Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in the Elderly with Alzheimer's Disease (D-PRESCRIBE-AD): Trial protocol and rationale of an open-label pragmatic, prospective randomized controlled trial.

CONTEXT: Potentially inappropriate prescribing of medications in older adults, particular those with dementia, can lead to adverse drug events including falls and fractures, worsening cognitive impairment, emergency department visits, and hospitalizations. Educational mailings from health plans to patients and their providers to encourage deprescribing conversations may represent an effective, low-cost, "light touch", approach to reducing the burden of potentially inappropriate prescription use in older adults with dementia. OBJECTIVES: The objective of the Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in Elderly with Alzheimer's Disease (D-PRESCRIBE-AD) trial is to evaluate the effect of a health plan based multi-faceted educational outreach intervention to community dwelling patients with dementia who are currently prescribed sedative/hypnotics, antipsychotics, or strong anticholinergics. METHODS: The D-PRESCRIBE-AD is an open-label pragmatic, prospective randomized controlled trial (RCT) comparing three arms: 1) educational mailing to both the health plan patient and their prescribing physician (patient plus physician arm, n = 4814); 2) educational mailing to prescribing physician only (physician only arm, n = 4814); and 3) usual care (n = 4814) among patients with dementia enrolled in two large United States based health plans. The primary outcome is the absence of any dispensing of the targeted potentially inappropriate prescription during the 6-month study observation period after a 3-month black out period following the mailing. Secondary outcomes include dose-reduction, polypharmacy, healthcare utilization, mortality and therapeutic switching within targeted drug classes. CONCLUSION: This large pragmatic RCT will contribute to the evidence base on promoting deprescribing of potentially inappropriate medications among older adults with dementia. If successful, such light touch, inexpensive and highly scalable interventions have the potential to reduce the burden of potentially inappropriate prescribing for patients with dementia. ClinicalTrials.gov Identifier: NCT05147428.

Relationships between the vaginal microbiota and genitourinary syndrome of menopause symptoms in postmenopausal women: the Study of Women's Health Across the Nation.

OBJECTIVE: To describe vaginal microbiota classified by community state types (CST) in a diverse cohort of postmenopausal women and evaluate relationships among genitourinary syndrome of menopause (GSM) symptoms (vaginal dryness, vulvovaginal irritation, sexual pain, dysuria, urinary urgency), CSTs, estrogen, vaginal maturation index (VMI), and vaginal pH. METHODS: In the Study of Women's Health Across the Nation, 1,320 women aged 60.4 to 72.5 years self-collected (2015-2017) vaginal samples analyzed for microbiota composition and structure (CSTs) using 16S rRNA gene amplicon sequencing, VMI, and pH. GSM symptoms were collected with self-administered questionnaires; interviewers elicited estrogen use and measured body mass index. Serum E2 and E1 were measured using high-performance liquid chromatography. We analyzed data using Pearson χ2 tests, analysis of variance, Kruskal-Wallis tests, and binomial logistic regression. RESULTS: The most frequently occurring CST was low Lactobacillus species IV-C (49.8%); 36.4% of women had CSTs dominated by Lactobacillus species. More than half of the women with vaginal atrophy biomarkers (VMI <50 and pH >5) had CST IV-C0, whereas women using estrogen or with higher E1 and E2 levels had a higher prevalence of Lactobacillus crispatus -dominated CST I ( P values < 0.001). Sexual pain was associated with atrophy biomarkers and independently associated with Streptococcus species-dominated CST IV-C1 (odds ratio, 2.26; 95% confidence intervals, 1.20-4.23). For all other GSM symptoms, we found no consistent associations with E1 or E2 levels, atrophy biomarkers, or any CST. CONCLUSIONS: Although close relationships exist among estrogen, CSTs, VMI, and pH, sexual pain was the only GSM symptom associated with the structure of vaginal microbiota and atrophy biomarkers.

Sexual functioning among breast cancer survivors and non-cancer controls over 5 years post diagnosis: Pink SWAN.

PURPOSE: To compare sexual functioning from diagnosis to 5 years post diagnosis among breast cancer survivors (BCS) and women without cancer (controls). PATIENTS AND METHODS: Analyses included 118 BCS and 1765 controls from 20 years of the longitudinal Study of Women's Health Across the Nation (SWAN), a multiracial/ethnic cohort of mid-life women assessed approximately annually from 1995 to 2015. Pink SWAN participants reported no cancer at SWAN enrollment and developed (BCS) or did not develop (controls) incident breast cancer after enrollment. Outcomes included: being sexually active or not, intercourse frequency, sexual desire, vaginal dryness, and pain with intercourse. Using longitudinal logistic regression, we compared BCS and controls on prevalence of sexual functioning outcomes with respect to years since diagnosis. In addition, we examined whether menopause transition stage, depressive symptoms, relationship satisfaction, vaginal dryness, or pain with intercourse modified the relation between breast cancer and sexual functioning outcomes. RESULTS: Adjusting for partner status, both BCS and controls reported similar declines over time in being sexually active, sexual intercourse frequency, and sexual desire. Among sexually active women, more BCS than controls consistently reported vaginal dryness with significant differences between 2 and 4 years post-diagnosis, and pain with intercourse, with statistically significant differences between 0.5 years post-diagnosis to 2 years post-diagnosis. Being post-menopausal and reporting depressive symptoms were significant effect modifiers for pain with intercourse with both variables having positive and stronger associations with pain among the controls than among BCS. CONCLUSION: Except for more reporting of vaginal dryness and pain with intercourse among BCS, negative changes in sexual function during mid-life were similar in those with and without breast cancer.

Sleep disturbance among breast cancer survivors and controls from midlife to early older adulthood: Pink SWAN.

PURPOSE: To compare sleep disturbance from 5 years pre- to 5 years post-diagnosis between breast cancer survivors (BCS) and women without cancer over the same period and to identify BCS subgroups exhibiting different sleep trajectories. METHODS: Analyses included data from 152 BCS and 2163 controls from 20 years of follow-up in the longitudinal Study of Women's Health Across the Nation (SWAN), a multi-racial/ethnic cohort study. SWAN participants were assessed approximately annually from 1995 to 2015 using a standardized protocol. Pink SWAN focused on women who reported no cancer at SWAN enrollment and developed incident breast cancer after enrollment or did not develop breast cancer. Nonparametric locally weighted scatterplot smoothing plots and linear mixed models were used to compare the prevalence of the most frequently reported sleep problem, frequently waking several times a night (a sleep maintenance problem) during the previous 2 weeks, between BCS and controls in the 5 years pre- to 5 years post-diagnosis. We characterized heterogeneity among BCS on this sleep problem using group-based trajectories and examined pre-diagnosis variables as predictors of group membership. RESULTS: No differences were found between BCS and controls in prevalence of frequent nighttime awakenings either before or after diagnosis. Among BCS, three trajectory groups were identified. Thirty-seven percent of BCS had consistently low prevalence of waking several times per night, 30% had high prevalence, and 33% had increasing prevalence which started 2 years pre-diagnosis. Prevalence of pre-diagnosis vasomotor symptoms, anxiety, depressive symptoms, and smoking differed among these groups. CONCLUSION: Among mid-aged women diagnosed with breast cancer, this diagnosis did not trigger/amplify a sleep maintenance problem. The majority of BCS had similar levels of this sleep problem from pre- to post-diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: Although sleep maintenance problems were not amplified by a cancer diagnosis, a subset of BCS may have sleep issues that should be monitored and treated, as indicated.

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.

Vasomotor symptoms in midlife women with incident breast cancer: pink SWAN.

PURPOSE: We compared trajectories of vasomotor symptoms (VMS) and their risk factors in women with breast cancer (BrCa) to those of cancer-free controls. METHODS: Data were from 15 nearly annual follow-up visits (1996-2017) of the multi-racial/ethnic cohort of midlife women enrolled in the Study of Women's Health Across the Nation (SWAN). We compared women with incident BrCa to controls for patterns of VMS, controlling for risk factors identified in bivariate analyses using multivariable longitudinal analyses. RESULTS: Characteristics at study entry largely did not differ between cases (n = 151) and controls (n = 2161). Adjusted prevalence of any VMS increased significantly among cases from diagnosis to 2.75 years post diagnosis [per-year adjusted odds ratio (aOR) = 1.76, 95% confidence interval (CI) 1.39-2.24], peaking at 2.75 years post diagnosis, whereas prevalence was stable among controls in this interval [aOR = 1.04, 95% CI 0.99-1.11]. Beyond 2.75 years post diagnosis, prevalence declined significantly in cases [aOR = 0.72, 95% CI 0.61-0.84] and less in controls [aOR = 0.96, 95% CI 0.92-1.00]. Patterns were similar for frequent VMS. Adjustment for tamoxifen use slightly reduced the per-year OR for any prevalent VMS post diagnosis, partially explaining excess VMS in cases. Other treatments were unassociated with VMS. CONCLUSIONS: Patterns of prevalent VMS reporting differed significantly between cases and controls, particularly post diagnosis, the latter only partially explained by tamoxifen use among cases. Risk factors for VMS largely did not differ between cases and controls.

Lowered progesterone metabolite excretion and a variable LH excretion pattern are associated with vasomotor symptoms but not negative mood in the early perimenopausal transition: Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition. STUDY DESIGN: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy. OUTCOME MEASURES: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C). RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood. CONCLUSION: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade in Persons with Alzheimer's Disease.

OBJECTIVES: Persons living with Alzheimer's disease (AD) may be at increased risk for prescribing cascades due to greater multimorbidity, polypharmacy, and the need for more complex care. Our objective was to assess the proportion of the antidopaminergic-antiparkinsonian medication prescribing cascades among persons living with Alzheimer's disease. SETTING: Two large administrative claims databases in the United States. PARTICIPANTS: We identified patients aged ≥50 on January 1, 2017, who were dispensed a drug used to treat Alzheimer's disease for at least 1 day in the 365 days prior to or on cohort entry date and who had medical and pharmacy coverage in the 365 days prior to the cohort entry date. We excluded individuals with a recent institutional stay. We identified incident antidopaminergic (antipsychotic/metoclopramide) use in the 183 days following cohort entry and identified subsequent incident antiparkinsonian drug use within 8 to 365 days. RESULTS: There were 121,538 patients with Alzheimer's disease eligible for inclusion. Approximately 62% were women with a mean age of 79.5 (SD ± 8.6). The mean number of drugs dispensed was 9.2 (SD ± 4.9). There were 36 incident antiparkinsonian users among 4,534 incident antipsychotic/metoclopramide users (0.8%). CONCLUSION: We determined that the proportion of antidopaminergic-antiparkinsonian medication prescribing cascades, widely considered as high-priority, was low. Our approach can be used to assess the proportion of prescribing cascades in populations considered to be at high risk and to prioritize system-level interventional efforts to improve medication safety in these patients.

Variation in Colorectal Cancer Screening Practices According to Cardiovascular Disease Status and Race/Ethnicity.

PURPOSE: To assess current estimates of colorectal cancer (CRC) screening practices in relation to cardiovascular disease (CVD) status and whether this association varies by race/ethnicity. METHODS: Cross-sectional analysis of the Behavioral Risk Factor Surveillance System data from 2012, 2014, 2016, and 2018 among US adults aged 50-75 years (n = 807,937). Participants' self-reported CRC screening practices were categorized as being up-to-date, not up-to-date, or never screened. Multinomial logistic regression was used to assess whether self-reported prevalent CVD was associated with CRC screening practices after adjusting for several potentially confounding variables; additional analyses were stratified by race/ethnicity. RESULTS: One-quarter of US adults had never been screened for CRC, while 67.0% reported being up-to-date with CRC screening. The proportion of Hispanics who had never been screened (35.3%) was higher than non-Hispanic Whites (23.5%) and Blacks (20.6%). Adults with CVD were less likely to never have been screened (adjusted odds ratio (aOR), 0.92; 95% confidence interval (CI), 0.88-0.95) or not to be up-to-date (aOR, 0.90; 95% CI, 0.86-0.94) on CRC screening than those without CVD. CONCLUSION: The presence of CVD is associated with better adherence to CRC screening guidelines. Poor CRC screening utilization in Hispanics should be a priority for further investigation and intervention.

Identifying women who share patterns of reproductive hormones, vasomotor symptoms, and sleep maintenance problems across the menopause transition: group-based multi-trajectory modeling in the Study of Women's Health Across the Nation.

OBJECTIVE: To identify groups of women who share levels and patterns of change in follicle-stimulating hormone (FSH), self-reported sleep maintenance problems, and frequent vasomotor symptoms (VMS) up to 10 years before and after their final menstrual period and to evaluate their premenopausal characteristics. METHOD: Group-based multi-trajectory modeling grouped 1,407 women from the Study of Women's Health Across the Nation who had an observed natural menopause and did not use hormone therapy, based on repeated measures of FSH, sleep maintenance problems, and frequent VMS relative to final menstrual period. Multivariable analyses assessed race/ethnicity, body mass index, smoking, and depressive symptoms as predictors of group membership. RESULTS: Women formed five distinct groups: (1) low symptoms (low VMS/sleep problems)/high FSH rise (N = 552; 39.2%); (2) moderate VMS and sleep problems/low FSH rise (N = 169; 12.0%); (3) dominant sleep problems (lower VMS/high sleep problems)/high FSH rise (N = 203; 14.4%); (4) dominant VMS (high VMS/lower sleep problems)/high FSH rise (N = 297; 21.1%)); and (5) high symptoms (high VMS/high sleep problems)/intermediate FSH rise (N = 186; 13.2%)). Multivariate analyses showed that race/ethnicity, premenopausal body mass index and depressive symptoms, and increasing depressive symptoms during the early phase of the transition predicted group membership. CONCLUSIONS: Women can be classified based on shared levels and patterns of FSH, sleep maintenance problems, and frequent VMS across the menopause transition. Either VMS or sleep maintenance problems can be dominant in the face of high FSH. Experiencing one menopause-related symptom or hormone profile does not automatically imply that another is also being experienced.

Impact of nulliparity, hypertensive disorders of pregnancy, and gestational diabetes on vasomotor symptoms in midlife women.

OBJECTIVE: To determine whether women with a history of nulliparity, hypertensive disorders of pregnancy (HDP), or gestational diabetes mellitus (GDM) have a higher odds of reporting vasomotor symptoms (VMS) at midlife. METHODS: A longitudinal analysis was performed with 2,249 women with pregnancy history data in the Study of Women's Health Across the Nation. Women were classified as nulliparous, no HDP/GDM, or a history of HDP/GDM. VMS (hot flashes, night sweats) were assessed separately at baseline and at each follow-up visit. VMS was recorded as any versus none; 0 , 1-5 , 6+ days in past 2 weeks. Pregnancy history was examined in relation to each VMS (hot flashes, night sweats) using generalized estimating equations adjusting for age (time-varying), site, race/ethnicity, education, financial strain, smoking, and body mass index. Models excluded women with hysterectomy/bilateral oophorectomy and observations with hormone therapy use. RESULTS: Women in the HDP/GDM group (n = 208, 9%) were more likely to be Black, financially strained, and overweight. Compared to women with no HDP/GDM, women with HDP/GDM had greater odds of reporting any hot flashes (OR:1.27; 95% CI:1.05-1.53). Nulliparous women had lower odds of any hot flashes (OR:0.64; 95% CI:0.51-0.80) and night sweats (OR:0.73; 95% CI:0.58-0.93) in age-adjusted models. Similar patterns were observed for frequency of hot flashes and night sweats; associations were attenuated to nonsignificance after adjusting for covariates. CONCLUSIONS: History of HDP/GDM may be associated with more VMS and nulliparity with fewer VMS, but not independently of sociodemographic factors. Our findings underscore the importance of social and economic disparities in both reproductive outcomes and VMS. VIDEO SUMMARY:: http://links.lww.com/MENO/A631.

http://links.lww.com/MENO/A631.

Health-related quality of life among breast cancer survivors and noncancer controls over 10 years: Pink SWAN.

BACKGROUND: The goal of this study was to compare health-related quality of life (HRQL) from diagnosis to 10 years postdiagnosis among breast cancer survivors (BCS) and women without cancer over the same period and to identify BCS subgroups exhibiting different HRQL trajectories. METHODS: Our analysis included 141 BCS and 2086 controls from the Study of Women's Health Across the Nation (SWAN), a multiracial/ethnic cohort study of mid-life women assessed approximately annually from 1995 to 2015. Pink SWAN participants reported no cancer at SWAN enrollment and developed (cases) or did not develop (controls) incident breast cancer after enrollment. We assessed HRQL with SF-36 Mental Component Summary and Physical Component Summary scores. We modeled each as a function of case/control status, years since diagnosis, years since diagnosis squared, and the interaction terms between case/control status and the 2 time variables in linear models. We characterized heterogeneity in postdiagnosis HRQL of cases using group-based trajectories. RESULTS: BCS had significantly lower HRQL compared with controls at diagnosis and 1 year postdiagnosis. By 2 years, BCS and controls no longer differed significantly. Among BCS, 2 trajectory groups were identified for both scores. For the Mental Component Summary, 88.4% of BCS had consistently good and 11.6% had very low scores. For the Physical Component Summary, 73.9% had good scores, and 26.1% had consistently low scores. Prediagnosis perceived stress and current smoking were related to being in the low mental trajectory group, and a higher number of comorbidities was related to being in the low physical trajectory group. CONCLUSION: Although the majority of BCS have HRQL similar to non-cancer controls after 2 years, subgroups of BCS continue to have low HRQL. Prediagnosis stress, comorbidities, and smoking are vulnerability factors for long-term, low HRQL in BCS.

Obesity, smoking, and risk of vasomotor menopausal symptoms: a pooled analysis of eight cohort studies.

BACKGROUND: Frequent and severe vasomotor symptoms during menopause are linked with adverse health outcomes. Understanding modifiable lifestyle factors for the risk of vasomotor menopausal symptoms is important to guide preventive strategies. OBJECTIVE: We investigated the associations between body mass index and smoking, their joint effects with the risk of vasomotor symptoms, and whether the associations differed by menopausal stage. STUDY DESIGN: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events pooled data on 21,460 midlife women from 8 studies (median age, 50 years; interquartile range, 49-51 years) for the cross-sectional analysis. Four studies provided data for the prospective analysis (n=11,986). Multinomial logistic regression models with 4 categories of frequency/severity for the outcome of vasomotor symptoms were used to estimate relative risk ratios and 95% confidence intervals that were adjusted for within-study correlation and covariates. RESULTS: At baseline, nearly 60% of the women experienced vasomotor symptoms. One-half of them were overweight (30%) or obese (21%), and 17% were current smokers. Cross-sectional analyses showed that a higher body mass index and smoking more cigarettes with longer duration and earlier initiation were all associated with more frequent or severe vasomotor symptoms. Never smokers who were obese had a 1.5-fold (relative risk ratio, 1.52; 95% confidence interval, 1.35-1.73) higher risk of often/severe vasomotor symptoms, compared with never smokers who were of normal-weight. Smoking strengthened the association because the risk of often/severe vasomotor symptoms was much greater among smokers who were obese (relative risk ratio, 3.02; 95% confidence interval, 2.41-3.78). However, smokers who quit at <40 years of age were at similar levels of risk as never smokers. Prospective analyses showed a similar pattern, but the association attenuated markedly after adjustment for baseline vasomotor symptoms. Furthermore, we found that the association between body mass index and vasomotor symptoms differed by menopausal status. Higher body mass index was associated with increased risk of vasomotor symptoms in pre- and perimenopause but with reduced risk in postmenopause. CONCLUSION: High body mass index (≥25 kg/m2) and cigarette smoking substantially increased women's risk for experiencing frequent or severe vasomotor symptoms in a dose-response manner, and smoking intensified the effect of obesity. However, the effect of body mass index on the risk of vasomotor symptoms was opposite among postmenopausal women. Maintaining a normal weight before the menopausal transition and quitting smoking at <40 years of age may mitigate the excess risk of vasomotor symptoms in midlife.

Healthy Lifestyle During the Midlife Is Prospectively Associated With Less Subclinical Carotid Atherosclerosis: The Study of Women's Health Across the Nation.

Background Measures of subclinical atherosclerosis are predictors of future cardiovascular outcomes as well as of physical and cognitive functioning. The menopausal transition is associated with accelerated progression of atherosclerosis in women. The prospective association between a healthy lifestyle during the midlife and subclinical atherosclerosis is unclear. Methods and Results Self-reported data on smoking, diet, and physical activity from 1143 women in the Study of Women's Health Across the Nation were used to construct a 10-year average Healthy Lifestyle Score ( HLS ) during the midlife. Markers of subclinical atherosclerosis were measured 14 years after baseline and included common carotid artery intima-media thickness ( CCA - IMT ), adventitial diameter ( CCA - AD ), and carotid plaque. The associations of average HLS with CCA - IMT and CCA - AD were estimated using linear models; the association of average HLS with carotid plaque was estimated using cumulative logit models. Average HLS was associated with smaller CCA - IMT and CCA - AD in the fully adjusted models ( P=0.0031 and <0.001, respectively). Compared with participants in the lowest HLS level, those in the highest level had 0.024 mm smaller CCA - IMT (95% confidence interval: -0.048, 0.000), which equals 17% of the SD of CCA - IMT , and 0.16 mm smaller CCA - AD (95% confidence interval: -0.27, -0.04), which equals 24% of the SD of CCA - AD . Among the 3 components of the HLS , abstinence from smoking had the strongest association with subclinical atherosclerosis. Conclusions Healthy lifestyle during the menopausal transition is associated with less subclinical atherosclerosis, highlighting the growing recognition that the midlife is a critical window for cardiovascular prevention in women.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Vasomotor Symptoms Across the Menopause Transition: Differences Among Women.

Vasomotor symptoms (VMS) are the primary menopausal symptoms, occurring in up 80% of women and peaking around the final menstrual period. The average duration is 10 years, longer in women with an earlier onset. Compared with non-Hispanic white women, black and Hispanic women are more likely and Asian women are less likely to report VMS. Risk factors include greater body composition (in the early stage of menopausal transition), smoking, anxiety, depression, sensitivity to symptoms, premenstrual syndrome, lower education, and medical treatments, such as hysterectomy, oophorectomy, and breast cancer-related therapies. VMS patterns over time and within higher-risk subgroups are heterogeneous across women.

Factors associated with developing vaginal dryness symptoms in women transitioning through menopause: a longitudinal study.

OBJECTIVE: To evaluate factors associated with incident self-reported vaginal dryness and the consequences of this symptom across the menopausal transition in a multiracial/ethnic cohort of community-dwelling women. METHODS: We analyzed questionnaire and biomarker data from baseline and 13 approximately annual visits over 17 years (1996-2013) from 2,435 participants in the Study of Women's Health Across the Nation, a prospective cohort study. We used discrete-time Cox proportional-hazards regression to identify predictors of incident vaginal dryness and to evaluate vaginal dryness as a predictor of pain during intercourse and changes in sexual intercourse frequency. RESULTS: The prevalence of vaginal dryness increased from 19.4% among all women at baseline (ages 42-53 years) to 34.0% at the 13th visit (ages 57-69 years). Advancing menopausal stage, surgical menopause, anxiety, and being married were positively associated with developing vaginal dryness, regardless of partnered sexual activity. For women not using hormone therapy, higher concurrent levels of endogenous estradiol were inversely associated (multivariable-adjusted hazard ratio: 0.94 per 0.5 standard deviation increase, 95% confidence interval: 0.91-0.98). Concurrent testosterone levels, concurrent dehydroepiandrosterone sulfate levels, and longitudinal change in any reproductive hormone were not associated with developing vaginal dryness. Both vaginal dryness and lubricant use were associated with subsequent reporting of pain during intercourse, but not with a decline in intercourse frequency. CONCLUSION: In these longitudinal analyses, our data support many clinical observations about the relationship between vaginal dryness, menopause, and pain during intercourse, and suggest that reporting of vaginal dryness is not related to androgen level or sexual intercourse frequency.

Lifelong estradiol exposure and risk of depressive symptoms during the transition to menopause and postmenopause.

OBJECTIVE: Depression risk increases during the menopausal transition (MT) and initial postmenopausal years-both times of significant fluctuations of estrogen. Research to date provides limited support for the hypothesis that estrogen fluctuations play a role in the greater susceptibility to midlife depression. Importantly, not all women report depressive symptoms during the MT, and recent reports suggest that duration of exposure to estradiol throughout the adult years may also play a role in vulnerability to depression. This study examines patterns of estrogen exposure during the reproductive years and risk of depression during the MT and early postmenopausal years. METHODS: A longitudinal, US community-based, multiethnic study of menopause. Data were collected at baseline and annually for 10 years, and included 1,306 regularly menstruating premenopausal women, aged 42 to 52 years at study entry. The main outcome was incidence of high level of depressive symptoms, Center for Epidemiological Studies Depression Scale (CES-D) score at least 16, in the MT and initial postmenopausal years, independent of premenopausal depression symptoms. Risk factors examined were duration of estrogen exposure (menarche to MT), duration of hormonal birth control use, pregnancies, and lactation. RESULTS: In a multivariate adjusted model, longer duration of estrogen exposure from menarche to MT onset was significantly associated with a reduced risk of depression (CES-D ≥16) during the MT and 10 years or less postmenopause (odds ratio 0.85, 95% confidence interval 0.78-0.92). Longer duration of birth control use was associated with a decreased risk of CES-D at least 16 (odds ratio 0.90, 95% confidence interval 0.83-0.98), but number of pregnancies or breastfeeding was not. CONCLUSIONS: Patterns of reproductive lifetime exposure to estrogen are associated with risk of high depressive symptoms during the MT and initial postmenopausal years; longer exposure to estrogen seemed protective.