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1.  Major Depression During and After the Menopausal Transition: Study of Women’s Health Across the Nation (SWAN) 
Psychological medicine  2011;41(9):1879-1888.
Background
It is unclear whether risk for major depression during the menopausal transition or immediately thereafter is increased relative to premenopause.
Objectives
To examine whether the odds of experiencing major depression were greater when women were perimenopausal or postmenopausal compared to when they were premenopausal, independent of a history of major depression at study entry and annual measures of vasomotor symptoms, serum levels or changes in estradiol, follicular stimulating hormone, or testosterone and relevant confounders.
Methods
Participants included the 221 African American and Caucasian women, aged 42–52, who were premenopausal at entry into the Pittsburgh site of a community-based study of menopause, the Study of Women’s Health Across the Nation (SWAN). We conducted the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) to assess diagnoses of lifetime, annual, and current major depression at baseline and annual follow-ups. Psychosocial and health factors, and blood samples for assay of reproductive hormones were obtained annually.
Results
Women were two to four times more likely to experience major depression episode when they were perimenopausal or early postmenopausal. Repeated measures logistic regression analyses showed that the effect of menopausal status was independent of history of major depression and annually measured upsetting life events, psychotropic medication use, vasomotor symptoms and serum levels of or changes in reproductive hormones. History of major depression was a strong predictor of major depression throughout the study.
Conclusions
The risk of major depression is greater for women during and immediately after the menopausal transition than when they are premenopausal.
doi:10.1017/S003329171100016X
PMCID: PMC3584692  PMID: 21306662
2.  Major depression and the metabolic syndrome 
The aim of this study is to characterize the relationship between major depression and the metabolic syndrome in a large community based sample of Australian men and women aged 26–90 years. A lifetime history of major depression was assessed by telephone interview following the DSM-III-R. A current history of metabolic syndrome was assessed following the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP AP-III) guidelines 1 to 3 years later. Logistic regression was used to estimate the association between depression and the metabolic syndrome, and its component criteria, controlling for age, sex and alcohol dependence. There was no association between a lifetime history of major depression and the presence of the metabolic syndrome. There was a weak association between depression and low high density lipoprotein cholesterol but not with other component criteria of the metabolic syndrome. Despite calls for interventions directed at depression to reduce the onset of the metabolic syndrome there are important failures to replicate in large samples such as this, no consensus regarding the threshold at which depression may pose a significant risk even allowing for heterogeneity across populations, and no consensus regarding confounders that may explain inter study differences. The absence of any dosage effect of depression on the associated risk for the metabolic syndrome in other unselected samples does not support a direct causal relationship. The call for intervention studies on the basis of the currently published evidence base is unwarranted.
doi:10.1375/twin.13.4.347
PMCID: PMC3150840  PMID: 20707705
Depressive disorder; major; Metabolic syndrome; Cardiovascular diseases
3.  Serum Estradiol Levels Are Not Associated with Urinary Incontinence in Mid-life Women Transitioning through Menopause 
Menopause (New York, N.y.)  2011;18(12):1283-1290.
Objective
We evaluated the relationship between annually measured serum endogenous estradiol and the development or worsening of stress and urge incontinence symptoms over 8 years in women transitioning through menopause.
Methods
This is a longitudinal analysis of women with incontinence in the Study of Women’s Health Across the Nation (SWAN), a multi-center, multi-racial/ethnic prospective cohort study of community-dwelling women transitioning through menopause. At baseline and each of 8 annual visits, SWAN elicited frequency and type of incontinence in a self-administered questionnaire and drew a blood sample on days 2-5 of the menstrual cycle. All endocrine assays were performed using a double-antibody chemiluminescent immunoassay. We analyzed data using discrete Cox survival models and generalized estimating equations with time dependent covariates.
Results
Estradiol levels drawn at either the annual visit concurrent with or previous to the first report of incontinence were not associated with the development of any (hazard ratio (HR) = 0.99, 95% CI 0.99, 1.01), stress, or urge incontinence in previously continent women. Similarly, estradiol levels were not associated with worsening of any (odds ratio (OR) = 1.00, 95% CI 0.99, 1.01), stress, or urge incontinence in incontinent women. Change in estradiol levels from one year to the next was also not associated with the development (HR = 0.98, 95% confidence interval 0.97, 1.00) or worsening (OR = 1.03, 95% CI 0.99, 1.05) of incontinence.
Conclusions
We found that annually measured values and year-to-year changes in endogenous estradiol levels had no effect on the development or worsening of incontinence in women transitioning through menopause.
doi:10.1097/gme.0b013e31821f5d25
PMCID: PMC3308014  PMID: 21785372
Urinary incontinence; Estradiol; Reproductive hormones; Menopause transition; Epidemiology; Prospective cohort study
4.  Factors Associated with Worsening and Improving Urinary Incontinence Across the Menopausal Transition 
Obstetrics and gynecology  2008;111(3):667-677.
Objective
To evaluate whether the menopausal transition is associated with worsening of urinary incontinence symptoms over 6 years in mid-life women.
Methods
We analyzed data from 2415 women who reported monthly or more incontinence in self-administered questionnaires at baseline and during the first 6 annual follow-up visits (1995–2002) of the prospective cohort Study of Women’s Health Across the Nation. We defined worsening as a reported increase and improving as a reported decrease in frequency of incontinence between annual visits. We classified the menopausal status of women not taking hormone therapy annually from reported menstrual bleeding patterns and hormone therapy use by interviewer questionnaire. We used Generalized Estimating Equations (GEE) methodology to evaluate factors associated with improving and worsening incontinence from year to year.
Results
Over 6 years, 14.7% of incontinent women reported worsening, 32.4% reported improvement, and 52.9% reported no change in the frequency of incontinence symptoms. Compared with pre-menopause, peri- and post menopause were not associated with worsening incontinence; for example, early peri-menopause was associated with improvement (OR 1.19; 95% CI 1.06, 1.35) and post-menopause reduced odds of worsening (OR 0.80; 95% CI 0.66, 0.95). Meanwhile, each pound of weight gain increased odds of worsening (OR 1.04; 95% CI 1.03, 1.05) and reduced odds of improving (OR 0.97; 95% CI 0.96, 0.98) incontinence.
Conclusion
In mid-life incontinent women, worsening of incontinence symptoms was not attributable to the menopausal transition. Modifiable factors such as weight gain account for worsening of incontinence during this life stage.
doi:10.1097/AOG.0b013e31816386ce
PMCID: PMC3598598  PMID: 18310370
5.  Relative Androgen Excess During the Menopausal Transition Predicts Incident Metabolic Syndrome in Mid-Life Women: SWAN 
Menopause (New York, N.Y.)  2009;16(2):257-264.
Background
During the menopausal transition, total testosterone remains unchanged while estrogen decreases markedly creating a state of relative androgen excess. We hypothesized that change in the testosterone/estradiol (T/E) ratio during the menopausal transition would be associated with incident metabolic syndrome.
Methods and Results
The association between incident metabolic syndrome and total estradiol, total testosterone, sex hormone binding globulin, the free androgen index (FAI), baseline ratio of total testosterone over total estradiol and the change of this ratio over time was evaluated in a multiethnic cohort of 1,862 pre- and perimenopausal women without diabetes enrolled in the Study of Women’s Health Across the Nation (SWAN). New cases (n=257) of the metabolic syndrome were identified in the cohort during 6296 woman-years of follow-up. The age adjusted total T/E ratio increased 10.1% per year during the 5 years of follow-up. Neither baseline nor change in estradiol were associated with incident metabolic syndrome. Low sex hormone biding globulin, free androgen index and high total testosterone at baseline all increased the risk of metabolic syndrome but their change over time did not. Both baseline total T/E ratio (1.41; 95% CI=1.17-1.1.69; P 0.001) and its rate of change (1.24; 95% CI=1.01-1.52; P 0.04) were associated with increased incident metabolic syndrome independent of ethnicity.
Conclusions
The interaction between testosterone and estradiol during the menopausal transition, rather than the individual change of each over time, is a factor in determination of risk for developing the metabolic syndrome during the menopausal transition. This relationship was independent of ethnicity and other factors associated with prevalent metabolic syndrome prior to the onset of the menopausal transition.
doi:10.1097/gme.0b013e318185e249
PMCID: PMC2950016  PMID: 18971793
Menopause; Testosterone; Estrogen; Metabolic; Syndrome
6.  Predictors of first lifetime episodes of major depression in midlife women 
Psychological medicine  2008;39(1):55-64.
Background
Little is known about factors that predict first lifetime episodes of major depression in middle-aged women. It is not known whether health-related factors and life stress pose more or less of a risk to the onset of clinical depression than does the menopausal transition.
Method
The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was used to assess diagnoses of lifetime, annual and current major depression in a community-based sample of premenopausal or early perimenopausal African American and White women. Menstrual cycle characteristics, psychosocial and health-related factors, and blood samples for assay of reproductive hormones were obtained annually. Two hundred and sixty-six women without a history of major depression at baseline constituted the cohort for the current analyses.
Results
Over 7 years of follow-up, 42 (15.8%) women met criteria for a diagnosis of major depression. Frequent vasomotor symptoms (VMS; hot flashes and/or night sweats) (HR 2.14, p=0.03) were a significant predictor of major depression in univariate analyses. After simultaneous adjustment for multiple predictors in Cox proportional hazards analyses, frequent VMS were no longer significant; lifetime history of an anxiety disorder (HR 2.20, p=0.02) and role limitations due to physical health (HR 1.88, p=0.07) at baseline and a very stressful life event (HR 2.25, p=0.04) prior to depression onset predicted a first episode of major depression.
Conclusions
Both earlier (e.g. history of anxiety disorders) and more proximal factors (e.g. life stress) may be more important than VMS in contributing to a first episode of major depression during midlife.
doi:10.1017/S0033291708003218
PMCID: PMC2905863  PMID: 18377672
Incident major depression; longitudinal study; menopause; midlife women
7.  Menopausal bone changes and incident fractures in diabetic women: a cohort study 
Summary
The purpose of this study was to evaluate the rate of bone loss and incident fractures in women with diabetes mellitus (DM) across menopause. During menopause, DM women experienced bone mineral density (BMD) loss that was faster at hip and slower at spine and had a higher risk of fractures, perhaps because of their earlier menopause. The increasing DM epidemic will contribute to higher fracture burden.
Introduction
Women with DM have a higher risk of fractures independent of age, body mass index (BMI), and BMD. Our objective is to evaluate if women with DM experience greater bone loss and more fractures across menopause.
Methods
Two thousand one hundred seventy one women, aged 42 to 52 years at baseline (1996), enrolled in the Study of Women's Health Across the Nation (SWAN), a prospective study, with 8 years of annual follow up. One thousand three hundred forty six (62%) completed annual visit 7 (2004). Women with baseline fasting blood glucose level of ≥126 mg/dl and those being treated for diabetes were designated as DM. Annual assessment of menopausal stage, BMD, and urinary N-telopeptide (NTx) were carried out. Rate of change in BMD across menopause and annual self-report data for risk of incident fractures by DM status were determined.
Results
Despite higher baseline BMD at hip (p=<0.001), and lumbar spine (p=<0.001), rate of decline in BMD was faster at hip (β=−0.45 vs. −0.11 gm/cm2/year, p=<0.001) for DM women, compared to non-DM. However, lumbar spine bone loss was slower in women with DM as compared to non-DM women (β=0.04 vs. −0.25 gm/cm2/year, p=0.004). DM women experienced menopause 3 years earlier than non-DM women (p=0.002), and age adjusted incident fractures were two fold higher in women with DM compared to non-DM (RR=2.20, 95% CI: 1.26–3.85, p=<0.006).
Conclusions
BMD loss is greater in hip and slower at spine in DM women during menopausal transition. Women with DM have a higher risk of fractures, perhaps because of their earlier menopause.
doi:10.1007/s00198-010-1357-4
PMCID: PMC2992105  PMID: 20658126
Bone; Density; Diabetes; Menopause; Women
8.  The ReSTAGE Collaboration: Defining Optimal Bleeding Criteria for Onset of Early Menopausal Transition 
Fertility and sterility  2007;89(1):129-140.
Study objective
Criteria for staging the menopausal transition are not established. This paper evaluates five bleeding criteria for defining early transition and provides empirically-based guidance regarding optimal criteria.
Design/Setting
Prospective menstrual calendar data from four population-based cohorts: TREMIN, Melbourne Women’s Midlife Health Project(MWMHP), Seattle Midlife Women’s Health Study(SMWHS), and Study of Women’s Health Across the Nation(SWAN) with annual serum follicle stimulating hormone (FSH) from MWMHP and SWAN.
Participants
735 TREMIN, 279 SMWHS, 216 MWMHP, and 2270 SWAN women aged 35-57 at baseline who maintained menstrual calendars.
Main outcome measure(s)
Age at and time to menopause for: standard deviation >6 and >8 days, persistent difference in consecutive segments >6 days, irregularity, and >=45 day segment. Serum follicle stimulating hormone concentration.
Results
Most women experienced each of the bleeding criteria. Except for persistent >6 day difference which occurs earlier, the criteria occur at a similar age and at approximately the same age as late transition in a large proportion of women. FSH was associated with all proposed markers.
Conclusions
The early transition may be best described by ovarian activity consistent with the persistent >6 day difference, but further study is needed, as other proposed criterion are consistent with later menstrual changes.
doi:10.1016/j.fertnstert.2007.02.015
PMCID: PMC2225986  PMID: 17681300
Menopausal Transition; Menopause; Menstrual cycle; Aging; Ovarian Function; Follicle Stimulating Hormone
9.  Change in health-related quality of life over the menopausal transition in a multiethnic cohort of middle-aged women: Study of Women’s Health Across the Nation (SWAN) 
Menopause (New York, N.Y.)  2009;16(5):860-869.
Objective
To examine change in health-related quality of life (HRQL) during the menopausal transition, controlling for chronological aging, symptoms, and other covariates.
Design
A prospective, longitudinal study of women aged 42–52 at baseline recruited at seven US sites (N=3302) in the multiethnic Study of Women’s Health Across the Nation (SWAN). Cohort eligible women had an intact uterus, at least one ovary, were not currently using exogenous hormones, were either pre- or early perimenopausal, and self-identified as one of the study’s designated racial/ethnic groups. Data from the baseline interview and six annual follow-up visits are reported. HRQL was assessed with five subscales from the SF-36 with reduced functioning defined as being in the lowest 25% on a subscale. Covariates included symptoms, medical conditions, sociodemographics variables, physical activity, and psychological factors.
Results
Adjusting for baseline age, chronological aging, and relevant covariates, the odds of reduced role physical functioning were significantly greater at late perimenopause (odds ratio [OR] = 1.46; 95% confidence interval [CI] = 1.08, 1.99) and postmenopause (OR = 1.49; 95% CI = 1.09, 2.04) compared to premenopause. Menopausal status was unrelated to bodily pain, vitality, role emotional or social functioning. Hormone therapy users were more likely to report reduced functioning. Other variables significantly related to HRQL across all domains included vasomotor symptoms, urine leakage, poor sleep, arthritis, depressed mood, perceived stress, and stressful life events.
Conclusions
The menopausal transition showed little impact on HRQL when adjusted for symptoms, medical conditions, and stress.
doi:10.1097/gme.0b013e3181a3cdaf
PMCID: PMC2743857  PMID: 19436224
health-related quality of life; women; menopause; ethnicity; SF-36
10.  Depressive Symptoms and the Metabolic Syndrome in Childhood and Adulthood 
Objective
To examine the reciprocal associations between depressive symptoms and clinical definitions of the metabolic syndrome in childhood and adulthood.
Design
Population-based prospective cohort study of 921 participants (538 women and 383 men) in Finland. The components of the metabolic syndrome were measured in childhood (mean age 12 years) and again in adulthood (mean age 33 years). A revised version of the Beck Depression Inventory was used to assess depressive symptoms at the mean ages of 24 and 33.
Main Outcome Measures
Metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP), the European Group for the Study of Insulin Resistance, and the International Diabetes Federation criteria.
Results
In women, depressive symptoms were associated with increased risk of the metabolic syndrome in adulthood (odds ratio for NCEP metabolic syndrome per 1 SD increase in depressive symptoms 1.40, 95% confidence interval 1.05-1.85). The metabolic syndrome in childhood, in turn, predicted higher levels of depressive symptoms in adulthood (p= 0.03). In men, no associations were found between depressive symptoms and the clinical definitions of the metabolic syndrome.
Conclusion
The process linking depressive symptoms with the metabolic syndrome may go into both directions and may begin early in life.
doi:10.1037/a0012646
PMCID: PMC3166561  PMID: 19210024
metabolic syndrome; depressive symptoms; obesity; cardiovascular disease; childhood
11.  Depressive symptoms during the menopausal transition 
Journal of affective disorders  2007;103(1-3):267-272.
Background
The influence of menopausal status on depressive symptoms is unclear in diverse ethnic groups. This study examined the longitudinal relationship between changes in menopausal status and the risk of clinically relevant depressive symptoms and whether the relationship differed according to initial depressive symptom level.
Methods
3302 African American, Chinese, Hispanic, Japanese, and White women, aged 42-52 years at entry into the Study of Women’s Health Across the Nation (SWAN), a community-based, multisite longitudinal observational study, were evaluated annually from 1995 through 2002. Random effects multiple logistic regression analyses were used to determine the relationship between menopausal status and prevalence of low and high depressive symptom scores (CES-D <16 or ≥ 16) over 5 years
Results
At baseline, 23% of the sample had elevated CES-D scores. A woman was more likely to report CES-D ≥16 when she was early peri-, late peri-, postmenopausal or currently/ formerly using hormone therapy (HT), relative to when she was premenopausal (OR range 1.30 to 1.71). Effects were somewhat stronger for women with low CES-D scores at baseline. Health and psychosocial factors increased the odds of having a high CES-D and in some cases, were more important than menopausal status.
Limitations
We used a measure of current depressive symptoms rather than a diagnosis of clinical depression. Thus, we can only make conclusions about symptoms current at annual assessments.
Conclusion
Most midlife women do not experience high depressive symptoms. Those that do are more likely to experience high depressive symptom levels when perimenopausal or postmenopausal than when premenopausal, independent of factors such as difficulty paying for basics, negative attitudes, poor perceived health, and stressful events.
doi:10.1016/j.jad.2007.01.034
PMCID: PMC2048765  PMID: 17331589
Depressive symptoms; menopause; longitudinal; CES-D
12.  Education eclipses ethnicity in predicting the development of the metabolic syndrome in different ethnic groups in midlife: the Study of Women’s Health Across the Nation (SWAN) 
Objective
To determine the respective roles of socio-economic status (SES) and ethnicity in the risk of incident metabolic syndrome in middle-aged women.
Design and participants
A total of 3302 pre- and peri-menopausal women, not receiving hormone therapy at baseline, took part in the Study of Women’s Health Across the Nation, a multi-site, community-based, longitudinal study of the menopausal transition. The main outcome measures were to ascertain the prevalence of the metabolic syndrome and the incidence of the metabolic syndrome over 5 years of follow-up.
Results
At baseline, the prevalence of the metabolic syndrome was 21% (n = 673). Among 2512 women without metabolic syndrome at baseline, 12.8% (n = 321) developed the metabolic syndrome during 5 years of follow-up. Both ethnicity and SES were significant univariate predictors of incident metabolic syndrome. In multivariate logistic regression models that included age at baseline, menopausal status and site, baseline smoking and alcohol consumption at follow-up visit 1, as well as baseline values of each of the components of the metabolic syndrome, only education was an independent predictor of incident metabolic syndrome.
Conclusion
Approximately 13% of peri-menopausal women developed the metabolic syndrome during the 5-year follow-up period. Education, but not ethnicity, was an independent predictor of incident metabolic syndrome risk.
doi:10.1111/j.1464-5491.2008.02596.x
PMCID: PMC2607571  PMID: 19046236
ethnicity; longitudinal studies; metabolic syndrome; socio-economic status; women
13.  Longitudinal Changes in Sexual Functioning as Women Transition Through Menopause: Results from the Study of Women’s Health Across the Nation (SWAN) 
Menopause (New York, N.Y.)  2009;16(3):442-452.
Objective
Sexual functioning is an important component of women’s lives. The extent to which the menopause transition is associated with decreased sexual functioning remains inconclusive. This study seeks to determine if advancing through the menopause transition is associated with changes in sexual functioning.
Design
A prospective, longitudinal cohort study of women aged 42–52 at baseline recruited at 7 US sites (N=3302) in the Study of Women’s Health Across the Nation (SWAN). Cohort eligible women had an intact uterus, at least one ovary, were not currently using exogenous hormones, were either pre- or early perimenopausal, and self-identified as one of the study’s designated racial/ethnic groups. Data from the baseline interview and six annual follow-up visits are reported. Outcomes are self-reported ratings of importance of sex; frequency of sexual desire, arousal, masturbation, sexual intercourse, and pain during intercourse; degree of emotional satisfaction and physical pleasure.
Results
Adjusting for baseline age, chronological aging, and relevant social, health, and psychological parameters, the odds of reporting vaginal or pelvic pain increased and desire decreased by late perimenopause. Masturbation increased at early perimenopause, but declined during postmenopause. Menopausal transition was unrelated to other outcomes. Health, psychological functioning, and importance of sex were related to all sexual function outcomes. Age, race/ethnicity, marital status, change in relationship, and vaginal dryness were also associated with sexual functioning.
Conclusions
Pain during sexual intercourse increases and sexual desire decreases over the menopausal transition. Masturbation increases during the early transition, but then declines in postmenopause. Adjusting for other factors, the menopausal transition was not independently associated with reports of the importance of sex, sexual arousal, frequency of sexual intercourse, emotional satisfaction with partner, or physical pleasure.
doi:10.1097/gme.0b013e3181948dd0
PMCID: PMC2908487  PMID: 19212271
sexual functioning; menopause; aging; diverse populations
14.  Association between Menopausal Transition Stages and Developing Urinary Incontinence 
Obstetrics and gynecology  2009;114(5):989-998.
Objective
To estimate whether menopause transition stage is independently associated with the development of incontinence symptoms.
Methods
We conducted a longitudinal analysis, using discrete proportional hazards models, of women who were continent at baseline in the Study of Women’s Health Across the Nation (SWAN), a multi-center, multi-racial/ethnic prospective cohort study of community-dwelling mid-life women transitioning through menopause. At baseline and each of the 6 annual visits, SWAN elicited frequency and type of incontinence in a self-administered questionnaire and classified menopausal stage from menstrual bleeding patterns.
Results
Compared to being in premenopause, being in the early peri-menopause (incidence 17.8 per 100 woman years) made it 1.34 times and being in the late peri-menopause (incidence 14.5 per 100 woman years) made it 1.52 times more likely for women to develop monthly or more frequent incontinence. In contrast, women in postmenopause (incidence 8.2 per 100 woman years) were approximately half as likely to develop this degree of incontinence. This pattern of association across the menopausal transition was similar for stress and urge incontinence. However, menopausal stage was not associated with developing more frequent incontinence (leaking several times per week or more). Worsening anxiety symptoms, a high baseline BMI, weight gain and new onset diabetes were associated with developing more frequent incontinence.
Conclusions
Menopausal transition stage was associated with developing monthly or more frequent but not weekly or more frequent incontinence, suggesting that only infrequent incontinence symptoms were attributable to the peri-menopause. Since modifiable factors such as anxiety, weight gain, and diabetes were associated with developing more frequent incontinence, determining whether healthy life changes and treating medical problems can prevent incontinence is a priority.
doi:10.1097/AOG.0b013e3181bb531a
PMCID: PMC3120214  PMID: 20168098
15.  Metabolic syndrome and onset of depressive symptoms in the elderly: findings from the three-city study 
Diabetes Care  2011;34(4):904-909.
Objective
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and onset of depressive symptoms according to different age-groups in a large general elderly population.
Research Design and Methods
Prospective cohort study of 4446 men and women aged 65 to 91 and free of depression or depressive symptoms at baseline (the Three-City study, France). MetS was defined using the NCEP-ATP III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale (CES-D) score≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
Results
After adjusting for a large range of potential confounders, we observed MetS to be associated with a 1.73-fold (95% CI: 1.02–2.95) odds for new-onset depressive symptoms in the youngest age group (65 to 70 at baseline), independently of cardiovascular diseases. No such association was seen in older age groups.
Conclusion
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged can be extended to older adults but not to the oldest ones. Further research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65 to 70.
doi:10.2337/dc10-1644
PMCID: PMC3064049  PMID: 21346185
Depressive symptoms; metabolic syndrome; elderly; prospective study
16.  Testosterone and Visceral Fat in Midlife Women: The Study of Women’s Health Across the Nation (SWAN) Fat Patterning Study 
Obesity (Silver Spring, Md.)  2009;18(3):604-610.
Visceral fat (VF) increases with the menopause and is an independent predictor of the metabolic syndrome, diabetes, and cardiovascular disease (CVD) in women. Little is known about how hormonal changes during the menopausal transition are related to the increase in VF. We aimed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors. The Study of Women’s Health Across the Nation (SWAN) is a longitudinal, community-based study. This report uses baseline data from a population-based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)–assessed VF in women at different stages of the menopausal transition. Included are 359 women (47.2% black), aged 42–60 years, who were randomly selected from a complete community census in which a 72% participation rate was achieved. In multivariate models, bioavailable testosterone was associated with VF independent of age, race, percent total body fat, and other cardiovascular risk factors. Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone–binding globulin (SHBG). As bioavailable testosterone was associated with VF even after adjusting for insulin resistance, this suggests that it plays an important role in regional fat distribution. Our findings may have direct implications in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk.
doi:10.1038/oby.2009.251
PMCID: PMC2866448  PMID: 19696765
17.  Accumulation of major depressive episodes over time in a prospective study indicates that retrospectively assessed lifetime prevalence estimates are too low 
BMC Psychiatry  2009;9:19.
Background
Most epidemiologic studies concerned with Major Depressive Disorder have employed cross-sectional study designs. Assessment of lifetime prevalence in such studies depends on recall of past depressive episodes. Such studies may underestimate lifetime prevalence because of incomplete recall of past episodes (recall bias). An opportunity to evaluate this issue arises with a prospective Canadian study called the National Population Health Survey (NPHS).
Methods
The NPHS is a longitudinal study that has followed a community sample representative of household residents since 1994. Follow-up interviews have been completed every two years and have incorporated the Composite International Diagnostic Interview short form for major depression. Data are currently available for seven such interview cycles spanning the time frame 1994 to 2006. In this study, cumulative prevalence was calculated by determining the proportion of respondents who had one or more major depressive episodes during this follow-up interval.
Results
The annual prevalence of MDD ranged between 4% and 5% of the population during each assessment, consistent with existing literature. However, 19.7% of the population had at least one major depressive episode during follow-up. This included 24.2% of women and 14.2% of men. These estimates are nearly twice as high as the lifetime prevalence of major depressive episodes reported by cross-sectional studies during same time interval.
Conclusion
In this study, prospectively observed cumulative prevalence over a relatively brief interval of time exceeded lifetime prevalence estimates by a considerable extent. This supports the idea that lifetime prevalence estimates are vulnerable to recall bias and that existing estimates are too low for this reason.
doi:10.1186/1471-244X-9-19
PMCID: PMC2685381  PMID: 19422724
18.  Duration of Lactation and Incidence of the Metabolic Syndrome in Women of Reproductive Age According to Gestational Diabetes Mellitus Status: A 20-Year Prospective Study in CARDIA (Coronary Artery Risk Development in Young Adults) 
Diabetes  2009;59(2):495-504.
OBJECTIVE
The objective of the study was to prospectively assess the association between lactation duration and incidence of the metabolic syndrome among women of reproductive age.
RESEARCH DESIGN AND METHODS
Participants were 1,399 women (39% black, aged 18–30 years) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, an ongoing multicenter, population-based, prospective observational cohort study conducted in the U.S. Women were nulliparous and free of the metabolic syndrome at baseline (1985–1986) and before subsequent pregnancies, and reexamined 7, 10, 15, and/or 20 years after baseline. Incident metabolic syndrome case participants were identified according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Complementary log-log models estimated relative hazards of incident metabolic syndrome among time-dependent lactation duration categories by gestational diabetes mellitus (GDM) adjusted for age, race, study center, baseline covariates (BMI, metabolic syndrome components, education, smoking, physical activity), and time-dependent parity.
RESULTS
Among 704 parous women (620 non-GDM, 84 GDM), there were 120 incident metabolic syndrome case participants in 9,993 person-years (overall incidence rate 12.0 per 1,000 person-years; 10.8 for non-GDM, 22.1 for GDM). Increased lactation duration was associated with lower crude metabolic syndrome incidence rates from 0–1 month through >9 months (P < 0.001). Fully adjusted relative hazards showed that risk reductions associated with longer lactation were stronger among GDM (relative hazard range 0.14–0.56; P = 0.03) than non-GDM groups (relative hazard range 0.44–0.61; P = 0.03).
CONCLUSIONS
Longer duration of lactation was associated with lower incidence of the metabolic syndrome years after weaning among women with a history of GDM and without GDM, controlling for preconception measurements, BMI, and sociodemographic and lifestyle traits. Lactation may have persistent favorable effects on women's cardiometabolic health.
doi:10.2337/db09-1197
PMCID: PMC2809964  PMID: 19959762
19.  Twelve-month, prospective, open-label study of repetitive transcranial magnetic stimulation for major depressive disorder in partial remission 
Background
The purpose of this study was to evaluate the long-term effect of repetitive transcranial magnetic stimulation (rTMS) as adjunctive treatment in patients with partial remission of major depressive disorder.
Methods
This was a 12-month, prospective, open-label study in patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for nonpsychotic major depressive disorder who responded to 8 weeks of medication treatment but did not reach remission. All patients were assigned to receive 10 sessions of rTMS applied at the left dorsolateral prefrontal cortex. During the course of rTMS, the patients were still taking their usual medication. Patients were followed up for 12 months to determine the long-term antidepressant effect.
Results
There were nine patients (seven women and two men) who met the inclusion criteria and agreed to receive rTMS. The mean Hamilton rating scale for depression (HAM-D) score prior to treatment with rTMS was 12.89 ± 2.15. At 12 months after treatment, the mean HAM-D score was 6.45 ± 1.67 using a Friedman test, and in patients with partial remission of major depressive disorder, the HAM-D score significantly decreased after treatment with rTMS at 12 months (P = 0.001). Seven patients (77.78%) had reached the stage of remission (HAM-D < 8) after treating with rTMS at 12 months. There were no serious adverse events. One patient had vertigo after the first session of treatment and one patient felt scalp contractions during treatment, and both fully recovered within half an hour with no medical intervention.
Conclusion
For patients with major depressive disorder in partial remission, high frequency rTMS at the left dorsolateral prefrontal cortex may provide benefits in adjunctive treatment with well tolerability. Also, follow-up findings show a long duration of benefit.
doi:10.2147/NDT.S35253
PMCID: PMC3433320  PMID: 22973105
depression; remission; magnetic stimulation; adjunctive; long term
20.  Metabolic Syndrome and Risk of Development of Atrial Fibrillation 
Circulation  2008;117(10):1255-1260.
Background
The metabolic syndrome consists of a cluster of atherosclerotic risk factors, many of which also have been implicated in the genesis of atrial fibrillation (AF). However, the precise role of the metabolic syndrome in the development of AF is unknown.
Methods and Results
This prospective, community-based, observational cohort study was based on an annual health check-up program in Japan. We studied 28 449 participants without baseline AF. We used 2 different criteria for the metabolic syndrome—the guidelines of the National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III) and those of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI)—to study the risk of development of new-onset AF. The metabolic syndrome was present in 3716 subjects (13%) and 4544 subjects (16%) using the NCEP-ATP III and AHA/NHLBI definitions, respectively. During a mean follow-up of 4.5 years, AF developed in 265 subjects (105 women). Among the metabolic syndrome components, obesity (age- and sex-adjusted hazard ratio [HR], 1.64), elevated blood pressure (HR, 1.69), low high-density lipoprotein cholesterol (HR, 1.52), and impaired insulin tolerance (HR, 1.44 [NCEP-ATP III] and 1.35 [AHA/NHLBI]) showed an increased risk for AF. The association between the metabolic syndrome and AF remained significant in subjects without treated hypertension or diabetes by the NCEP-ATP III definition (HR, 1.78) but not by the AHA/NHLBI definition (HR, 1.28).
Conclusions
The metabolic syndrome was associated with increased risk of AF. The metabolic derangements of the syndrome may be important in the pathogenesis of AF.
doi:10.1161/CIRCULATIONAHA.107.744466
PMCID: PMC2637133  PMID: 18285562
arrhythmia; diabetes mellitus; hypercholesterolemia; hypertension; metabolic syndrome X; risk factors; obesity
21.  Are there Bi-directional Associations between Depressive Symptoms and C-Reactive Protein in Mid-life Women? 
Brain, behavior, and immunity  2009;24(1):96-101.
OBJECTIVE:
To test whether depressive symptoms are related to subsequent C-reactive protein (CRP) levels and/or whether CRP levels are related to subsequent depressive symptoms in mid-life women.
METHODS:
Women enrolled in the Study of Women's Health Across the Nation (SWAN) were followed for seven years and had measures of CES-Depression scores and CRP seven times during the follow-up period. Women were pre- or early peri-menopausal at study entry and were of Caucasian, African American, Hispanic, Japanese, or Chinese race/ethnicity. Analyses were restricted to initially healthy women.
RESULTS:
Longitudinal mixed linear regression models adjusting for age, race, site, time between exams, and outcome variable at year X showed that higher CES-D scores predicted higher subsequent CRP levels and vice versa over a 7-year period. Full multivariate models adjusting for body mass index, physical activity, medications, health conditions, and other covariates showed that higher CRP levels at year X predicted higher CES-D scores at year X+1, p = 0.03. Higher depressive symptoms predicted higher subsequent CRP levels at marginally significant levels, p=0.10.
CONCLUSIONS:
Higher CRP levels led to higher subsequent depressive symptoms, albeit the effect was small. The study demonstrates the importance of considering bi-directional relationships for depression and other psychosocial factors and risk for heart disease.
doi:10.1016/j.bbi.2009.08.005
PMCID: PMC2844108  PMID: 19683568
Depression; inflammation; menopause; women; longitudinal; C-reactive protein
22.  Metabolic Syndrome and Onset of Depressive Symptoms in the Elderly 
Diabetes Care  2011;34(4):904-909.
OBJECTIVE
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and the onset of depressive symptoms according to different age-groups in a large, general elderly population.
RESEARCH DESIGN AND METHODS
This was a prospective cohort study of 4,446 men and women aged 65–91 years who were free of depression or depressive symptoms at baseline (the Three-City Study, France). MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale score ≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
RESULTS
After adjusting for a large range of potential confounders, we observed MetS to be associated with 1.73-fold (95% CI 1.02–2.95) odds for new-onset depressive symptoms in the youngest age-group (65–70 years at baseline), independently of cardiovascular diseases. No such association was seen in older age-groups.
CONCLUSIONS
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged people can be extended to older adults but not to the oldest ones. Additional research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65–70 years.
doi:10.2337/dc10-1644
PMCID: PMC3064049  PMID: 21346185
23.  Longitudinal Change in Reproductive Hormones and Depressive Symptoms Across the Menopausal Transition 
Archives of general psychiatry  2010;67(6):598-607.
Context
The contribution of reproductive hormones to mood has been the focus of considerable research. Results from clinical and epidemiological studies have been inconsistent. It remains unclear whether alterations in serum hormone levels across the menopausal transition are linked to depressive symptoms.
Objectives
To evaluate the relationship between serum hormone levels and high depressive symptoms and whether hormone levels or their change might explain the association of menopausal status with depressive symptoms previously reported in a national sample of midlife women.
Design
A longitudinal, community-based, multisite study of menopause. Data were collected at baseline and annually from December 1995 to January 2008 on a range of factors. Early follicular phase serum samples were assayed for levels of estradiol, follicle-stimulating hormone, testosterone, and dehydroepiandrosterone sulfate.
Setting
Seven communities nationwide.
Participants
A community-based sample of 3302 multiethnic women, aged 42 to 52 years, still menstruating and not using exogenous reproductive hormones.
Main Outcome Measure
Depressive symptoms assessed with the Center for Epidemiological Studies Depression Scale (CES-D). The primary outcome was a CES-D score of 16 or higher.
Results
In multivariable random-effects logistic regression models, log-transformed testosterone level was significantly positively associated with higher odds of a CES-D score of 16 or higher (odds ratio=1.15; 95% confidence interval, 1.01–1.31) across 8 years, and a larger increase in log-transformed testosterone from baseline to each annual visit was significantly associated with increased odds of a CES-D score of 16 or higher (odds ratio=1.23; 95% confidence interval, 1.04–1.45). Less education, being Hispanic, and vasomotor symptoms, stressful life events, and low social support at each visit were each independently associated with a CES-D score of 16 or higher. No other hormones were associated with a CES-D score of 16 or higher. Being perimenopausal or post-menopausal compared with being premenopausal remained significantly associated with a CES-D score of 16 or higher in all analyses.
Conclusions
Higher testosterone levels may contribute to higher depressive symptoms during the menopausal transition. This association is independent of menopausal status, which remains an independent predictor of higher depressive symptoms.
doi:10.1001/archgenpsychiatry.2010.55
PMCID: PMC3129620  PMID: 20530009
24.  Metabolic syndrome and risk of incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study 
Background
Several aspects concerning the relationship between the metabolic syndrome and incident diabetes are incompletely understood including the magnitude of the risk estimate, potential gender differences in the associations between the metabolic syndrome and incident diabetes, the associations between the components of the metabolic syndrome and incident diabetes, and whether the metabolic syndrome provides additional prediction beyond its components. To shed light on these issues, we examined the prospective association between the metabolic syndrome defined by the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) and diabetes.
Methods
We used data for 2796 men and women aged 35–65 years from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study followed for an average of 6.9 years. This analysis employed a case-cohort design that included 697 participants who developed diabetes and 2099 participants who did not. Incident diabetes was identified on the basis of self-reports and verified by contacting the patient's attending physician.
Results
The adjusted hazard ratio for the NCEP definition was 4.62 (95% confidence interval [CI]: 3.90–5.48) and that for the IDF definition was 4.59 (95% CI: 3.84–5.50). The adjusted hazard ratios for the NCEP but not IDF definition were higher for women than men. When participants who had no cardiometabolic abnormalities were used as the reference group for the NCEP definition, the adjusted hazard ratio for having 3 or more abnormalities increased to 22.50 (95% CI: 11.21–45.19). Of the five components, abdominal obesity and hyperglycemia were most strongly associated with incident diabetes.
Conclusion
In this study population, both definitions of the metabolic syndrome provided similar estimates of relative risk for incident diabetes. The increase in risk for participants with the metabolic syndrome according to the NCEP definition was very large when contrasted with the risk among those who had no cardiometabolic abnormalities.
doi:10.1186/1475-2840-7-35
PMCID: PMC2627822  PMID: 19077281
25.  Depressive Symptoms are Related to Progression of Coronary Calcium in Midlife Women: The Study of Women’s Health Across the Nation (SWAN) Heart Study 
American heart journal  2011;161(6):1186-1191.e1.
Background
Major depression and depressive symptoms are associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis is less well known, particularly in women and minorities. This study examined whether depressive symptoms are associated with progression of coronary artery calcification (CAC) among women at mid-life.
Methods
The Study of Women’s Health Across the Nation (SWAN) is a longitudinal, multi-site study assessing health and psychological factors in mid-life women. An ancillary study (SWAN Heart) evaluated subclinical atherosclerosis in women who reported no history of CVD or diabetes. In 346 women, CAC was measured twice by electron beam computed tomography, an average of 2.3 years apart. Progression, defined as an increase by 10 Agatston units or more, was analyzed using relative risk regression. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression (CES-D) Scale.
Results
Progression of CAC was observed in 67 women (19.1%). Each 1–SD higher CES-D score at baseline related to a 25% increased risk of CAC progression [RR 1.25, CI 1.06–1.47, p=0.007], adjusting for age, time between scans, ethnicity, education, menopausal status, and known CVD risk factors. This risk was similar to the risk induced by BMI [RR 1.31, CI 1.11–1.54, p=0.001] and systolic blood pressure [RR 1.28, CI 1.06–1.55, p=0.01].
Conclusions
Depressive symptoms were independently associated with progression of CAC in this cohort of midlife women. Depressive symptoms may represent a risk factor that is potentially modifiable for early prevention of CVD in women.
doi:10.1016/j.ahj.2011.03.017
PMCID: PMC3140211  PMID: 21641367
atherosclerosis; coronary calcium; women; depression; epidemiology

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