulitis. We examined smoking and alcohol consumption and risk of incident diverticulitis in a large cohort of women. We conducted a prospective study of 84,232 women in the Nurses' Health Study II (NHS II) who were 39-52 years old and without known diverticulitis at baseline in 2003. Smoking was ascertained every 2 years and alcohol use every 4 years. We used Cox proportional hazards regression to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). During 1,139,660 person-years of follow up, we identified 3018 incident cases of diverticulitis. After adjustment for other risk factors, current (HR, 1.20; 95% CI, 1.04-1.39) and past smoking (HR, 1.20; 95% CI, 1.11-1.30) were associated with increased risk of diverticulitis when compared with never smokers. Women who consumed ≥30 g/d of alcohol had a multivariate HR of 1.26 (95% CI, 1.05-1.50) when compared with women who did not drink. A joint analysis of smoking and alcohol found that individuals who ever smoked and consumed ≥15 g/d of alcohol were at highest risk of diverticulitis (multivariate HR, 1.60; 95% CI, 1.16-2.21), compared with participants who never smoked and reported no alcohol use. In this large prospective study of women, smoking and alcohol consumption were associated with an increased risk of incident diverticulitis. These data highlight additional modifiable risk factors for diverticulitis that may aid in prevention.

Factors associated with maternal hyperglycaemia and neonatal hypoglycaemia after antenatal betamethasone administration in women with diabetes in pregnancy.

Bespoke glycaemic control strategies following antenatal corticosteroids for women with diabetes in pregnancy (DIP) may mitigate hyperglycaemia. This study aims to identify predictive factors for the glycaemic response to betamethasone in a large cohort of women with DIP. Evaluation of a prospective cohort study of 347 consecutive DIP pregnancies receiving two doses of 11.4 mg betamethasone 24 h apart between 2017 and 2021 and treated with the Pregnancy-IVI intravenous insulin protocol. Regression modelling identified factors associated with maternal glycaemic time-in-range (TIR) and maternal insulin requirements following betamethasone. Factors associated with neonatal hypoglycaemia (glucose <2.6 mmol/L) in infants born within 48 h of betamethasone administration (n = 144) were investigated. The mean maternal age was 31.9 ± 5.8 years, with gestational age at betamethasone of 33.5 ± 3.4 weeks. Gestational diabetes was present in 81% (12% type 1; 7% type 2). Pre-admission subcutaneous insulin was prescribed for 63%. On-infusion maternal glucose TIR (4.0-7.8 mmol/L) was 83% [IQR 77%-90%] and mean on-IVI glucose was 6.6 ± 0.5 mmol/L. Maternal hypoglycaemia (<3.8 mmol/L) was uncommon (0.47 h/100 on-IVI woman hours). Maternal glucose TIR was negatively associated with indicators of insulin resistance (type 2 diabetes, polycystic ovary syndrome), late-pregnancy complications (pre-eclampsia, chorioamnionitis) and the 1-h OGTT result. Intravenous insulin requirements were associated with type of diabetes, pre-eclampsia and intrauterine infection, the 1-h OGTT result and the timing of betamethasone administration. Neonatal hypoglycaemia was associated with pre-existing diabetes but not with measures of glycaemic control. An intravenous infusion protocol effectively controls maternal glucose after betamethasone. A risk-factor-based approach may allow individualisation of therapy.

Sleep and sleep disorders during pregnancy and postpartum: The Life-ON study

Objectiveto prospectively assess sleep and sleep disorders during pregnancy and postpartum in a large cohort of women. Methodsmulticenter prospective Life-ON study, recruiting consecutive pregnant women at a gestational age between 10 and 15 weeks, from the local gynecological departments. The study included home polysomnography performed between the 23rd and 25th week of pregnancy and sleep-related questionnaires at 9 points in time during pregnancy and 6 months postpartum. Results439 pregnant women (mean age 33.7 ± 4.2 yrs) were enrolled. Poor quality of sleep was reported by 34% of women in the first trimester of pregnancy, by 46% of women in the third trimester, and by as many as 71% of women in the first month after delivery. A similar trend was seen for insomnia. Excessive daytime sleepiness peaked in the first trimester (30% of women), and decreased in the third trimester, to 22% of women. Prevalence of restless legs syndrome was 25%, with a peak in the third trimester of pregnancy. Polysomnographic data, available for 353 women, revealed that 24% of women slept less than 6 h, and 30.6% of women had a sleep efficiency below 80%. Sleep-disordered breathing (RDI≥5) had a prevalence of 4.2% and correlated positively with BMI. ConclusionsThe Life-ON study provides the largest polysomnographic dataset coupled with longitudinal subjective assessments of sleep quality in pregnant women to date. Sleep disorders are highly frequent and distributed differently during pregnancy and postpartum. Routine assessment of sleep disturbances in the perinatal period is necessary to improve early detection and clinical management.

Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Disease-Free Survival Does Not Differ According to Fertility Preservation Technique for Young Women With Breast Cancer

ABSTRACT Approximately 5% of breast cancer cases occur in women younger than 40 years, and the 5-year overall survival for women between the ages of 15 and 44 years is 90%. As the childbearing age increases, so too does the proportion of women who wish to achieve pregnancy after breast cancer. The conception rate among these women is 40% lower than the general population, as a result of advanced age and the gonadal toxicity of chemotherapy. Fertility preservation (FP) techniques enable young patients to freeze gametes before treatment; however, the most recommended method of FP is oocyte or embryo vitrification after controlled ovarian hyperstimulation (COH), which has limited safety data in breast cancer patients. This retrospective cohort study aimed to evaluate disease-free survival (DFS) in a large cohort of women with breast cancer who underwent FP techniques with or without COH. Patients with breast cancer between 18 and 43 years old referred for FP to 2 university hospitals between July 2013 and July 2019 were included. Women not included in the FP program after oncofertility counseling, those with stage 4 disease at diagnosis or history of other invasive cancer, or those with gonadotoxic treatment have been excluded. Patients were split into 2 groups, with the STIM group receiving at least 1 COH protocol using a gonadotropin-releasing hormone antagonist with or without an aromatase inhibitor and the no STIM group not undergoing ovarian stimulation. Patient characteristics, obstetric variables, and oncology characteristics were collected from medical records. Disease-free survival and overall survival were estimated using Kaplan-Meier plots and compared between the 2 groups by log-rank test. A total of 740 women (76.7%) who attended oncofertility consultations for breast cancer were included. Of these, 328 (44.3%) underwent at least 1 ovarian stimulation cycle, and 412 (55.7%) had an FP technique without exogenous FSH administration. The STIM group was significantly older and had lower values in ovarian reserve tests, and more women in the no STIM group underwent a mastectomy and neoadjuvant chemotherapy. The proportion of patients with hormone receptor-positive tumors was equal in both groups. Letrozole was coadministered with exogenous gonadotropin in 39.3% of women in the STIM group (Let-COH). Overall, 16.8% of patients had a tumor still present on oocyte retrieval after COH, of which 55% received a Let-COH protocol. Follow-up data were available for 80.9% (559/740) of patients. Cancer recurrence was documented in 87 patients (27 in STIM, 60 in no STIM), and DFS was not statistically different between the groups (log-rank test P = 0.09). Neither difference in DFS nor overall survival was observed in the Let-COH group compared with those undergoing COH after breast surgery. Kaplan-Meier estimates of overall survival at 4 years were 97.6% in the STIM and 93.6% in the no STIM groups, and after adjusting for prognostic parameters, the risk of death remained significantly lower in the STIM group (hazards ratio, 0.55 [0.35–0.85]). The results of this large retrospective cohort study demonstrate that the use of COH for FP patients with breast cancer before or after breast tumor surgery is safe; however, a longer duration of follow-up will provide a more definite safety profile.

Parkinson's Disease Case Ascertainment in the Sister Study: A Cohort for Environmental Health Research.

Large prospective studies are essential for investigating the environmental causes of Parkinson's disease (PD), but diagnosis via clinical exams is often infeasible. To present case ascertainment strategy and data collection in a US cohort of women. In the Sister Study (n = 50,884, baseline ages 55.6±9.0), physician-made PD diagnoses were first reported by participants or their proxies. Cohort-wide follow-up surveys collected data on subsequent diagnoses, medication usage and PD-relevant motor and nonmotor symptoms. We contacted self-reported PD cases and their treating physicians to obtain relevant diagnostic and treatment history. Diagnostic adjudication was made via expert review of all available data, except nonmotor symptoms. We examined associations of nonmotor symptoms with incident PD, using multivariable logistic regression models and reported odds ratio (OR) and 95% confidence intervals (CI). Of the 371 potential PD cases identified, 242 diagnoses were confirmed. Compared with unconfirmed cases, confirmed cases were more likely to report PD diagnosis from multiple sources, medication usage, and motor and nonmotor feature consistently during the follow-up. PD polygenic risk score was associated with confirmed PD (ORinter-quartile range = 1.74, 95% CI: 1.45-2.10), but not with unconfirmed cases (corresponding OR = 1.05). Hyposmia, dream-enacting behaviors, constipation, depression, unexplained weight loss, dry eyes, dry mouth, and fatigue were significantly related to PD risk, with ORs from 1.71 to 4.88. Only one of the eight negative control symptoms was associated with incident PD. Findings support our PD case ascertainment approach in this large cohort of women. PD prodromal presentation is likely beyond its well-documented profile.

O-014 Clustering identifies distinct subtypes of PCOS – Towards a Rationale Approach to PCOS classification

Abstract Study question Does unsupervised clustering identify biologically distinct subtypes in a cohort of women with polycystic ovary syndrome (PCOS) diagnosed by Rotterdam criteria? Summary answer This study demonstrates that unsupervised hierarchical clustering of eight pre-defined quantitative reproductive and metabolic traits identifies biologically distinct subtypes in women with PCOS. What is known already PCOS is a common, heterogeneous, endocrine disorder in women of reproductive-age. PCOS diagnosed by NIH or non-NIH Rotterdam criteria or by self-report is generally genetically similar. Using Hierarchical Clustering (HC), we have previously identified discrete, stable PCOS subtypes, which we designated reproductive (higher LH, FSH, SHBG) and metabolic (higher BMI, insulin, glucose), in a United States cohort of ∼900 PCOS women diagnosed by NIH criteria (Dapas et al. PLoS Med, 2020). The cases that did not cluster were designated “background subtype”. The subtypes appeared to capture biologically meaningful differences because they were associated with distinct and novel genome-wide significant loci. Study design, size, duration In the current study, we applied HC to the same traits (BMI, LH, FSH, DHEAS, SHBG, testosterone, fasting insulin and fasting glucose). We then assessed whether additional traits differed between the subtypes thus identified: anti-Müllerian hormone (AMH), total follicle count, modified Ferriman-Gallwey score, estrogen, TSH, DHEA, cortisol, androstenedione, prolactin, LDL, HDL, triglycerides and cholesterol. Participants/materials, setting, methods Women of European ancestry, aged 13-45 years, n = 2502, with PCOS according to the Rotterdam criteria were included; n = 1067 also fulfilled NIH criteria. All quantitative traits were log-transformed to approximate a normal distribution. Z-scores were used to compare the differences between the three clusters using ANCOVA, corrected for age. Pair-wise comparison of the different clusters was performed using Fisher’s least significance difference method and adjusted for multiple testing. Main results and the role of chance We replicated discrete subtypes in this large cohort of women with PCOS defined by the Rotterdam criteria. There were 1026 cases in the metabolic subtype, 450 cases in the reproductive subtype and 1026 in the background subtype. Cases in the reproductive subtype had significantly (all P &amp;lt; 0.001) higher serum AMH levels, follicle counts and HDL levels compared to the metabolic and background subtypes. These findings suggest that the reproductive subtype captures affected women with the alterations in folliculogenesis characteristic of PCOS, without using PCOM to define this subtype. In contrast, the cases in the metabolic subtype had significantly (all P &amp;lt; 0.001) higher triglyceride and LDL levels compared to the other subtypes providing further evidence that this subtype identifies cases with cardiometabolic risk. Androstenedione and TSH levels were significantly increased in the metabolic subtype compared to the background subtype (P &amp;lt; 0.001) and to both subtypes (P = 0.004), respectively. Cortisol and prolactin levels did not differ among the three subtypes. All results did not differ when the analysis was limited to NIH PCOS cases. Overall, our findings suggest that these PCOS subtypes have different etiologies and clinical outcomes. Subtyping may enable precision medicine approaches to the management of what is currently classified as PCOS. Limitations, reasons for caution A limitation of the study is that we have not replicated these findings in an independent cohort. We have not used an orthogonal method, such as genome-wide association, to confirm that the subtypes capture biologically distinct groups. Wider implications of the findings Taken together with our previous studies suggesting that the genetic architecture of these subtypes differs, the current study implies that PCOS consists of several etiologically distinct disorders. Our findings provide an example of the power of modern disease classification based on objective biologic differences rather than expert opinion. Trial registration number Not applicable

Polygenic risk score calibration and association with breast cancer in diverse ancestries.

10505 Background: Polygenic risk scores (PRS) have been shown to substantially improve breast cancer (BC) risk prediction when incorporated into traditional risk assessment models. However, PRS developed primarily in women of European ancestry have shown poor performance when applied to non-European populations. We previously described development and validation of a multiple-ancestry PRS (MA-PRS) that is based on individual ancestral genetic composition. MA-PRS has been incorporated into the Tyrer-Cuzick model for use in clinical practice and has been shown to provide independent value to the model. Here, we describe performance of the MA-PRS in a large cohort of women from diverse ancestral backgrounds. Methods: The study cohort included 203,586 patients who were referred for hereditary cancer testing and negative for pathogenic variants in genes associated with BC. MA-PRS was calculated as previously described based on 149 SNPs (93 BC and 56 ancestry-informative). Association of MA-PRS with invasive BC status (affected vs unaffected) was analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Calibration was assessed by examining the MA-PRS distribution within unaffected patients, and through goodness-of-fit tests. All analyses were conducted within the full cohort and within ancestral subpopulations. Odds ratios (ORs) are reported per standard deviation. Results: One-fifth (43,782/203,586, 21.5%) of patients were diagnosed with invasive BC, and 60,657 (29.8%) of patients reported BC in a first degree relative. The MA-PRS distribution was centered around zero among unaffected patients overall and within each subpopulation. MA-PRS significantly improved BC risk prediction over clinical factors in the full cohort (OR = 1.43, 95% CI:1.41-1.44) and within each ancestral subpopulation (Table). The strongest associations were observed in Ashkenazi Jewish (OR = 1.56, 95% CI:1.39-1.76) and South Asian (OR = 1.49,95% CI: 1.23-1.81) populations. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. Conclusions: The breast cancer MA-PRS based on genetic ancestral composition is well-calibrated and strongly associated with BC in all tested ancestral populations. Incorporation of PRS adds independent information to risk models and supports equitable access to personalized BC risk management. [Table: see text]

Prevalence and severity of bowel disorders in the third trimester of pregnancy

Bowel-related disorders are common conditions associated with pregnancy and are a cause of significant distress and healthcare burden. However, there is a lack of data in the literature about these disorders. This study aimed to investigate bowel dysfunctions during the third trimester of pregnancy in a large cohort of women using the validated bowel domain of the Italian version of the Pelvic Floor Questionnaire for Pregnant and Postpartum Women. This was a secondary analysis of a multicenter cross-sectional study conducted in hospitals in Italy and Italian-speaking Switzerland. Women in the third trimester of pregnancy were asked to complete the Italian Pelvic Floor Questionnaire for Pregnant and Postpartum Women. During the study period, 927 pregnant women in the third trimester of pregnancy responded to the questionnaire and were included in the analysis. Overall bowel dysfunctions were reported by 29.6% of patients. Constipation was reported by 66.6% of pregnant women, whereas symptoms of obstructed defecation were reported by 49.9% of patients. In contrast, urgency was reported by 41.1% of patients. Incontinence to flatus and incontinence to stool were reported by 45.1% and 2.8% of patients, respectively. Moreover, age >35 years, familiarity with pelvic floor disorders, nicotine abuse, and pelvic floor contraction inability were identified as independent risk factors for at least 1 bowel symptom. Bowel symptoms are extremely common in the third trimester of pregnancy and can greatly affect a patient's quality of life; therefore, bowel symptoms deserve to be investigated and managed properly. The use of validated questionnaires represents a precious tool to investigate functional symptoms that could be very frequent and disabling in this particular period of life for women.