Chronic stress, social support, and symptoms at midlife. Is there a buffering effect?

OBJECTIVES: This study was designed to examine associations among measures of stress, social support, and symptoms at midlife. Specifically, the study examined whether support buffered against the negative effects of stress on severity of symptoms grouped via factor analyses into emotional instability, vaso-somatic symptoms, mood disturbances, and aches and pains. METHODS: We used cross-sectional data from n = 119 women aged 40-55 in Nagaland, India. Midlife symptoms were measured with the help of questionnaires, and factor analysis was used to identify latent factors. Stress and social support were measured by Perceived Stress Scale and Multidimensional Scale of Perceived Social Support, respectively. Chronic stress was measured by fingernail cortisol. RESULTS: After adjusting for menopausal status, tobacco use, body mass index, and socioeconomic status, cortisol level was positively associated with emotional instability (p < 0.01), vaso-somatic symptom score (p < 0.05), and total symptoms at midlife (p < 0.05). Familial support was negatively associated with emotional instability (p < 0.05) and total symptoms at midlife (p < 0.05). However, no significant associations were observed with spousal or friend support. Although no significant interactions between stress, social support, and symptoms at midlife were observed, spousal support when stratified as high and low support using the means, perceived stress and vaso-somatic symptoms indicated an interaction. CONCLUSION: Cortisol level and support from family were independently associated with symptoms at midlife. The study highlights the importance of family ties and support for navigating the stressors of everyday life among women in Nagaland.

The bidirectional association between premenstrual disorders and perinatal depression: A nationwide register-based study from Sweden.

BACKGROUND: Premenstrual disorders (PMDs) and perinatal depression (PND) share symptomology and the timing of symptoms of both conditions coincide with natural hormonal fluctuations, which may indicate a shared etiology. Yet, there is a notable absence of prospective data on the potential bidirectional association between these conditions, which is crucial for guiding clinical management. Using the Swedish nationwide registers with prospectively collected data, we aimed to investigate the bidirectional association between PMDs and PND. METHODS AND FINDINGS: With 1,803,309 singleton pregnancies of 1,041,419 women recorded in the Swedish Medical Birth Register during 2001 to 2018, we conducted a nested case-control study to examine the risk of PND following PMDs, which is equivalent to a cohort study, and transitioned that design into a matched cohort study with onward follow-up to simulate a prospective study design and examine the risk of PMDs after PND (within the same study population). Incident PND and PMDs were identified through clinical diagnoses or prescribed medications. We randomly selected 10 pregnant women without PND, individually matched to each PND case on maternal age and calendar year using incidence density sampling (N: 84,949: 849,482). We (1) calculated odds ratio (OR) and 95% confidence intervals (CIs) of PMDs using conditional logistic regression in the nested case-control study. Demographic factors (country of birth, educational level, region of residency, and cohabitation status) were adjusted for. We (2) calculated the hazard ratio (HR) and 95% CIs of PMDs subsequent to PND using stratified Cox regression in the matched cohort study. Smoking, BMI, parity, and history of psychiatric disorders were further controlled for, in addition to demographic factors. Pregnancies from full sisters of PND cases were identified for sibling comparison, which contrasts the risk within each set of full sisters discordant on PND. In the nested case-control study, we identified 2,488 PMDs (2.9%) before pregnancy among women with PND and 5,199 (0.6%) among controls. PMDs were associated with a higher risk of subsequent PND (OR 4.76, 95% CI [4.52,5.01]; p < 0.001). In the matched cohort with a mean follow-up of 7.40 years, we identified 4,227 newly diagnosed PMDs among women with PND (incidence rate (IR) 7.6/1,000 person-years) and 21,326 among controls (IR 3.8). Compared to their matched controls, women with PND were at higher risk of subsequent PMDs (HR 1.81, 95% CI [1.74,1.88]; p < 0.001). The bidirectional association was noted for both prenatal and postnatal depression and was stronger among women without history of psychiatric disorders (p for interaction < 0.001). Sibling comparison showed somewhat attenuated, yet statistically significant, bidirectional associations. The main limitation of this study was that our findings, based on clinical diagnoses recorded in registers, may not generalize well to women with mild PMDs or PND. CONCLUSIONS: In this study, we observed a bidirectional association between PMDs and PND. These findings suggest that a history of PMDs can inform PND susceptibility and vice versa and lend support to the shared etiology between both disorders.

Construct Validation of the Dietary Inflammatory Index (DII) among Young College-Aged Women.

The Dietary Inflammatory Index (DII) is designed to assess the inflammatory potential of the diet. While previous research has utilized DII among college-aged women, no study to date has validated it in this population. We conducted a construct validation of DII among 393 healthy women aged 18-31 years against a robust panel of 14 inflammatory biomarkers, including CRP, IL-1ß, IL-4, IL-6, IL-10, and TNF-α, which were used in the development of DII. Three linear regression models were constructed: (1) an age-adjusted model, (2) the most parsimonious model based on likelihood ratio tests, and (3) a fully adjusted model for age, race, body mass index, waist circumference, physical activity, smoking status, and nonsteroidal anti-inflammatory drug use. DII was derived from the Harvard food frequency questionnaire and categorized into quartiles. Consistent with our hypothesis, DII was negatively and significantly associated with back-transformed IL-10 levels, confirming that a more pro-inflammatory diet was associated with lower levels of an anti-inflammatory cytokine (Model 3: Q4 vs. Q1 ß = 0.62; 95% CI: 0.42, 0.93; p-trend = 0.04). While validated in other populations, DII may not be a suitable tool for assessing the inflammatory potential of the diet among college-aged women.

Feasibility, Acceptability, and Preliminary Effects of a Video-Based Intervention for Smoking Cessation Among People with HIV in Kathmandu, Nepal: A Single-Armed Pilot Study.

Despite the evidence of the disproportionate burden of tobacco use among people with HIV (PWH), little effort has been made to design and test smoking cessation interventions for PWH in resource-limited countries. We assessed the feasibility, acceptability, and preliminary effects of a video-based smoking cessation intervention consisting of eleven 3-8-minute sessions among PWH in Nepal, a lower-middle-income country. Guided by the phased-based model, our 3-month intervention focused on setting the quit date, smoking cessation, and abstinence maintenance. We screened 103 PWH over three weeks for our single-arm trial, with 53 considered eligible and 48 recruited (91%). Forty-six participants watched all video clips, while two watched 7-9. All participants were retained at a 3-month follow-up. The 1-week point prevalence abstinence (self-report supported with expired carbon monoxide levels < 5ppm) at 3-month follow-up was 39.6%. Most (90%) participants reported "very much" or "much" comfort with watching the videos on their smartphones, and all would recommend the intervention to other PWH who smoke. Overall, our pilot trial demonstrated the feasibility, acceptability, and high-level efficacy of the video-based smoking cessation intervention highlighting its potential for scaling up in Nepal and other resource-limited countries.

The association between anthropometric factors and anti-Müllerian hormone levels in premenopausal women.

Adiposity has been associated with several health conditions as well as timing of menopause. Prior epidemiologic studies on the association of adiposity and anti-Müllerian hormone (AMH) have been inconsistent. We evaluated the relations of anthropometric measures with AMH at two time periods in a subset of premenopausal participants in the Nurses' Health Study II. This prospective study included 795 women who provided a premenopausal sample in 1996-1999 and in 2010-2012. Current weight and height, and weight at age 18 were assessed in 1989 and weight again in 1996-1999. Waist and hip circumference were measured and reported in 1993. In linear regression models adjusted for smoking, reproductive events, and other factors, AMH was inversely related to BMI at age 18 (P = .03) and in 1996-1999 (P < .0001). Higher waist circumference was related to lower AMH levels in 1996-1999 (p = .0009). BMI in 1996-1999 was inversely associated with AMH levels in 2010-2012 (P = .005). Weight gain between age 18 and 1996-1999 was strongly inversely associated with AMH levels in 1996-1999 (P < .0001) and in 2010-2012 (P < .0001). Our results indicate that adiposity and weight gain are associated with lower AMH levels, suggesting an adverse impact on ovarian function.

Anti-Müllerian hormone levels and breast cancer risk in the study of women's health across the nation.

PURPOSE: The relation of premenopausal anti-Müllerian hormone (AMH) levels with breast cancer risk has been evaluated in a few studies, but primarily in non-Hispanic White women. METHODS: We evaluated the association of AMH levels with breast cancer risk in Study of Women's Health Across the Nation (SWAN), a multi-ethnic cohort of women. At enrollment, participants had an intact uterus and ≥ 1 ovary, and ≥ 1 menstrual period in the last 3 months. AMH at first measurement was assessed in 1,529 pre- or perimenopausal women using a high-sensitivity ELISA assay; values were natural log transformed. Breast cancer diagnoses were assessed at enrollment and subsequent follow-up visits through 2018 (median 6.1 years). RESULTS: In total, 84 women reported an incident breast cancer diagnosis. In multivariable Cox regression models adjusting for age, race and ethnicity, body mass index, and other factors, higher AMH levels were associated with a non-significant increased breast cancer risk. Compared to women in the 1st quartile, the hazard ratio (95% confidence interval) for women in the 4th quartile was 1.77 (0.87-3.60). CONCLUSION: Our results did not suggest a significant association between AMH and breast cancer risk; however, estimates were consistent with prior studies that reported positive associations.

Estrogenic Activity and Risk of Invasive Breast Cancer Among Postmenopausal Women in the Nurses' Health Study.

BACKGROUND: Estrogens increase breast cancer risk through estrogen receptor (ER)-mediated pathway activation. It is unclear whether a broader assessment of plasma compounds that lead to ER activation would be more strongly related to risk than measurement of individual estrogens. METHODS: A prospective nested case-control study was conducted among postmenopausal women in the Nurses' Health Study, that included 371 cases with blood samples collected prior to breast cancer diagnosis and 731 matched controls. Total estrogen pathway activity (EA) was assessed via a luciferase reporter assay using plasma-treated T47D-Kbluc (ATCC) human breast cancer cells. We also assessed the contribution of EA to risk, independent of circulating estrone, estradiol, and estrone sulfate concentrations. Multivariable ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression adjusting for breast cancer risk factors. RESULTS: Women in the highest, versus lowest EA quartile had an 86% increased risk of invasive breast cancer (ORQ4vsQ1, 1.86; 95% CI = 1.16-2.97). After accounting for estradiol only, a weaker association was observed (ORQ4vsQ1, 1.27; 95% CI = 0.75-2.17). No association was observed after accounting for all three estrogens (ORQ4vsQ1, 1.01; 95% CI = 0.56-1.84). CONCLUSIONS: A positive association between EA and breast cancer risk was observed. However, the association was substantially attenuated after accounting for levels of other estrogens. IMPACT: Our study provides a first detailed assessment of a breast cancer cell line-based EA assay and postmenopausal breast cancer risk.

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.

Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial: a randomized controlled trial.

BACKGROUND: Vitamin D insufficiency is associated with risks of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited. OBJECTIVES: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidences. METHODS: The study was a 5-year, randomized, placebo-controlled trial among 2495 male participants ≥60 years and post-menopausal female participants ≥65 years from a general Finnish population who were free of prior CVD or cancer. The study had 3 arms: placebo, 1600 IU/day, or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative subcohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers, and cancer death. RESULTS: During the follow-up, there were 41 (4.9%), 42 (5.0%), and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (compared with placebo: HR: 0.97; 95% CI: 0.63-1.49; P = 0.89), and 3200 IU/d (HR: 0.84; 95% CI: 0.54-1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%), and 40 (4.8%) participants in the placebo, 1600 IU/d (HR: 1.14; 95% CI: 0.75-1.72; P = 0.55), and 3200 IU/d (HR: 0.95; 95% CI: 0.61-1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the subcohort, the mean baseline serum 25-hydroxyvitamin D concentration was 75 nmol/L (SD, 18 nmol/L). After 12 months, the concentrations were 73 nmol/L (SD, 18 nmol/L), 100 nmol/L (SD, 21 nmol/L), and 120 nmol/L (SD, 22 nmol/L) in the placebo, 1600 IU/d, and 3200 IU/d arms, respectively. CONCLUSIONS: Vitamin D3 supplementation did not lower the incidences of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline.

Association of In Utero Exposures With Risk of Early Natural Menopause.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

The association of parity and breastfeeding with anti-Müllerian hormone levels at two time points.

OBJECTIVE: To evaluate the association between parity and breastfeeding and anti-Müllerian hormone levels (AMH) and change in AMH levels over time. Furthermore, we examined whether AMH levels mediate the relation of parity and breastfeeding with age at menopause. STUDY DESIGN: Observational, prospective cohort study. MAIN OUTCOME MEASURES: AMH levels were assessed in a subset of premenopausal participants in the Nurses' Health Study II, including 1619 women who provided a blood sample in 1996-1999 and an additional 800 women who provided a second premenopausal sample in 2010-2012. RESULTS: In multivariable linear regression models adjusted for parity, body mass index, smoking, and other factors, mean log AMH levels in 1996-1999 were 39% higher in women reporting ≥25 months of total breastfeeding vs. <1 month (P for trend = 0.009). Parity was not associated with AMH levels after adjustment for breastfeeding. Neither parity nor breastfeeding was associated with decline in AMH levels over 11 to 15 years. Breastfeeding duration was positively associated with age at menopause (P for trend = 0.01), with evidence that the association was mediated via AMH. CONCLUSIONS: Our results suggest that breastfeeding is associated with higher AMH levels and later onset of menopause, and support the hypothesis that observed relations of parity with AMH levels and menopause timing may be largely attributable to breastfeeding.

Association of oral contraceptives and tubal ligation with antimüllerian hormone.

OBJECTIVE: Oral contraceptives (OCs) and tubal ligation are commonly used methods of contraception that may impact ovarian function. Few studies have examined the association of these factors with antimüllerian hormone (AMH), a marker of ovarian aging. METHODS: We examined the association of OC use and tubal ligation with AMH in the Nurses' Health Study II prospective cohort among a subset of 1,420 premenopausal participants who provided a blood sample in 1996-1999. History of OC use and tubal ligation were reported in 1989 and updated every 2 years until blood collection. We utilized generalized linear models to assess whether mean AMH levels varied by duration of and age at first use of OCs and history, age, and type of tubal ligation. RESULTS: In multivariable models adjusted for smoking, reproductive events, and other lifestyle factors, we observed a significant, inverse association between duration of OC use and mean AMH levels (P for trend = 0.036). Compared to women without a tubal ligation, AMH levels were significantly lower when the procedure included a clip, ring, or band (1.04 ng/ml vs 1.72 ng/ml, P < 0.01). AMH levels were not associated with age at first use of OCs or age at tubal ligation. CONCLUSIONS: Our analysis found an association between duration of OC use and certain types of tubal ligation with mean AMH levels. Further research is warranted to confirm the long-term association of these widely used contraceptive methods with AMH.

Video Summary:http://links.lww.com/MENO/A860 .

Is Alcohol Consumption Associated With Risk of Early Menopause?

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses' Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0-14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

Inflammation in Relation to Intensity and Duration of Cigarette Smoking Among People Living with HIV.

Both inflammation and smoking are independent predictors of morbidity and mortality among people living with HIV (PLHIV). As smoking burden is likely to exacerbate inflammation, we tested the hypothesis that higher intensity and longer duration of smoking are positively associated with C-reactive protein (CRP, an inflammatory marker) among 284 PLHIV in Kathmandu, Nepal. We measured smoking status, intensity of smoking, smoking duration, and CRP concentrations. In total, 22.9% of never smokers, 24.3% former smokers, and 34.1% current smokers had high CRP (> 3 mg/l). The median intensity and duration of smoking were 12 (cigarettes/day) and 19 years, respectively. Intensity of smoking (beta for increase in number of cigarettes/day: ß = 0.245; p = 0.017), smoking duration (beta for 1-year increase in smoking: ß = 0.341; p = 0.013), and pack-years of smoking (beta for 1-pack-years of smoking increase: ß = 0.351; p = 0.002) were each positively associated with CRP concentrations. While quitting is important, reducing the intensity and duration of smoking until quitting might be helpful in reducing the levels of inflammation, thereby in mitigating HIV-related harms.

Association of Parity and Breastfeeding With Risk of Early Natural Menopause.

Importance: Pregnancy and breastfeeding prevent ovulation and may slow the depletion of the ovarian follicle pool. These factors may lower the risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. Objective: To examine the association of parity and breastfeeding with the risk of early menopause. Design, Setting, and Participants: This population-based cohort study within the Nurses' Health Study II cohort (1989-2015) included premenopausal participants who were aged 25 to 42 years at baseline. Response rates were 85% to 90% for each cycle, and follow-up continued until menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, loss to follow-up, or end of follow-up in May 2015. Hypotheses were formulated after data collection. Data analysis took place from February to July 2019. Exposures: Parity (ie, number of pregnancies lasting ≥6 months) was measured at baseline and every 2 years. History and duration of total and exclusive breastfeeding were assessed 3 times during follow-up. Menopause status and age were assessed every 2 years. Main Outcomes and Measures: Risk of natural menopause before age 45 years. Results: At baseline, 108 887 premenopausal women aged 25 to 42 years (mean [SD] age, 34.1 [4.6] years; 102 246 [93.9%] non-Hispanic white) were included in the study. In multivariable models, higher parity was associated with lower risk of early menopause. Hazard ratios were attenuated with adjustment for breastfeeding but remained significant. Compared with nulliparous women, those reporting 1, 2, 3, and 4 or more pregnancies lasting at least 6 months had hazard ratios for early menopause of 0.92 (95% CI, 0.79-1.06), 0.84 (95% CI, 0.73-0.96), 0.78 (95% CI, 0.67-0.92), and 0.81 (95% CI, 0.66-1.01), respectively (P for trend = .006). In multivariable models also adjusted for parity, hazard ratios for duration of exclusive breastfeeding of 1 to 6, 7 to 12, 13 to 18, and 19 or more months were 0.95 (95% CI, 0.85-1.07), 0.72 (95% CI, 0.62-0.83), 0.80 (95% CI, 0.66-0.97), and 0.89 (95% CI, 0.69-1.16), respectively, compared with less than 1 month of exclusive breastfeeding (P for trend = .001). Despite the significant test for trend, estimates were not observed to be lower as duration of exclusive breastfeeding increased. In a stratified analysis of parous women, risk of early menopause was lowest among those reporting exclusive breastfeeding for 7 to 12 months in each level of parity (women with 2 pregnancies and 7-12 months of breastfeeding: HR, 0.79; 95% CI, 0.66-0.96; ≥3 pregnancies and 7-12 months of breastfeeding: HR, 0.68; 95% CI, 0.52-0.88; 2 pregnancies and ≥13 months of breastfeeding: HR, 0.87; 95% CI, 0.66-1.15; ≥3 pregnancies and 13-18 months of breastfeeding: HR, 0.86; 95% CI, 0.66-1.13; and ≥3 pregnancies and ≥19 months of breastfeeding: HR, 0.98; 95% CI, 0.72-1.32). Conclusions and Relevance: In this study, an inverse association of parity with risk of early menopause was observed. Breastfeeding was associated with significantly lower risk, even after accounting for parity. Breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause.

Sexual orientation and benign breast disease in a cohort of U.S. women.

PURPOSE: Several studies indicate that sexual minority (e.g., bisexual, lesbian) women may be at an increased risk for breast cancer. However, we know little about how risk factors, such as benign breast disease (BBD)-which can confer nearly a fourfold breast cancer risk increase-may vary across sexual orientation groups. METHODS: Among Nurses' Health Study II participants followed from 1989 to 2013 (n = 99,656), we investigated whether bisexual and lesbian women were more likely than heterosexual women to have breast cancer risk factors including a BBD diagnosis (self-reported biopsy or aspiration confirmed, n = 11,021). Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Compared to heterosexuals, sexual minority participants more commonly reported certain breast cancer risk factors including increased alcohol intake and nulliparity. However, sexual minority participants were more likely than heterosexuals to have certain protective factors including higher body mass index and less oral contraceptive use. When evaluating age- and family history-adjusted rates of BBD diagnoses across sexual orientation groups, bisexual (HR 1.04, 95% CI [0.78, 1.38]) and lesbian (0.99 [0.81, 1.21]) women were just as likely as heterosexuals to have a BBD diagnosis. Results were similar after adjusting for other known breast cancer risk factors. CONCLUSIONS: In this cohort of women across the U.S., sexual minorities were more likely than heterosexuals to have some breast cancer risk factors-including modifiable risk factors such as alcohol intake. Heterosexual, bisexual, and lesbian women were equally as likely to have a BBD diagnosis.

Protein intake and the risk of premenstrual syndrome.

OBJECTIVE: To examine the relationship between protein intake and the risk of incident premenstrual syndrome (PMS). DESIGN: Nested case-control study. FFQ were completed every 4 years during follow-up. Our main analysis assessed protein intake 2-4 years before PMS diagnosis (for cases) or reference year (for controls). Baseline (1991) protein intake was also assessed. SETTING: Nurses' Health Study II (NHS2), a large prospective cohort study of registered female nurses in the USA.ParticipantsParticipants were premenopausal women between the ages of 27 and 44 years (mean: 34 years), without diagnosis of PMS at baseline, without a history of cancer, endometriosis, infertility, irregular menstrual cycles or hysterectomy. Incident cases of PMS (n 1234) were identified by self-reported diagnosis during 14 years of follow-up and validated by questionnaire. Controls (n 2426) were women who did not report a diagnosis of PMS during follow-up and confirmed experiencing minimal premenstrual symptoms. RESULTS: In logistic regression models adjusting for smoking, BMI, B-vitamins and other factors, total protein intake was not associated with PMS development. For example, the OR for women with the highest intake of total protein 2-4 years before their reference year (median: 103·6 g/d) v. those with the lowest (median: 66·6 g/d) was 0·94 (95 % CI 0·70, 1·27). Additionally, intakes of specific protein sources and amino acids were not associated with PMS. Furthermore, results substituting carbohydrates and fats for protein were also null. CONCLUSIONS: Overall, protein consumption was not associated with risk of developing PMS.

A Prospective Study of Dairy-Food Intake and Early Menopause.

Early natural menopause, the cessation of ovarian function prior to age 45 years, affects approximately 10% of women and increases risk of cardiovascular disease and other adverse conditions. Laboratory evidence suggests a potential role of dairy foods in the ovarian aging process; however, no prior epidemiologic studies have evaluated how dairy-food intake is associated with risk of early menopause. We therefore evaluated how intakes of total, low-fat, high-fat, and individual dairy foods were associated with early menopause in Nurses' Health Study II. Women who were premenopausal at the start of follow-up in 1991 were followed until 2011 for early menopause. Food frequency questionnaires were used to assess dietary intake. In Cox proportional hazards models adjusting for age, smoking, and other factors, total baseline dairy-food intake of ≥4 servings/day versus <4 servings/week was associated with 23% lower risk of early menopause (hazard ratio = 0.77, 95% confidence interval: 0.64, 0.93; P for trend = 0.08). Associations appeared to be limited to low-fat dairy foods (for ≥2 servings/day vs. <3 servings/month, hazard ratio = 0.83, 95% confidence interval: 0.68, 1.01; P for trend = 0.02), whereas high-fat dairy-food intake was not associated with early menopause. Low-fat dairy foods may represent a modifiable risk factor for reducing risk of early menopause among premenopausal women.

A prospective study of inflammatory biomarker levels and risk of early menopause.

OBJECTIVE: Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated. METHODS: We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, interleukin-6 (IL6) levels with incident early menopause among Nurses' Health Study II participants who provided a premenopausal blood sample in 1996 to 1999. Cases (n = 328) were women reporting natural menopause between blood collection and age 45.Controls (n = 492) included (1) 328 women with menopause after age 47, matched 1:1 with cases on age at blood collection and other factors; and (2) 164 additional women with menopause after age 45. RESULTS: In multivariable models comparing cases and n = 492 controls, we observed a significant association of sTNFR2 levels and risk of early menopause (P = 0.002). Compared with women with the lowest sTNFR2 levels, odds ratios (95% CIs) for quartiles 2 to 4 were 0.60 (0.38-0.95), 0.93 (0.61-1.43), and 1.40 (0.93-2.11). Results further adjusting for antimüllerian hormone levels were similar in magnitude, as were results from sensitivity analyses of matched cases and controls (n = 328 pairs), nonsmokers, and leaner women. C-reactive protein and IL6 levels were unrelated to risk. CONCLUSIONS: The observation of lower risk of early menopause among women with moderate sTNFR2 levels compared with women with lower and higher levels warrants further prospective study.

Physical activity is not related to risk of early menopause in a large prospective study.

STUDY QUESTION: Is physical activity associated with incident early menopause? SUMMARY ANSWER: Physical activity is not associated with incident early menopause. WHAT IS KNOWN ALREADY: Lifestyle factors such as physical activity may influence menopause timing, but results from prior research are inconsistent. STUDY DESIGN, SIZE, DURATION: We evaluated the association between physical activity and the occurrence of early natural menopause in a prospective cohort study, the Nurses' Health Study II. Women were followed prospectively from 1989 to 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our analysis included 107 275 women who were premenopausal at baseline. Menopause status was self-reported biennially. Time per week participating in specific activities was reported approximately every 4 years and used to calculate metabolic task hours per week (MET h/week). We used Cox proportional hazards model to evaluate the association between physical activity and incidence of natural menopause before age 45 years while controlling for potential confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: There were 2 786 study members who experienced menopause before the age of 45. After adjustment for age, smoking and other factors, we observed no association between adulthood physical activity and early menopause. For example, compared to women reporting <3 MET h/week, the hazard ratio for women in the highest category (≥42 MET h/week) of cumulatively-averaged total physical activity was 0.89 (95% confidence interval: 0.76-1.04; P-trend: 0.26). Neither moderate nor strenuous activity in adolescence and young adulthood were related to risk. The relation of physical activity and early menopause did not vary across strata of body mass index or smoking status. LIMITATIONS, REASONS FOR CAUTION: Physical activity and menopausal status were self-reported, but repeated assessment of physical activity and prospective report of menopause status likely reduce the potential for non-differential misclassification. While the majority of our study participants were white, it is unlikely that the physiological relation of activity and early menopause varies by ethnicity. WIDER IMPLICATIONS OF THE FINDINGS: Findings from our large prospective study do not support an important association between physical activity and early menopause. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by UM1CA176726 and R01HD078517 from the National Institutes of Health, Department of Health and Human Services. No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.