Age at menarche and risk of vasomotor menopausal symptoms: a pooled analysis of six studies.

OBJECTIVE: To examine the association between age at menarche and risk of vasomotor menopausal symptoms (VMS) and whether midlife body mass index (BMI) modified the association. DESIGN: A pooled analysis of six cohort studies. SETTING: The International collaboration on the Life course Approach to reproductive health and Chronic disease Events (InterLACE). POPULATION: 18 555 women from the UK, USA and Australia. METHODS: VMS frequency data (never, rarely, sometimes and often) were harmonised from two studies (n = 13 602); severity data (never, mild, moderate and severe) from the other four studies (n = 4953). Multinominal logistic regression models were used to estimate relative risk ratios (RRRs) and 95% CIs adjusted for confounders and incorporated study as random effects. MAIN OUTCOME MEASURES: Hot flushes and night sweats. RESULTS: Frequency data showed that early menarche ≤11 years was associated with an increased risk of 'often' hot flushes (RRR 1.48, 95% CI 1.24-1.76) and night sweats (RRR 1.59, 95% CI 1.49-1.70) compared with menarche at ≥14 years. Severity data showed similar results, but appeared less conclusive, with RRRs of 1.16 (95% CI 0.94-1.42) and 1.27 (95% CI 1.01-1.58) for 'severe' hot flushes and night sweats, respectively. BMI significantly modified the association as the risk associated with early menarche and 'often' VMS was stronger among women who were overweight or obese than those of normal weight, while this gradient across BMI categories was not as strong with the risk of 'severe' VMS. CONCLUSIONS: Early age at menarche is a risk factor for VMS, particularly for frequent VMS, but midlife BMI may play an important role in modifying this risk. TWEETABLE ABSTRACT: Overweight and obesity exacerbate the risk of vasomotor symptoms associated with early menarche.

Bleeding patterns during the menopausal transition in the multi-ethnic Study of Women's Health Across the Nation (SWAN): a prospective cohort study.

OBJECTIVE: Previous studies describing menses duration and heaviness of flow during the menopausal transition (MT) have been short in duration and limited to white women. We estimated the frequency of and risk factors for prolonged bleeding, spotting and heavy bleeding during the MT in an ethnically diverse population. DESIGN: Prospective community-based cohort study. SETTING USA: southeastern Michigan, northern California and Los Angeles, California. POPULATION: A total of 1320 midlife women who participated in the Study of Women's Health Across the Nation (SWAN) Menstrual Calendar Substudy. Participants included African-American, white, Chinese, and Japanese women. METHODS: Women completed daily menstrual calendars from 1996 to 2006, and provided information on hormone therapy, smoking and physical activity. Annual measures included height and weight. Kaplan-Meier survival analysis and multivariable regression were used to analyse the data. MAIN OUTCOME MEASURES: Menses of 10+ days, spotting of 6+ days, heavy bleeding of 3+ days. RESULTS: At least three occurrences of menses 10+ days was reported by 77.7% (95% confidence interval [95% CI] 56.7-93.2), of 6+ days of spotting by 66.8% (95% CI 55.2-78.0) and of 3+ days of heavy bleeding by 34.5% (95% CI 30.2-39.2) of women. Menses of 10+ days, 6+ days of spotting, and 3+ days of heavy bleeding were associated with MT stage, uterine fibroids, hormone use and ethnicity. Body mass index was associated with 3+ days of heavy bleeding. CONCLUSIONS: These data provide clinicians and women with important information about the expected frequency of prolonged and heavy bleeding and spotting during the menopausal transition that may facilitate clinical decision making.

Ovarian adrenal interactions during the menopausal transition.

Observations over the past decade using longitudinal data reveal a gender-specific shift in adrenal steroid production. This shift is represented by an increase in the circulating concentrations of delta 5 steroids in 85% of all women and is initiated only after the menopausal transition has begun. While the associated rise in the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), is modest, the parallel rises in dehydroepiandrosteone (DHEA) and androstenediol (Adiol) are much more robust. These increases in circulating steroid concentrations are qualitatively similar on average between ethnicities but quantitatively different between individual women. Both circulating testosterone (T) and androstenedione (Adione) also rise concomitantly but modestly by comparison. This phenomenon presents a new and provocative aspect to the endocrine foundations of the menopausal transition and may provide important clues to understanding the fundamentals of mid-aged women's healthy aging, particularly an explanation for the wide diversity in phenotypes observed during the MT as well as their different responses to hormone replacement therapies. Experimental studies using the nonhuman primate animal model show an acute adrenal response to human chorionic gonadotropin (hCG) challenge as well as the presence of luteinizing hormone receptors (LHR) in their adrenal cortices. These experimental results support the concept that LHRs are recruited to the adrenal cortices of mid-aged women that subsequently function to respond to increasing circulating LH to shunt pregnenolone metabolites towards the delta 5 pathway. Future investigations are required to determine the relationship of these changes in adrenal function to symptoms and health outcomes of mid-aged women.

Factors related to declining luteal function in women during the menopausal transition.

CONTEXT: Reproductive hormones are incompletely characterized during the menopause transition (MT). HYPOTHESIS: Increased anovulation and decreased progesterone accompany progress through the MT. DESIGN: The Daily Hormone Study (DHS) of the Study of Women's Health Across the Nation (SWAN) included 848 women aged 43-53 yr at baseline who collected daily urine for one cycle or up to 50 d annually for 3 yr. MAIN OUTCOME MEASURES: LH, FSH, estrone conjugates, and pregnanediol glucuronide levels were assessed. Cycles were classified by presumed luteal (ovulatory) status and bleeding. Hormones were related to time in study, age, menopausal status, and selected variables. RESULTS: Ovulatory-appearing cycles declined from 80.9% at baseline to 64.7% by the third assessment (H3). Cycles presumed anovulatory and not ending with bleeding by 50 d (anovulatory/nonbleeding) increased from 8.4 to 24% by H3 and were associated with progress to early perimenopause [odds ratio (OR) = 2.66; confidence interval (CI) = 1.17-6.04] or late perimenopause (OR = 56.21; CI = 18.79-168.12; P < 0.0001), African-American ethnicity (OR = 1.91; CI = 1.06-3.43), and less than high school education (OR = 3.51; CI = 1.62-7.62). Anovulatory cycles ending with bleeding remained at about 10% from baseline to H3; compared with ovulatory cycles, they were associated with obesity (OR = 4.68; CI = 1.33-16.52) and more than high school education (OR = 2.12; CI = 1.22-3.69; P = 0.02). Serum estradiol in both the highest and lowest categories was associated with anovulatory/nonbleeding collections. Pregnanediol glucuronide decreased 6.6% for each year on study. Insulin sensitivity measures did not relate strongly to menstrual cycle hormones. CONCLUSIONS: Anovulation without bleeding represents progression of the MT. A small but detectable decrease in luteal progesterone excretion occurs as women progress through the MT.

Assessing menstrual cycles with urinary hormone assays.

The Study of Women's Health Across the Nation (SWAN) is a multiethnic cohort study of middle-aged women enrolled at seven US sites. A subset of 848 women completed a substudy in which their urinary gonadotropins and sex steroid metabolites were assessed during one complete menstrual cycle or up to 50 consecutive days. Urine was analyzed for LH, FSH, estrone conjugates (E1c), and pregnanediol glucuronide (Pdg). To prepare for serial analysis of this large, longitudinal database in a population of reproductively aging women, we examined the performance of algorithms designed to identify features of the normal menstrual cycle in midreproductive life. Algorithms were based on existing methods and were compared with a "gold standard" of ratings of trained observers on a subset of 396 cycles from the first collection of Daily Hormone Substudy samples. In evaluating luteal status, overall agreement between and within raters was high. Only 17 of the 396 cycles evaluated were considered indeterminate. Of the 328 cycles rated as containing evidence of luteal activity (ELA), 320 were considered ELA by use of a Pdg threshold detection algorithm. Of 51 cycles that were rated as no evidence of luteal activity, only 2 were identified by this algorithm as ELA. Evaluation of the day of the luteal transition with methods that detected a change in the ratio of E1c to Pdg provided 85-92% agreement for day of the luteal transition within 3 days of the raters. Adding further conditions to the algorithm increased agreement only slightly, by 1-8%. We conclude that reliable, robust, and relatively simple objective methods of evaluation of the probability and timing of ovulation can be used with urinary hormonal assays in early perimenopausal women.

Self-defined menopausal status in a multi-ethnic sample of midlife women.

OBJECTIVES: This study aimed to identify factors associated with women's perceived menopausal status and to evaluate agreement between women's self-designation and a menstrually-based classification in a multi-ethnic sample of women. METHODS: A cross-sectional survey was conducted as part of a large, seven-site, multi-ethnic study, the Study of Women's Health Across the Nation (SWAN). All variables were assessed by self-report in 13952 women aged 40-55 years. Multiple linear regression was used to assess determinants of self-defined menopausal status, stratifying by race/ethnicity within three anatomical/hormone use strata. Kappa statistics were used to evaluate agreement between the self-defined and menstrually-based classifications. RESULTS: For women with an intact uterus, at least one ovary and not using hormones, menstrual patterns explained about half the variance in self-defined menopause status with older women classifying themselves later in the transition. Disagreement between menstrually-based and self-defined menopausal status was 39, 38, 36, 32 and 29% for Hispanic, African-American, Japanese, Caucasian, and Chinese women, respectively (kappa statistics=0.46, 0.41, 0.40, 0.53 and 0.58). Women with vasomotor symptoms tended to self-designate themselves as being in transition regardless of their menstrual patterns. Age and 12 months of amenorrhea explained about 40% of the variance in self-categorization among women using hormones with an intact uterus. Bilateral oophorectomy, age and time since surgery explained about 20% of the variance among post-surgical women. CONCLUSIONS: Menstrual characteristics are strong predictors of women's self-perceived menopausal status. However, additional factors, including symptoms and cultural differences in the meaning of specific bleeding patterns, are also relevant and require further investigation.

An electronic menstrual cycle calendar: comparison of data quality with a paper version.

OBJECTIVES: This pilot study compared a prototype electronic menstrual calendar on a handheld computer with a paper calendar for data quality and participants' perceptions. DESIGN: Twenty-three women completed identical information about menstrual bleeding and symptoms using paper and electronic calendars for 1 month each. RESULTS: Use of the paper calendar resulted in more missing data than the electronic calendar for bleeding characteristics (13% vs. 4%) and symptoms (35% vs. 4%). The electronic calendar's ability to log data entries revealed retrospective entry for 61% of the data. Total data entry and cleaning time was reduced by 81% with the electronic calendar. Overall, participants preferred the electronic (70%) to the paper (22%) calendar. CONCLUSIONS: Data quality with conventional paper calendars may be poorer than recognized. The data-logging feature, unique to the electronic calendar, is critical for assessing data quality. Electronic menstrual calendars can be useful data collection tools for research in women's health.

A longitudinal study of weight and the menopause transition: results from the Massachusetts Women's Health Study.

OBJECTIVE: Results of past studies of menopause and weight are inconsistent, in part because of problems in study design and analyses, such as retrospective assessment of age at menopause and failure to control for confounding factors. To address such shortcomings, we conducted multivariate analyses on longitudinal data from a large, community-based sample of initially pre- and perimenopausal women who were making the transition through menopause. DESIGN: Data were from the second phase of the Massachusetts Women's Health Study, a cohort of 418 women aged 50-60 years in 1986. We assessed the relationship between menopause transition and weight, after accounting for previous weight; age; and the behavioral factors of smoking, exercise, and annual ethanol consumption. Menopause status was defined in terms of months of amenorrhea. The association of hormone replacement therapy and weight also was examined. RESULTS: Menopause transition was not consistently associated with increased weight, and use of hormone replacement therapy was not significantly related to weight. Behavioral factors--particularly exercise and ethanol consumption--were more strongly related to weight than was menopause transition. CONCLUSIONS: These results are consistent with findings from other studies that suggest that the weight increases experienced by middle-aged women in the United States are not a result of the menopause transition.

Menstrual bleeding, hormones, and the menopausal transition.

The perimenopause represents a time of great variability in reproductive hormone dynamics and menstrual cycle characteristics, but age-related changes begin prior to this. These changes include a gradual increase in follicle stimulating hormone (FSH) levels, a gradual shortening of mean cycle length, and a decline in the number of ovarian follicles. The onset of perimenopause is thought to occur with the first break in menstrual cycle regularity. With the onset of cycle irregularities, hormone concentrations exhibit large increases in variability and unpredictability, rather than following a gradual trend with the approach of menopause, the final menstrual period. Abrupt spikes in gonadotropins and considerable fluctuations in estradiol and inhibin levels have been observed. Variability is the norm in the perimenopause, with hormonal fluctuations contributing to the visible signs of menstrual cycle and bleeding irregularities. To date there is no single endocrine indicator to serve as an adequate marker of menopausal status. This paper provides a review of research to date on patterns of reproductive hormones and menstrual bleeding during the menopausal transition. An understanding of such patterns can contribute to a better ability to distinguish "normal" transitional events from more serious pathology.

The Health Belief Model and HIV risk behaviours: a causal model analysis among Anglos, African-Americans and Mexican-Americans.

A causal model of the Health Belief Model (HBM) is empirically evaluated which emphasizes possible indirect paths linking distal demographic and seriousness/susceptibility variables to HIV risk behaviours among Anglo, African-American, and Mexican-American adults. A specific focus of the paper is upon alcohol-related expectancies (anticipation of disinhibitory effects of alcohol upon sexual behavior) as a 'barrier' to preventive behaviours. Ethnic comparisons stem both from the paucity of available research on the HBM in minority populations and from recent questions regarding the applicability of rational models such as the HBM among minority groups. Analyses of data from a community sample of 1390 adults indicate relatively consistent direct effects of barriers for males and benefits for females upon HIV risk behaviors. The analyses suggest distinct paths operative among males and females. The susceptibility-barriers-risk behaviours path among males may suggest that alcohol-related expectancies (barriers in this model) may be more strongly related to risk behaviours among males than minority females.

Can follicle-stimulating hormone be used to define menopausal status?

OBJECTIVE: To assess the ability of the level of follicle-stimulating hormone (FSH) to distinguish among premenopausal, perimenopausal, and postmenopausal women. METHODS: We examined cross-sectional and longitudinal data from the second phase of the Massachusetts Women's Health Study (1986 to 1995), a population-based cohort of 427 premenopausal and perimenopausal women identified from the first phase of the Massachusetts Women's Health Study (1981 to 1986). RESULTS: Boxplots of FSH levels throughout the menopausal transition displayed considerable overlap. Logistic regressions and their resulting receiver operating characteristic curves further demonstrated that, although FSH is a statistically significant predictor of menopausal status, no single value of FSH is expedient for distinguishing premenopausal from perimenopausal or perimenopausal from postmenopausal women. CONCLUSION: FSH alone is not an effective predictor of transition into the perimenopausal or postmenopausal period. Specifically, the frequently recommended FSH cutoff of 40 IU/L is inappropriate by itself for clinical determination of postmenopausal status.

Interviewer effects in a cohort study. Results from the Massachusetts Women's Health Study.

Although interviewer error is widely recognized as an important source of variation in epidemiologic investigations, scant published information exists documenting the impact of interviewer variation on study findings. Using data from the Massachusetts Women's Health Study, a population-based cohort study of 2,569 middle-aged women (1982-1987), the authors evaluated interviewer variation in responses to different types of questions, and assessed the impact of interviewer variation on inferences derived from study data. Respondent sociodemographic and lifestyle characteristics were similar for the four study interviewers at the first follow-up. No interviewer variation was detected for questions concerning recall of specific events, but responses to questions regarding recall of subjective or personal information or those which required further probing did differ significantly by interviewer. Adjustment for interviewer effects had no impact on the conclusions obtained from one analysis of predictors of depression, despite significant interviewer variation in the outcome and predictor variables, but it did change conclusions from an analysis of the impact of support networks on psychological symptoms, wherein the interviewer variable was strongly related to the outcome after data were controlled for predictor variables. Given these findings, examination of data for interviewer effects is advisable despite incorporation of quality control measures in a study's design.

Psychosocial, behavioral, and health factors related to menopause symptomatology.

Despite wide variation in the reporting of hot flashes and night sweats among menopausal women, what differentiates symptomatic from asymptomatic women is not well understood. In this article, we use longitudinal data from a large cohort of initially premenopausal women to address premenopausal factors predictive of length of the perimenopause, frequency of hot flash/night sweat (HF/NS) reporting, bothersomeness of HF/NS, and treatment seeking during menopause. The sample for analysis consists of 454 women from the Massachusetts Women's Health Study who were premenopausal at baseline and postmenopausal by the sixth and last study follow-up. Each of the four study outcomes was modeled as a function of premenopausal characteristics using logistic regression. Results confirm a wide range of symptom reporting, with 23% of women not reporting HF/NS at any of the six interviews. Variables related to greater frequency of HF/NS reporting included a longer perimenopause, more psychological and physical symptoms prior to menopause, lower education, and more negative attitudes toward menopause prior to menopause. Symptom bothersomeness was related to greater frequency of HF/NS reporting, smoking, and being divorced. Variables that predicted medical doctor consultation were greater frequency and bothersomeness of symptoms, higher education, and greater health care utilization. We conclude that general symptom reporting, attitudes toward menopause, and lifestyle factors can explain some of the individual variation in symptom reporting.

Understanding the variability in the effectiveness of community heart health programs: a meta-analysis.

Over the past 25 years, community interventions to reduce cardiovascular disease (CVD) have been conducted around the world with very mixed results. This study uses meta-analysis to assess whether the variation in the observed effectiveness of community heart health programs (CHHP) is related to characteristics of the intervention program, the population under study, or the evaluation methods. A CHHP is defined as any primary prevention program that attempted to reduce the population burden of CVD by shifting the distribution of risk factors in a general population. To be included in the meta-analysis, a study must have utilized a reference group in the evaluation, employed a repeated independent cross-sectional measurement design, and reported sufficient outcome information for at least one of four major risk factors: smoking, total cholesterol, blood pressure, and body weight. Results of these studies are summarized with the effect size measure (Yi1-Yi2)-(Yr1-Yr2)Sr1 where Y = outcome measure, S = standard deviation of the outcome measure, 1 = baseline, 2 = follow-up. i = intervention, and r = reference community. This measure, which reports the net change in the intervention group in terms of the variability in the reference population before the start of the intervention, permits comparison across different outcome measures and facilitates the aggregation of effects across studies. Generalized least squares regression, which permits the incorporation of multiple, dependent effect sizes from a single study, was used to assess the impact of characteristics of the intervention (prevention strategy, type of mass communication, community organization, and environmental change), the population (setting, gender, year of follow-up measurement), and the evaluation design and implementation (the number of communities, matching of communities, the follow-up time, the response rate, and covariate adjustment in the analysis) on the effect sizes. The results of this analysis suggest that the characteristics of the evaluation method account for much of the heterogeneity in the outcome of CHHPs, though some intervention characteristics also play a role.

Does collecting repeated blood samples from each subject improve the precision of estimated steroid hormone levels?

Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in women.

The everyday impacts of providing informal care to dependent elders and their consequences for the care recipients.

Longitudinal data were used to identify the relationship between different areas of negative impact and elder and caregiver characteristics. The extent and predictors of persistence and development of negative impact in different areas and the relationship between caregiving impact and subsequent caregiving patterns, including termination of care and institutionalization of the elder, were also examined. Caregiving exerted the greatest toll on a caregiver's personal life reported by 61%, in comparison to family life (18%), or employment (15%-20%). Those at particular risk of negative impact included offspring and other-relative caregivers who resided with the elder. All areas of negative impact persisted over time but did not result in any major disruption in care for the elder. However, those elders whose caregivers experienced personal impact were twice as likely to be institutionalized.

A comparison of anlaytic methods for non-random missingness of outcome data.

Missing outcome values occur frequently in survey data and are rarely missing randomly. Depending on the pattern of missingness, the choice of analytic method has implications for accuracy of the estimated outcome distribution as well as multivariate models. Data from a study of patterns of care in disabled elders were used to evaluate several common methods when missingness of the outcome was nonrandom. Results from single and multiple model-based imputation were compared with results from complete-case analysis and mean imputation. By ignoring nonrespondents' covariate information, the latter two methods yielded biased estimates of population means. Mean imputation and single model-based imputation underestimated standard errors by treating imputed values as if they were observed. Mean imputation also distorted the relationship between the outcome and predictors. Multiple model-based imputation provided an easily implemented method of adjustment for non-random non-response in both univariate and multivariate analyses.

Longitudinal patterns and correlates of hormone replacement therapy use in middle-aged women.

Patterns of hormone replacement therapy (HRT) use over time and predictors of initiating or discontinuing use were examined in a longitudinal study. A cohort of 2,425 women aged 45-55 years identified from a population-based random survey in Massachusetts in 1981-1982 was followed by six telephone interviews, 9 months apart. Cohort participants were either premenopausal (66.8%) or in early perimenopause (33.2%). During the study, prevalence of use was low overall (12.3%) and was considerably higher for surgical menopause (45%) than for peri- (9.3%), natural (4.5%), or premenopause (1.5%). Predictors of HRT uptake and discontinuation (from time t - 1 to time t) were examined by repeated-measures logistic regression, stratified by surgical status. For surgical menopause, the only significant predictor of HRT uptake was recent surgery (odds ratio = 4.4; 95% confidence interval 2.73-7.22), while for nonsurgical subjects, menopausal status (primarily perimenopause), prior use of HRT, health care utilization, hot flashes, alcohol consumption, regular exercise, and leaner body mass were all significant predictors of uptake. Discontinuing HRT was inversely associated with surgical and perimenopause and positively related to prior short-term use and health care utilization. Nonsurgical HRT users had a somewhat more favorable cardiovascular risk profile than did nonusers.