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Menopause (New York, N.Y.)  2013;20(9):911-921.
The relatively modest benefit in vasomotor symptom relief seen in clinical trials of isoflavones may reflect once-daily dosing as well as low percentages of participants able to metabolize daidzein to equol, a potentially more biologically active isoflavone. This pilot study examined whether symptom reduction was greater with more frequent administration as well as with higher daily doses. In addition, we explored possible effect modification by equol producer status.
We randomized 130 peri- (no menses in past three months) and postmenopausal (12+ months amenorrhea) women with an average of 5+ moderate/severe hot flashes per day to treatment arms with varying total daily isoflavone doses and dosing frequency, separately for equol producers and non-producers. Participants recorded daily frequency and severity of hot flashes. Analyses compared mean daily hot flash intensity scores (sum of hot flashes weighted by severity) by total daily dose and by dosing frequency. Dose- and frequency-related differences also were compared for equol producers and non-producers.
Hot flash intensity scores were lowest in women randomized to the highest total daily dose (100-200mg) and in women randomized to the highest dosing frequency (2-3 times daily), with greater benefits in nighttime than in daytime scores. Dose-related and frequency-related differences were somewhat larger in equol producers than in non-producers.
These results suggest that a 2-3 times per day dosing frequency may improve the benefit of isoflavones for vasomotor symptom relief, particularly in equol producers and for nighttime symptoms. Larger studies are needed to confirm these findings.
PMCID: PMC3723773  PMID: 23511704
Vasomotor symptoms; isoflavones; equol producers
2.  Sensitivity and Specificity of Recalled Vasomotor Symptoms in a Multiethnic Cohort 
American Journal of Epidemiology  2008;168(12):1452-1459.
Many epidemiologic studies include symptom checklists assessing recall of symptoms over a specified time period. Little research exists regarding the congruence of short-term symptom recall with daily self-reporting. The authors assessed the sensitivity and specificity of retrospective reporting of vasomotor symptoms using data from 567 participants in the Study of Women's Health Across the Nation (1997–2002). Daily assessments were considered the “gold standard” for comparison with retrospective vasomotor symptom reporting. Logistic regression was used to identify predictors of sensitivity and specificity for retrospective reporting of any vasomotor symptoms versus none in the past 2 weeks. Sensitivity and specificity were relatively constant over a 3-year period. Sensitivity ranged from 78% to 84% and specificity from 85% to 89%. Sensitivity was lower among women with fewer symptomatic days in the daily assessments and higher among women reporting vasomotor symptoms in the daily assessment on the day of retrospective reporting. Specificity was negatively associated with general symptom awareness and past smoking and was positively associated with routine physical activity and Japanese ethnicity. Because many investigators rely on symptom recall, it is important to evaluate reporting accuracy, which was relatively high for vasomotor symptoms in this study. The approach presented here would be useful for examining other symptoms or behaviors.
PMCID: PMC2727191  PMID: 18953064
data collection; hot flashes; mental recall; sensitivity and specificity; sweating; vasomotor system
3.  Cardiovascular risk factor knowledge and risk perception among HIV-infected adults 
The Journal of the Association of Nurses in AIDS Care : JANAC  2013;25(1):10.1016/j.jana.2013.07.006.
Cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality in HIV-infected adults. Research in non-infected populations has suggested that knowledge of CVD risk factors significantly influences perceptions of risk. This cross-sectional study describes CVD risk factor knowledge and risk perception in HIV-infected adults. We recruited 130 HIV-infected adults (mean age = 48 years, 62% male, 56% current smokers, mean years since HIV diagnosis, 14.7). The mean CVD risk factor knowledge score was fairly high. However, controlling for age, CVD risk factor knowledge was not predictive of perceived risk (F[1,117] = 0.13, p > .05). Estimated risk and perceived risk were weakly, but significantly, correlated, r(126) = .24, p = .01. HIV-infected adults are at increased risk for CVD. Despite having adequate risk factor knowledge, CVD risk perception was inaccurate. Improving risk perception and developing CVD risk reduction interventions for this population are imperative.
PMCID: PMC3875835  PMID: 24070645
cardiovascular disease; heart disease; HIV; risk factor knowledge; risk perception
4.  Phone-Delivered Mindfulness Training for Patients with Implantable Cardioverter Defibrillators: Results of a Pilot Randomized Controlled Trial 
The reduction in adrenergic activity and anxiety associated with meditation may be beneficial for patients with implantable cardioverter defibrillators.
To determine the feasibility of a phone-delivered mindfulness intervention in patients with defibrillators and to obtain preliminary indications of efficacy on mindfulness and anxiety.
Clinically stable outpatients were randomized to a mindfulness intervention (8 weekly individual phone sessions) or to a scripted follow-up phone call. We used the Hospital Anxiety and Depression Scale and the Five Facets of Mindfulness to measure anxiety and mindfulness; and multivariate linear regression to estimate the intervention effect on pre-post intervention changes in these variables.
We enrolled 45 patients (23 mindfulness, 22 control; age 43–83; 30 % women). Retention was 93 %; attendance was 94 %. Mindfulness (beta = 3.31; p = .04) and anxiety (beta = − 1.15; p = .059) improved in the mindfulness group.
Mindfulness training can be effectively phone-delivered and may improve mindfulness and anxiety in cardiac defibrillator outpatients.
PMCID: PMC3758416  PMID: 23605175
mindfulness; anxiety; implantable cardioverter defibrillators; phone-delivery
5.  Adverse Effects of Induced Hot Flashes on Objectively Recorded and Subjectively Reported Sleep: Results of a Gonadotropin-Releasing Hormone Agonist Experimental Protocol 
Menopause (New York, N.Y.)  2013;20(9):905-914.
The impact of hot flashes on sleep is of great clinical interest, but results are inconsistent, especially when both hot flashes and sleep are measured objectively. Using objective and subjective measurements, we examined the impact of hot flashes on sleep by inducing hot flashes with a gonadotropin-releasing hormone agonist (GnRHa).
The GnRHa leuprolide was administered to 20 healthy premenopausal volunteers without hot flashes or sleep disturbances. Induced hot flashes were assessed objectively (skin-conductance monitor) and subjectively (daily diary) during one-month follow-up. Changes from baseline in objective (actigraphy) and subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) were compared between women who did and did not develop objective hot flashes, and, in parallel analyses, subjective hot flashes.
New-onset hot flashes were recorded in 14 (70%) and reported by 14 (70%) women (80% concordance). Estradiol was universally suppressed. Objective sleep efficiency worsened in women with objective hot flashes and improved in women without objective hot flashes (median decrease 2.6%, increase 4.2%, p=0.005). Subjective sleep quality worsened more in those with than without subjective hot flashes (median increase PSQI 2.5 vs. 1.0, p=0.03). Objective hot flashes were not associated with subjective sleep quality, nor were subjective symptoms linked to objective sleep measures.
This experimental model of induced hot flashes demonstrates a causal relationship between hot flashes and poor sleep quality. Objective hot flashes result in worse objective sleep efficiency, while subjective hot flashes worsen perceived sleep quality.
PMCID: PMC3687015  PMID: 23481119
hot flashes; vasomotor symptoms; sleep; quality-of-life; depressive symptoms; actigraphy
6.  Classifying Menopausal Stage by Menstrual Calendars and Annual Interviews: Need for Improved Questionnaires 
Menopause (New York, N.Y.)  2013;20(7):727-735.
To assess agreement between menopausal transition stages defined by annual interview or annual follicle-stimulating hormone measures and menopausal transition stages defined by the monthly menstrual calendar, as well as factors associated with discordance.
These analyses used daily self-recorded menstrual calendar data from 1996–2006, annual interviews, and annual follicle-stimulating hormone measures. Participants were from 4 study sites of the Study of Women’s Health Across the Nation Boston, southeastern Michigan, Oakland, and Los Angles, and four racial/ethnic groups: African-American, Caucasian, Chinese, and Japanese. Women who had a defined final menstrual period (FMP) and who never went on hormones were included (n=379). Cohen’s Kappa for 2 by 2 tables were calculated for two definitions of agreement. Logistic regression was used to identify factors associated with discordance.
Poor agreement between annual interview and menstrual calendar data was found for early menopausal transition (Kappa= −0.13, 95%CI: −0.25, −0.02) and late menopausal transition (Kappa= −0.18, 95%CI: −0.26, −0.11). For late stage, Chinese women (OR=2.16, 95%CI= 1.08, 4.30), African-American women (OR=2.39, 95%CI= 1.00, 5.71), and women with a high school education or less (OR=2.16, 95%CI= 1.08, 4.30) were more likely to be discordant. Poor agreement between annual follicle-stimulating hormone measures and menstrual calendars was also found for early menopausal transition (Kappa= −0.44, 95%CI: −0.57, −0.30) and late menopausal transition (Kappa= −0.32, 95%CI: −0.42, −0.23)
New questions need to be developed to accurately identify the start of the menopausal transition and should be evaluated in a multi-ethnic population with varying educational backgrounds.
PMCID: PMC3686995  PMID: 23481122
female; menopause; perimenopause; menstrual cycle; questionnaires; bias
7.  Factors Related to Age at Natural Menopause: Longitudinal Analyses From SWAN 
American Journal of Epidemiology  2013;178(1):70-83.
Early age at the natural final menstrual period (FMP) or menopause has been associated with numerous health outcomes and might be a marker of future ill health. However, potentially modifiable factors affecting age at menopause have not been examined longitudinally in large, diverse populations. The Study of Women's Health Across the Nation (SWAN) followed 3,302 initially premenopausal and early perimenopausal women from 7 US sites and 5 racial/ethnic groups, using annual data (1996–2007) and Cox proportional hazards models to assess the relation of time-invariant and time-varying sociodemographic, lifestyle, and health factors to age at natural FMP. Median age at the FMP was 52.54 years (n = 1,483 observed natural FMPs). Controlling for sociodemographic, lifestyle, and health factors, we found that racial/ethnic groups did not differ in age at the FMP. Higher educational level, prior oral contraceptive use, and higher weight at baseline, as well as being employed, not smoking, consuming alcohol, having less physical activity, and having better self-rated health over follow-up, were significantly associated with later age at the FMP. These results suggest that age at the natural FMP reflects a complex interrelation of health and socioeconomic factors, which could partially explain the relation of late age at FMP to reduced morbidity and mortality.
PMCID: PMC3698989  PMID: 23788671
age; education; ethnicity; menopause; oral contraceptives; race; smoking; weight
Cancer  2013;119(9):1652-1659.
Germline mutations in BRCA1/2 are related to increased lifetime risk of breast and ovarian cancer. While risk-reducing salpingo-oophorectomy reduces the risk for both cancers, loss of fertility is a major concern. A recent study suggested an association of BRCA1 mutation with occult primary ovarian insufficiency. The aim of this study was to determine whether BRCA1/2 mutation carriers have earlier onset of natural menopause than unaffected women.
Materials and Methods
Caucasian BRCA1/2 carriers (n=382) were identified within the UCSF Breast Cancer Risk Program Registry and compared to non-clinic-based Caucasian women in Northern California (n=765). We compared the two groups regarding median age at natural menopause before and after adjustment for known risk factors, and examined the role of smoking within each group, using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses.
The median age at natural menopause in BRCA1/2 carriers was significantly earlier than the unaffected sample (50 vs 53years, p-value<0.001). The unadjusted hazard ratio for natural menopause comparing BRCA1/2 carriers to unaffected women was 4.06(95% confidence interval 3.03-5.45), 3.98(2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (≥20cigarettes/day), the median age at natural menopause was 46 vs.49years for non-smokers (p-value=0.027).
BRCA1/2 mutation was associated with significantly earlier age at natural menopause, and heavy smoking compounded this risk. As the relationship between menopause and end of natural fertility is considered fixed, these findings suggest a risk of earlier infertility among BRCA1/2 carriers.
PMCID: PMC3634895  PMID: 23362014
menopause; BRCA1 gene; BRCA2 gene; primary ovarian insufficiency; smoking; carcinogenesis
9.  The Relationship Between Dietary Phytoestrogens and Development of Urinary Incontinence in Midlife Women 
Menopause (New York, N.Y.)  2013;20(4):428-436.
Because exogenous estrogen treatment has been associated with a higher risk of urinary incontinence, our objective was to evaluate the longitudinal relationships of dietary phytoestrogen intakes (isoflavones, coumestans and lignans) and the development of incontinence in midlife women transitioning through menopause.
The Study of Women’s health Across the Nation (SWAN) Phytoestrogen Study was developed within SWAN, a community-based, multisite, multi-racial/ethnic, prospective cohort study. SWAN interviewers administered a food consumption assessment at baseline and at follow-up visits 5 and 9. The SWAN Phytoestrogen study created a phytonutrient data base that allowed estimation of usual daily intakes of four isoflavones, four lignans and coumestrol. On an annual self-administered questionnaire, participants reported on frequency and type of incontinence. We used discrete proportional hazards models to evaluate whether estimated daily intake of each phytoestrogen class at the visit previous to the first report of incontinence was associated with the development of monthly or more incontinence compared to remaining continent.
We found no association or patterns of association between developing any, stress or urge incontinence and the reported daily dietary intake of isoflavones, coumestrol, and lignans in the visit previous to the onset of incontinence.
The results of this longitudinal study provide important information to better understand estrogen-like substances on the continence mechanism in midlife women. Our study shows that neither high nor low dietary intakes of isoflavones, coumestrol and lignans prevent stress or urge incontinence. Future studies should evaluate whether serum levels of phytoestrogens or their metabolites impact incontinence symptoms.
PMCID: PMC3568456  PMID: 23096248
Phytoestrogen; isoflavone; coumestrol; lignan; urinary incontinence
10.  Phytoestrogen and Fiber Intakes in Relation to Incident Vasomotor Symptoms: Results From the Study of Women’s Health Across the Nation 
Menopause (New York, N.Y.)  2013;20(3):305-314.
While reduction of vasomotor symptoms (VMS, hot flashes/night sweats) has been reported in postmenopausal women who used isoflavones, a clear dose-response has not been shown, has largely not been reported for perimenopausal women and has largely only been for reducing prevalent VMS, not preventing newly developing VMS. We analyzed longitudinal data from the Study of Women’s Health Across the Nation (SWAN) for the relation of dietary phytoestrogens and fiber intake to incident VMS in this multi-racial/ethnic cohort.
SWAN included 3302 pre- and early perimenopausal women, 1651 of whom reported no VMS at baseline, who were followed with annual visits for 10 years. Dietary intakes of isoflavones, coumestrol, lignans and fiber were assessed by a food frequency questionnaire at baseline and annual visits 5 and 9 and interpolated for intervening years. Number of days of having VMS in the past two weeks was self-reported annually. Using generalized estimating equations multinomial logistic regressions, we modeled incident VMS in relation to isoflavones, lignans, fiber, coumestrol, or total phytoestrogens intake and covariates.
No consistent monotonic relations were observed for any dietary phytoestrogens or fiber to incident VMS, although adjusted odds ratios for some individual quartiles were statistically significant.
To be certain of any effect of dietary phytoestrogens or fiber in preventing incident VMS, a randomized, placebo-controlled, double-masked trial with sufficient numbers of women in different racial/ethnic, menopausal status and metabolic groups with years of follow-up is required, but our results suggest that a clinically significant or large effect is unlikely.
PMCID: PMC3566363  PMID: 23435028
diet; phytoestrogens; vasomotor symptoms; menopause; race/ethnicity
11.  Severity of Depressive Symptoms and Accuracy of Dietary Reporting among Obese Women with Major Depressive Disorder Seeking Weight Loss Treatment 
PLoS ONE  2014;9(2):e90361.
An elevation in symptoms of depression has previously been associated with greater accuracy of reported dietary intake, however this association has not been investigated among individuals with a diagnosis of major depressive disorder. The purpose of this study was to investigate reporting accuracy of dietary intake among a group of women with major depressive disorder in order to determine if reporting accuracy is similarly associated with depressive symptoms among depressed women. Reporting accuracy of dietary intake was calculated based on three 24-hour phone-delivered dietary recalls from the baseline phase of a randomized trial of weight loss treatment for 161 obese women with major depressive disorder. Regression models indicated that higher severity of depressive symptoms was associated with greater reporting accuracy, even when controlling for other factors traditionally associated with reporting accuracy (coefficient  =  0.01 95% CI = 0.01 – 0.02). Seventeen percent of the sample was classified as low energy reporters. Reporting accuracy of dietary intake increases along with depressive symptoms, even among individuals with major depressive disorder. These results suggest that any study investigating associations between diet quality and depression should also include an index of reporting accuracy of dietary intake as accuracy varies with the severity of depressive symptoms.
PMCID: PMC3938682  PMID: 24587338
12.  Reliable Change in Depression during Behavioral Weight Loss Treatment among Women with Major Depression 
Obesity (Silver Spring, Md.)  2013;21(3):E211-E218.
Although behavioral weight loss interventions generally have been shown to improve depressive symptoms, little is known as to whether some people with major depressive disorder experience worsening of depression during a weight loss intervention. We examined rates and predictors of change in depression symptoms among 148 obese women with major depressive disorder who participated in a trial comparing depression treatment plus behavioral weight loss treatment (Behavioral Activation; BA) to behavioral weight loss treatment alone (Lifestyle Intervention; LI). A statistically reliable change in depression was calculated as ≥ 9 points on the Beck Depression Inventory in this sample. At 6 months, 73% of participants in BA and 54% of participants in LI showed reliable improvement in depression symptoms and 1.5% of participants in BA and 1.3% of participants in LI showed reliable worsening in depression symptoms. Rates of reliable change were similar at 12 months. Participants who experienced reliable improvement in depression lost significantly more weight than those who did not in both conditions. In the LI condition, baseline psychiatric variables and change in physical activity during treatment were also related to reliable improvement in depression. We found no evidence for an iatrogenic effect of behavioral weight loss treatment on depressive symptoms among obese women with major depressive disorder; rather, behavioral weight loss treatment appears to be associated with significant concurrent improvement in depression. Even greater rates of reliable improvement were observed when depression treatment was added to weight loss treatment.
PMCID: PMC3630462  PMID: 23592677
13.  Dietary Phytoestrogen Intakes and Cognitive Function During the Menopause Transition: Results from the SWAN Phytoestrogen Study 
Menopause (New York, N.y.)  2012;19(8):894-903.
Phytoestrogens, which consist mainly of isoflavones, lignans and coumestans have estrogenic and anti-inflammatory properties. Prior research suggests that higher dietary or supplemental intakes of isoflavones and lignans are related to better cognitive performance in middle aged and older women.
We conducted longitudinal analysis of dietary phytoestrogens and cognitive performance in a cohort of African-American, white, Chinese and Japanese women undergoing the menopause transition (MT). Tests were: Symbol Digit Modalities, East Boston Memory and Digits Span Backward. Phytoestrogens were assessed by Food Frequency Questionnaire. We modeled each cognitive score as a function of concurrent value of the primary predictors (highest tertile of isoflavones, lignans or coumestrol) and covariates including MT stage.
Coumestrol and isoflavone intakes were 10 and 25 times greater, respectively, in Asian versus non-Asian participants. During late perimenopause and postmenopause, Asian women with high isoflavone intakes did better on processing speed, but during early perimenopause and postmenopause, high isoflavone Asian consumers performed worse on verbal memory. The highest isoflavone consumers among non-Asians likewise posted lower verbal memory scores during early perimenopause. A verbal memory benefit of higher dietary lignan consumption was apparent only during late perimenopause, when women from all ethnic/racial groups who were in the highest tertile of intake demonstrated a small advantage. Coumestrol was unrelated to cognitive performance.
Cognitive effects of dietary phytoestrogens are small, appear to be class-specific, vary by menopause stage and cognitive domain and differ among ethic/racial groups (but whether this is related to dose or to host factors cannot be discerned).
PMCID: PMC3376653  PMID: 22415567
menopause transition; cognitive function; phytoestrogen; isoflavone; lignan; coumestrol
14.  Progression of female reproductive stages associated with bipolar illness exacerbation 
Bipolar disorders  2012;14(5):515-526.
Late perimenopause and early postmenopause confer an increased risk of depression in the population, yet bipolar disorder mood course during these times remains unclear.
Clinic visits in 519 premenopausal, 116 perimenopausal including 13 women transitioning from perimenopause to postmenopause, and 133 postmenopausal women with bipolar disorder who received naturalistic treatment in the multisite STEP-BD study over 19.8±15.5 months were analyzed for mood state. History of postpartum and perimenstrual mood exacerbation and current hormone therapy were evaluated as potential mood predictors.
A progression in female reproductive stage (premenopause, perimenopause, and postmenopausae) was significantly associated with percent of visits decreasing in euthymia (29.3%, 27.0%, 25.0%, respectively, p<0.05) decreasing in syndromal mood elevation (5.3%, 4.1%, and 3.0%, respectively, p<0.001), and increasing in subsyndromal symptoms (47.3%, 50.7%, and 52.7%, respectively, p = 0.05). Thirteen women transitioning from peri- to postmenopause had a significantly greater proportion of visits in syndromal depression (24.4%, p<0.0005) compared to premenopausal, perimenopausal and postmenopausal women, while depression in the latter three groups (18.1%, 18.1%, and 19.3%, respectively) did not differ. Perimenstrual and/or postpartum mood exacerbation, or hormone therapy did not significantly alter depression during perimenopause.
A progression in female reproductive stages was associated with bipolar illness exacerbation. A small number of women transitioning from perimenopause to postmenopause had significantly greater depression than other female reproductive groups. Euthymia and mood elevation decreased with progressing female reproductive stage. Menstrual cycle or postpartum mood exacerbation, or current hormone therapy use, was not associated with perimenopausal depression. Future studies, which include hormonal assessments, are needed to confirm these preliminary findings.
PMCID: PMC3407285  PMID: 22650986
Bipolar Disorder; Menopause; Depression; Mood Disorders; Women
15.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
16.  Association of Menopausal Vasomotor Symptoms With Increased Bone Turnover During the Menopausal Transition 
The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage. We analyzed data from 2283 participants of the Study of Women's Health Across the Nation, a longitudinal community-based cohort study of women aged 42 to 52 years at baseline. At baseline and annually through follow-up visit 8, participants provided questionnaire data, urine samples, serum samples, and anthropometric measurements. Using multivariable repeated-measures mixed models, we examined associations between annually assessed VMS frequency and annual NTX measurements. Our results show that mean adjusted NTX was 1.94 nM of bone collagen equivalents (BCE)/mM of creatinine higher among early perimenopausal women with any VMS than among early perimenopausal women with no VMS (p < .0001). Mean adjusted NTX was 2.44 nM BCE/mM of creatinine higher among late perimenopausal women with any VMS than among late perimenopausal women with no VMS (p = .03). Among premenopausal women, VMS frequency was not significantly associated with NTX level. When NTX values among women with frequent VMS (≥6 days in past 2 weeks) were expressed as percentages of NTX values among women without frequent VMS, the differences were 3% for premenopausal women, 9% for early perimenopausal women, 7% for late perimenopausal women, and 4% for postmenopausal women. Adjustment for serum follicle-stimulating hormone (FSH) level greatly reduced the magnitudes of associations between VMS and NTX level. We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179323  PMID: 20878774
17.  ‘Persistence’ improves the 60 days amenorrhea marker of entry to late stage menopausal transition for women aged 40–44 
Menopause (New York, N.Y.)  2010;17(1):191-193.
The ReSTAGE collaboration evaluated four menstrual markers of entry to late stage menopausal transition
To assess the additional usefulness of ‘persistence’ in relation to a clinically accessible menstrual marker of late menopausal transition, taking age into account
Secondary analysis of menstrual calendar data in two ReSTAGE-collaborating studies with comparatively low age at entry
Sixty days of amenorrhea is as useful for predicting time to the final menstrual period as the currently accepted 90-day marker for women aged over 45. For those aged between 40 and 44 years, recurrence of the 60-day marker within the next 10 cycles is a better indicator than a single occurrence of the 60-day marker or the 90-day marker.
60-day amenorrhea is as reliable a marker of late menopausal transition as the traditional 90-day marker for women aged over 45. For those aged 40–44, keeping menstrual records to check for a recurrence of the 60-day marker will be useful.
PMCID: PMC2806487  PMID: 19713872
menopause; transition; menstrual; marker; clinical; 60 days amenorrhea; persistence
18.  Are Changes in Cardiovascular Disease Risk Factors in Midlife Women due to Chronological Aging or to the Menopausal Transition? 
This prospective study examined if changes in traditional and novel coronary heart disease (CHD) risk factors are greater within a year of the final menstrual period (FMP), relative to changes that occur before or after that interval, in a multi-ethnic cohort.
Understanding the influence of the menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian samples.
The Study of Women’s Health across the Nation (SWAN) is a prospective study of the menopausal transition in 3302 minority (African American, Hispanic, Japanese, or Chinese) and Caucasian women. After 10 annual exams, 1054 women had achieved a FMP not due to surgery and without HT use prior to FMP. Measured CHD risk factors included lipids and lipoproteins, glucose, insulin, blood pressure, fibrinogen, and C-reactive protein. We compared which of two models provided a better fit to the observed risk factor changes over time in relation to FMP: a linear model, consistent with chronological aging, or a piece-wise linear model, consistent with ovarian aging.
Only total cholesterol, LDL-C, and apolipoprotein-B demonstrated substantial increases within the 1 year interval before and after FMP, consistent with menopause-induced changes. This pattern was similar across ethnic groups. The other risk factors were consistent with a linear model, indicative of chronological aging.
Women experience a unique rise in lipids at the time of FMP. Monitoring lipids in perimenopausal women should enhance primary prevention of CHD.
PMCID: PMC2856606  PMID: 20082925
Menopause; risk factors; lipids; inflammation; race
19.  Lipid Changes During the Menopause Transition in Relation to Age and Weight 
American Journal of Epidemiology  2009;169(11):1352-1361.
Few studies have prospectively examined lipid changes across the menopause transition or in relation to menopausal changes in endogenous hormones. The relative independent contributions of menopause and age to lipid changes are unclear. Lipid changes were examined in relation to changes in menopausal status and in levels of estradiol and follicle-stimulating hormone in 2,659 women followed in the Study of Women's Health Across the Nation (1995–2004). Baseline age was 42–52 years, and all were initially pre- or perimenopausal. Women were followed annually for up to 7 years (average, 3.9 years). Lipid changes occurred primarily during the later phases of menopause, with menopause-related changes similar in magnitude to changes attributable to aging. Total cholesterol, low density lipoprotein cholesterol, triglycerides, and lipoprotein(a) peaked during late peri- and early postmenopause, while changes in the early stages of menopause were minimal. The relative odds of low density lipoprotein cholesterol (≥130 mg/dL) for early postmenopausal, compared with premenopausal, women were 2.1 (95% confidence interval: 1.5, 2.9). High density lipoprotein cholesterol also peaked in late peri- and early postmenopause. Results for estradiol and follicle-stimulating hormone confirmed the results based on status defined by bleeding patterns. Increases in lipids were smallest in women who were heaviest at baseline.
PMCID: PMC2727246  PMID: 19357323
body weight; lipids; menopause
20.  Presence of vasomotor symptoms is associated with lower bone mineral density 
Menopause (New York, N.Y.)  2009;16(2):239-246.
To determine whether women with vasomotor symptoms (VMS) have lower bone mineral density (BMD) than women without VMS.
We analyzed data from baseline to annual follow-up visit 5 for 2213 participants in the bone substudy of the Study of Women’s Health Across the Nation. At baseline, women were aged 42 to 52 years, had intact uterus and ≥1 ovary, were not using exogenous hormones, were not pregnant or lactating, and were pre- or early perimenopausal. Menopausal stage and VMS were assessed by annual questionnaire. Menopausal stages were premenopausal, early perimenopausal, late perimenopausal, and postmenopausal. Using repeated measures mixed models, we determined the association between VMS (any vs. none) and BMD (by dual x-ray absorptiometry) within each menopause status category.
After controlling for age, time within each menopausal stage, race/ethnicity, study site, and baseline menopause stage, postmenopausal women with any VMS had lower lumbar (0.008g/cm2 lower, P=0.001) and lower total hip (0.005 g/cm2 lower, P=0.04) BMD than postmenopausal women without VMS. Compared to early perimenopausal women without VMS, early perimenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.0001). Premenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.03), compared to premenopausal women without VMS.
Even in the earliest menopause transition stages, women with VMS had lower BMD than women without VMS. Effects varied by anatomical site, being most evident in postmenopausal women at the lumbar spine and total hip, and among premenopausal and early perimenopausal women at the femoral neck.
PMCID: PMC2695505  PMID: 19002017
Menopause; hot flashes; vasomotor symptoms; bone mineral density
21.  Sex steroid metabolism polymorphisms and mammographic density in pre- and early perimenopausal women 
We examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17β-HSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women.
The Study of Women's Health Across the Nation is a longitudinal community-based cohort study. We analyzed data from 451 pre- and early perimenopausal participants of the ancillary SWAN Mammographic Density study for whom we had complete information regarding mammographic density, genotypes, and covariates. With multivariate linear regression, we examined the relation between percentage mammographic breast density (outcome) and each SNP (primary predictor), adjusting for age, race/ethnicity, parity, cigarette smoking, and body mass index (BMI).
After multivariate adjustment, the CYP1B1 rs162555 CC genotype was associated with a 9.4% higher mammographic density than the TC/TT genotype (P = 0.04). The CYP19A1 rs936306 TT genotype was associated with 6.2% lower mammographic density than the TC/CC genotype (P = 0.02). The positive association between CYP1A1 rs2606345 and mammographic density was significantly stronger among participants with BMI greater than 30 kg/m2 than among those with BMI less than 25 kg/m2 (Pinteraction = 0.05). Among white participants, the ESR1 rs2234693 CC genotype was associated with a 7.0% higher mammographic density than the CT/TT genotype (P = 0.01).
SNPs in certain genes encoding sex steroid metabolism enzymes and ESRs were associated with mammographic density. Because the encoded enzymes and ESR1 are expressed in breast tissue, these SNPs may influence breast cancer risk by altering mammographic density.
PMCID: PMC2750112  PMID: 19630952
22.  The Relationship of Bleeding Patterns to Daily Reproductive Hormones in Women Approaching Menopause 
Obstetrics and gynecology  2008;112(1):101-108.
To discover early hormonal predictors of menopause and the stages of the menopausal transition, and to understand the hormonal basis behind the bleeding abnormalities common in the menopausal transition.
A cohort of 804 women aged 42–52 collected daily first void urine samples for one complete menstrual cycle or 50 days (whichever came first) once a year for 3 years. Urine was assayed for excreted levels of follicle-stimulating hormone, luteinizing hormone, estrogen metabolites, and progesterone metabolites which were normalized for creatinine concentration. Anovulation was defined by an algorithm based on progesterone secretion. Menstrual bleeding parameters were derived from daily calendars. Correlations between bleeding characteristics, hormone concentrations, and other potential clinical predictors were analyzed using multivariable logistic regression models.
An ethnically diverse population of women (mean age of 47) with a majority in the early perimenopause was studied. Approximately 20% of all cycles were anovulatory. Short cycle intervals (fewer than 21 days) were common early in the menopause transition and were associated with anovulation (44%). Long cycle intervals (more than 36 days) also were associated with anovulatory cycles (65%). Both short (1–3 days) and long (more than 8 days) duration of menstrual bleeding were associated with anovulation, 18% and 23%, respectively. Women with anovulatory cycles were less likely to report heavy menstrual bleeding as compared to those with ovulatory cycles. Heavy bleeding was not associated with steroid hormone concentrations but was associated with obesity and with the self-reported presence of leiomyomata.
Among women in the early menopause transition, abnormalities in timing of menstrual bleeding (cycle intervals or bleeding duration) have a hormonal basis and are frequently associated with anovulation. In contrast, abnormally heavy periods do not appear to have a steroid hormonal basis and are less likely after anovulatory cycles. Heavy periods are associated with obesity and leiomyomata.
PMCID: PMC2666050  PMID: 18591314
23.  Chronic Disease Medication Use in Managed Care and Indemnity Insurance Plans 
Health Services Research  2003;38(2):595-612.
To evaluate the impact of managed care on the use of chronic disease medications.
Data Source
Claims data from 1997 from two indemnity and three independent practice association (IPA) model managed care insurance plans.
Research Design
Cross-sectional analysis of claims data.
Data Collection
Adult patients with diabetes mellitus (DM, n=26,444), congestive heart failure (CHF, n=7,978), and asthma (n=9,850) were identified by ICD-9 codes. Chronic disease medication use was defined through pharmacy claims for patients receiving one or more prescriptions for drugs used in treating these conditions. Using multiple logistic regression we adjusted for patient case mix and the number of primary care visits.
Principal Findings
With few exceptions, managed care patients were more likely to use chronic disease medications than indemnity patients. In DM, managed care patients were more likely to use sulfonylureas (43 percent versus 39 percent for indemnity), metformin (26 percent versus 18 percent), and troglitazone (8.8 percent versus 6.4 percent), but not insulin. For CHF patients, managed care patients were more likely to use loop diuretics (45 percent versus 41 percent), ACE inhibitors or angiotensin receptor blockers (50 percent versus 41 percent), and beta-blockers (23 percent versus 16 percent), but we found no differences in digoxin use. In asthma, managed care patients were more likely to use inhaled corticosteroids (34 percent versus 30 percent), systemic corticosteroids (18 percent versus 16 percent), short-acting beta-agonists (42 percent versus 33 percent), long-acting beta-agonists (9.9 percent versus 8.6 percent), and leukotriene modifiers (5.4 percent versus 4.1 percent), but not cromolyn or methylxanthines. Statistically significant differences remained after multivariate analysis that controlled for age, gender, and severity.
Chronic disease patients in these managed care plans are more likely to receive both inexpensive and expensive medications. Exceptions included older medications partly supplanted by newer therapies. Differences may be explained by the fact that patients in indemnity plans face higher out-of-pocket costs and managed care plans promote more aggressive medication use. The relatively low likelihood of condition-specific medications in both plan types is a matter of concern, however.
PMCID: PMC1360905  PMID: 12785563
Managed care; physician; practice patterns; medication prescribing; chronic disease

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