The Midlife Women's Health Study - a study protocol of a longitudinal prospective study on predictors of menopausal hot flashes.

BACKGROUND: The Midlife Women's Health Study (MWHS) was developed to address some of the gaps in knowledge regarding risk factors for hot flashes among generally healthy midlife women during their menopausal transition. This manuscript describes the methods from the study and the main findings that were published to date, with a focus on predictors of hot flashes. This study was initially funded to test the hypothesis that obesity is associated with an increased risk of hot flashes through mechanisms that involve ovarian failure, altered sex steroid hormone levels, and selected genetic polymorphisms. METHODS/DESIGN: The MWHS was conducted between 2006 and 2015 as a prospective longitudinal population-based study of generally healthy midlife women (ages 45 to 54 years) during their natural menopausal transition. Women were eligible if they had intact uteri and both ovaries and reported having at least 3 menstrual periods in the last 12 months. Exclusion criteria included pregnancy, cancer, and use of hormonal/hormone-like supplements. Overall, 780 women were recruited into the study. The majority of study participants were followed for 4 to 7 years. At annual visits, women donated blood and urine samples, completed questionnaires, had a vaginal ultrasound, and had their anthropometric measurements taken. DISCUSSION: Several risk factors for menopausal hot flashes were identified or confirmed, including older age, perimenopausal status, current and former cigarette smoking, lower estradiol levels, lower progesterone levels, black race, and depressive symptoms. Factors that were associated with decreased odds of hot flashes included moderate alcohol consumption and more than 5 years of cessation of cigarette smoking. Body mass index was not associated with hot flashes. The MWHS has provided important information regarding hot flashes. The study methods are rigorous and can be easily adopted by research groups investigating naturally occurring menopausal hot flashes.

Risk Factors for Extended Duration and Timing of Peak Severity of Hot Flashes.

OBJECTIVE: To identify risk factors associated with the duration of hot flashes and the time of peak hot flash severity in mid-life women. METHODS: A cohort of 647 women reporting hot flashes were followed for 1-7 years, with survey data and hormone measurements. Survival analysis determined the association of risk factors with the duration of hot flashes. Linear regression determined the association of risk factors with the time of peak severity. Final models were determined through stepwise model selection. RESULTS: Average hot flash duration was 2.5 years (range: 1-33), with peak severity on average at 2.96 years (range: 1-20). Duration of hot flashes was associated with race, education, menopause status, smoking history, BMI, alcohol consumption, leisure activity levels, and levels of estradiol and progesterone. In the final model, only race, alcohol consumption, leisure activity, and menopause were retained. White women had significantly shorter hot flash durations than non-white women. Women consuming at least 12 alcoholic drinks in the previous year had a significantly shorter duration of hot flashes with a smaller effect of hot flash duration on increasing in time to peak severity compared to those who consumed less than 12 alcoholic drinks in that year. Higher serum progesterone levels were associated with later peak severity if the duration of the hot flashes was less than 2 years and an earlier peak severity otherwise. CONCLUSIONS: These results suggest that some behaviors (such as moderate alcohol consumption) are associated with shorter durations of hot flashes, and that progesterone was associated with the dynamics of hot flash severity.

Phthalate metabolite levels and menopausal hot flashes in midlife women.

During the menopausal transition, a woman's reproductive capacity declines, her hormone milieu changes, and her risk of hot flashes increases. Exposure to phthalates, which can be found in personal care products, can also result in altered reproductive function. Here, we investigated the associations between phthalate metabolite levels and midlife hot flashes. Eligible women (45-54 years of age) provided detailed information on hot flashes history and donated urine samples (n=195). Urinary phthalate metabolite levels were measured by HPLC-MS/MS. A higher total sum of phthalate metabolites commonly found in personal care products was associated with an increased risk of ever experiencing hot flashes (odds ratio (OR)=1.45; 95% confidence interval (CI)=1.07-1.96), hot flashes in the past 30days (OR=1.43; 95%CI=1.04-1.96), and more frequent hot flashes (OR=1.47; 95%CI=1.06-2.05). These data suggest that some phthalate exposures from personal care products are associated with menopausal hot flashes in women.

The Associations Between Body Mass Index, Smoking, and Alcohol Intake with Ovarian Volume in Midlife Women.

BACKGROUND: Despite the fact that ovarian volume is a marker of reproductive aging, there is little understanding of factors related to ovarian volume among aging women. The objective of this analysis was to examine the associations between body mass index (BMI), cigarette smoking, and alcohol intake with ovarian volume among midlife women. MATERIALS AND METHODS: Data were analyzed from 771 women (45-54 years of age at baseline) enrolled in the Midlife Women's Health Study, a cohort study that was initiated in 2006. At annual clinic visits, height and weight were measured, a transvaginal ultrasound was performed to measure ovarian volume, blood was drawn to measure hormone concentrations, and a comprehensive questionnaire was administered. Generalized linear models and repeated measures mixed models were conducted to examine the associations between BMI, cigarette smoking, and alcohol intake with ovarian volume, adjusting for age and race. RESULTS: Age was significantly and negatively associated with ovarian volume. However, BMI, smoking, and alcohol use were not associated with ovarian volume either when stratified by menopausal status or when adjusting for age and race. Estradiol, but not progesterone or testosterone, was significantly and positively associated with ovarian volume overall and among both white and black participants (p < 0.05). CONCLUSIONS: This study provides insight into the associations between BMI, smoking, and alcohol use with ovarian volume among midlife women. The findings are somewhat consistent with the published literature and, thus, indicate that these factors may not be clinically important in terms of ovarian volume during the menopausal transition.

Risk factors for hot flashes among women undergoing the menopausal transition: baseline results from the Midlife Women's Health Study.

OBJECTIVE: The aim of this study was to examine the associations of demographic characteristics, health behaviors, and hormone concentrations with the experience of any, current, more severe, and more frequent midlife hot flashes. METHODS: Baseline data from 732 women aged 45 to 54 years who were enrolled in the Midlife Women's Health Study were analyzed. A clinic visit was conducted to collect blood samples for hormone assays and to measure ovarian volume using transvaginal ultrasound. A self-administered questionnaire ascertained information on demographic factors, health habits, and hot flash history. Multivariable logistic regression was conducted to examine associations between potential risk factors and hot flash outcomes. RESULTS: Approximately 45% of participants reported experiencing midlife hot flashes. In covariate-adjusted models, older age, perimenopause status, current and past cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flash outcomes. In addition, history of oral contraceptive use was associated with increased odds of any hot flashes. In contrast, higher current alcohol intake was significantly associated with decreased odds of any, current, and more severe hot flashes. Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all hot flash outcomes. CONCLUSIONS: Although the temporality of such associations is not known because of the cross-sectional nature of the data, these observed relationships can help to identify women at risk for hot flashes.

Change in body mass index, weight, and hot flashes: a longitudinal analysis from the midlife women's health study.

BACKGROUND: The goals of this study were to examine the associations between body mass index (BMI), as well as BMI change and weight change, with midlife hot flashes. METHODS: Data were analyzed from an ongoing 5-year cohort study of 631 midlife women (ages 45-54 years) recruited from Baltimore, Maryland, and its surrounding counties. Height and weight were measured at clinic visits conducted annually. Questionnaires administered at each clinic visit collected detailed data on hot flashes, including the severity and frequency, and other covariates. Data were analyzed using logistic regression and generalized estimated equation models, adjusting for potential confounders. RESULTS: Among women enrolled in the study, 45.2% reported hot flashes and 32.0% were categorized as being obese (BMI ≥30 kg/m(2)) at baseline. At baseline, BMI was not significantly associated with ever experiencing hot flashes (BMI ≥30 versus <25 kg/m(2): odds ratio [OR] 0.92; 95% confidence interval [CI]: 0.58, 1.15) or any of the other hot flashes outcomes (recent, frequent, or severe). In addition, no statistically significant associations between BMI, BMI change, or weight change, and the hot flash outcomes were observed in the longitudinal models (for example, any hot flashes: BMI ≥30 versus <25 kg/m(2): OR 0.81; 95% CI: 0.56, 1.17). CONCLUSION: BMI, BMI change, and weight change during midlife were not related to hot flashes in this study. The data suggest that other factors, such as smoking habits, are more important in determining hot flashes risk during midlife.

Genetic polymorphisms in the aryl hydrocarbon receptor-signaling pathway and sleep disturbances in middle-aged women.

OBJECTIVE: We aimed to determine if selected genetic polymorphisms in the aryl hydrocarbon receptor (AHR)-signaling pathway and circadian locomotor output cycles kaput (CLOCK) are associated with insomnia and early awakening in middle-aged women. METHODS: Women aged 45 to 54years (n=639) were recruited into a middle-aged health study and agreed to complete questionnaires and donate blood samples. Questionnaires were used to assess sleep outcomes. Blood samples were processed for genotyping for the selected polymorphisms: AHR (rs2066853), AHR repressor (AHRR) (rs2292596), aryl hydrocarbon nuclear translocator (ARNT) (rs2228099), and CLOCK (rs1801260). Data were analyzed using multivariable logistic regression. RESULTS: Women heterozygous for the AHRR alleles (GC) had decreased odds of insomnia compared to women homozygous for the AHRR_C allele (adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.49-0.96). Women with at least one of the AHRR_G or CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.64; 95% CI, 0.43-0.96). Additionally, women homozygous for the AHRR_G and CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.56; 95% CI, 0.35-0.89). None of the selected single nucleotide polymorphisms (SNPs) or combinations of SNPs were significantly associated with early awakening. CONCLUSIONS: Selected genetic polymorphisms in the AHR-signaling pathway (i.e., AHRR) and CLOCK may play a role in decreasing the risk for experiencing insomnia during the menopausal transition.

Genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway as potential risk factors of menopausal hot flashes.

OBJECTIVE: We sought to determine if genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway are associated with menopausal hot flashes via hormone levels. STUDY DESIGN: Women (n = 639) aged 45-54 years completed a study survey and provided blood for genetic and hormone analyses. The associations were analyzed using multivariable logistic regression and generalized linear models. RESULTS: Women carrying CYP1B1 (rs1800440) GG genotype had 3-fold greater odds of experiencing hot flashes for ≥1 year compared to the AA genotype (adjusted odds ratio [OR], 3.05; 95% confidence interval [CI], 1.12-8.25). Adding serum estradiol concentrations to the confounder-adjusted model resulted in a nonsignificant association (adjusted OR, 2.59; 95% CI, 0.91-7.18). Carriers of both CYP1B1 (rs1800440) G and CYP1B1 (rs1058636) G alleles had higher odds of experiencing hot flashes for ≥1 year compared to women homozygous for the major alleles (adjusted OR, 1.77; 95% CI, 1.06-2.96), even after adjustment for serum estradiol. CONCLUSION: CYP1B1 is associated with menopausal hot flashes via pathways that may involve changes in serum estradiol concentration.

A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women.

OBJECTIVE: To test whether a synonymous single nucleotide polymorphism (A→G; rs700518) in the CYP19A1 gene, which encodes the enzyme aromatase, is associated with an increased risk for hypertension of midlife women. METHODS: In a cross-sectional study, 639 midlife women were recruited. Eligible women had their blood pressure, weight and height measured, and donated a blood sample for hormone and genetic analyses. The participants also completed a detailed study survey. Women were grouped according to their genotype, blood pressure measurements, and medical history. The data were analyzed using logistic and linear regression models. The study had 80% power to detect small differences in mean systolic blood pressure (SBP; 4.5 mmHg) and diastolic blood pressure (DBP; 3 mmHg). RESULTS: The selected polymorphism was significantly associated with hypertension and SBP in unadjusted analyses. Interestingly, women with hypertension were more likely to be homozygous for the A allele (AA) compared to women who were not categorized as having hypertension. Further, the mean SBP was significantly higher for women who were homozygous for the A allele when compared to women carrying the other genotypes (AG or GG). The unadjusted association between DBP values and genotype was of borderline statistical significance (p=0.07). However, after adjustment for potential confounders (age, race, body mass index (BMI), smoking and physical activity), the associations between genotype and hypertension/blood pressure were attenuated and not statistically significant. CONCLUSION: The rs700518 polymorphism in the CYP19A1 is not associated with hypertension in our sample of midlife women. Other factors, including race and BMI, appear to play a greater role.

Somatic symptoms among cosmetologists compared to women in other occupations.

BACKGROUND: Although the literature pertaining to the cosmetology occupation and specific health effects, such as asthma, dermatitis, and reproductive function, has grown substantially, little information is available about whether cosmetologists are at increased risk of other symptoms compared to women working in other occupations. Thus, the purpose of this study was to determine if cosmetologists of reproductive age are at increased risk of self-reported symptoms compared to women of the same age working in other occupations. METHODS: Data were analyzed from 450 cosmetologists and 511 women in other occupations, aged 21-55 years, in the Baltimore metropolitan region who responded to a mailed survey that ascertained detailed data on symptoms as well as usual work tasks. RESULTS: The data showed that cosmetologists were at increased risk of memory and sleep disturbances, muscle weakness, throat irritation, and hot flashes compared to women of the same age working in other occupations after adjustment for confounders, including cigarette smoking. Among the cosmetologists, handling cleaning supplies; hair bleaching; use of straighteners, texturizers, or permanent chemicals; and several nail care work tasks were associated with one or more of the queried symptoms. CONCLUSIONS: Findings from this study suggest that, compared to noncosmetologists, cosmetologists are at increased risk for a number of symptoms reported to be associated with decreased quality of life. These symptoms may also reflect chronic exposure to chemicals that have been shown to be related to more severe long-term health outcomes.

Adverse health outcomes among cosmetologists and noncosmetologists in the Reproductive Outcomes of Salon Employees (ROSE) study.

The purpose of this study was to examine adverse health outcomes, including those related to cardiovascular and skin health as well as respiratory functions, among cosmetologists aged 21 to 55 yr and to compare data to women of the same age working in other occupations. Self-reported data were analyzed from 450 cosmetologists and 511 women in other occupations who participated in the Reproductive Outcomes of Salon Employees (ROSE) study in Maryland. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed using logistic regression to examine the associations between cosmetologist occupation and each adverse health outcome adjusted for age, education, and smoking status. Cosmetologists were at significantly increased risk of depression compared to noncosmetologists after adjustment for age, education, and smoking status (OR 1.49; 95% CI 1.10, 2.00). There were no statistically significant associations between cosmetology occupation and the other adverse health outcomes, including those related to allergies and skin disorders, in both the unadjusted and adjusted analyses. Cosmetologists may be exposed to chemicals in the salon that lead to depression. Future study needs to be conducted to examine specific chemical exposures in the salon. This will help to provide information required for the development of best occupational safety practices among salon workers.

Health outcomes of children born to cosmetologists compared to children of women in other occupations.

The purpose of the study was to examine the health of children born to cosmetologists compared to the health of children of women working in other occupations. Cross-sectional data were analyzed from 319 cosmetologists and 366 women in other occupations aged 21 to 55 years who reported at least one live birth. Repeated-measures modeling was used to account for lack of independence among multiple pregnancies per participant. The results showed that cosmetologist occupation was associated with having a child with a learning disorder; however, the strength of this association was attenuated and the odds ratio was not statistically significant after confounder adjustment. Cosmetologist occupation was not associated with other adverse health outcomes among the children born to women in such an occupation, including urinary/kidney health problems. The findings indicate that cosmetologists are not at increased risk of having a child with medical problems compared to women in other occupations.

Serum leptin levels, hormone levels, and hot flashes in midlife women.

OBJECTIVE: To examine the associations between serum leptin levels, sex steroid hormone levels, and hot flashes in normal weight and obese midlife women. DESIGN: Cross-sectional study. SETTING: University clinic. PATIENT(S): 201 Caucasian, nonsmoking women aged 45 to 54 years with a body mass index of <25 kg/m2 or >or=30 kg/m2. INTERVENTION(S): Questionnaire, fasting blood samples. MAIN OUTCOME MEASURE(S): Serum leptin and sex steroid hormone levels. RESULT(S): Correlation and regression models were performed to examine associations between leptin levels, hormone levels, and hot flashes. Leptin levels were associated with BMI, with "ever experiencing hot flashes" (questionnaire), with hot flashes within the last 30 days, and with duration of hot flashes (>1 year, P=.03). Leptin was positively correlated with testosterone, free testosterone index, and free estrogen index and inversely associated with levels of sex hormone-binding globulin. In women with a body mass index>or=30 kg/m2, leptin levels no longer correlated with testosterone levels. CONCLUSION(S): Serum leptin levels are associated with the occurrence and duration of hot flashes in midlife women; however, no correlation was found between leptin and serum estradiol.

Hot flashes and blood pressure in midlife women.

OBJECTIVES: Recent epidemiological studies suggest that hot flashes may have a detrimental impact on the cardiovascular system. The purpose of this study was to examine the associations between hot flashes and blood pressure among women aged 45-54 years who had never used hormone therapy. STUDY DESIGN: Data were analyzed from 603 women who participated in the Midlife Health Study, a cross-sectional study conducted in the Baltimore Metropolitan region. MAIN OUTCOME MEASURES: All participants came to the clinic where systolic and diastolic blood pressures were measured, height and weight were assessed, and a questionnaire was administered that ascertained detailed data on history of hot flashes and participant demographics and health habits. RESULTS: The data showed that 56.9% of the participants reported ever experiencing hot flashes. In the age-adjusted analyses, both systolic and diastolic blood pressures were significantly and positively associated with hot flashes. However, the estimates were markedly attenuated and not statistically significant after adjustment for age, race, smoking status, current alcohol use, body mass index, and use of an anti-hypertensive agent or a cholesterol-lowering medication. Similar results were observed for moderate or severe hot flashes, hot flashes experienced for one or more years, and hot flashes experienced within the previous 30 days. CONCLUSIONS: These findings indicate that hot flashes are not significantly associated with blood pressure during midlife.

Cigarette smoking, androgen levels, and hot flushes in midlife women.

OBJECTIVE: To test the hypothesis that cigarette smoking is associated with hot flushes through a mechanism involving androgen levels, progesterone levels, sex hormone-binding globulin levels, or the ratio of androgens to estrogens. METHODS: Women with and without hot flushes were recruited from Baltimore, Maryland, and the surrounding counties. Women were between 45 and 54 years of age, with at least three menstrual periods in the previous 12 months, and were not postmenopausal. Study participants completed a questionnaire and gave a blood sample for hormone measurements. RESULTS: Current smokers had significantly higher androstenedione levels and a higher androgen-to-estrogen ratio than never smokers. Current smokers had significantly lower progesterone levels compared with never smokers. Former and current cigarette smokers had increased odds of experiencing hot flushes compared with never smokers (former: odds ratio [OR] 1.41, 95% confidence interval [CI] 0.99-2.01; current: OR 2.43, 95% CI 1.28-4.62). This association, however, was not attenuated by the addition of hormones to the smoking and hot-flush model. CONCLUSION: Cigarette smoking is associated with hot flushes through a mechanism that may not involve alterations in hormone levels or their ratios. LEVEL OF EVIDENCE: II.

Correlates of depressive symptoms among women undergoing the menopausal transition.

OBJECTIVE: Studies indicate that approximately 25% of women undergoing the menopausal transition experience depressive symptoms. The purpose of this study was to examine whether menopausal status was associated with the experiencing of depression among midlife women, to assess which demographic and health habit characteristics were associated with depressive symptoms experienced during the menopausal transition, and to analyze the associations between hormone levels and depressive symptoms. METHODS: Data from a community-based sample of 634 women aged 45 to 54 years were analyzed. Each participant completed a questionnaire and provided a blood sample that was used to measure estrogen and androgen concentrations by enzyme-linked immunosorbent assay. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression Scale (CES-D). RESULTS: Approximately 25% of the women in the study were experiencing depressive symptoms (CES-D >or=16). The data showed that being a current smoker, having little/no regular physical activity, being in poor health, and reporting a greater number of menopausal symptoms were independently and significantly associated with depressive symptoms. Menopausal status and the measured hormone levels were not significant independent correlates of depressive symptoms. CONCLUSIONS: These findings confirm the relatively high prevalence of depressive symptoms among midlife women and suggest that certain demographic, health habit, and menopausal symptom characteristics may be more important correlates of depressive symptoms in midlife than menopausal status and hormone levels.

Current alcohol use, hormone levels, and hot flashes in midlife women.

Current alcohol use is associated with a lower risk of hot flashes through a mechanism that does not include changes in sex steroid hormone levels.

Genetic polymorphisms, hormone levels, and hot flashes in midlife women.

OBJECTIVE: Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. METHODS: In a cross-sectional study design, midlife women aged 45-54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. RESULTS: A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3betaHSD were both associated with hot flashes. CONCLUSION: Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women.

Association between race and hot flashes in midlife women.

OBJECTIVE: Studies suggest that African American women may have a greater risk of hot flashes compared to Caucasian women, but the reasons for this are unknown. This study tested the hypothesis that African American women have an increased risk of hot flashes due to racial differences in risk factors for hot flashes, including high body mass index (BMI) and lower estrogen levels. METHODS: A population-based study was conducted among women aged 45-54 years. Participants were divided into women who reported ever experiencing hot flashes (n=356) and women who reported never experiencing hot flashes (n=257). Participants provided a blood sample for hormone assays, were weighed and measured, and completed a questionnaire. RESULTS: Among peri-menopausal women, African American women were more likely than Caucasian women to report any hot flashes (RR=2.08), severe hot flashes (RR=2.19), and hot flashes for more than 5 years (RR=1.61). The risk ratios for the associations between race and the hot flash outcomes were attenuated after controlling for other important hot flash risk factors (i.e. obesity and low estrogen levels). CONCLUSIONS: African American women have an increased risk of hot flashes compared to Caucasian women due to racial differences in a number of risk factors for hot flashes, including advanced age, obesity, current smoking, less than 12 drinks in the past year, and lower estrogen levels.

Cigarette smoking, estrogen levels, and hot flashes in midlife women.

OBJECTIVE: The aims of this study were to examine the association of smoking with the occurrence, frequency, and severity of hot flashes and to determine whether the mechanism by which active cigarette smoking increases the risk of hot flashes is by lowering estradiol and estrone levels. METHODS: A case-control study was conducted among women aged 45-54 years to examine risk factors for hot flashes. Cases were women who reported ever experiencing hot flashes (n = 353). Controls were women who reported never experiencing hot flashes (n = 258). Each participant completed a questionnaire and provided a blood sample that was used to measure estradiol and estrone levels. RESULTS: The results showed that both current and ever smokers had higher odds than never smokers of experiencing any and more severe hot flashes. Further, significant positive associations were observed between frequency and duration of smoking and the experiencing of any and more severe hot flashes. Smoking was not associated with estradiol or estrone levels in univariate analyses. In addition, the odds ratios for the associations between the cigarette smoking variables and hot flashes did not change when the hormone variables were added to the model. CONCLUSIONS: These findings indicate that smoking is associated with the occurrence of any and more severe hot flashes, independent of estrogen levels.