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1.  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
2.  Major Depression During and After the Menopausal Transition: Study of Women’s Health Across the Nation (SWAN) 
Psychological medicine  2011;41(9):1879-1888.
It is unclear whether risk for major depression during the menopausal transition or immediately thereafter is increased relative to premenopause.
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.
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.
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.
The risk of major depression is greater for women during and immediately after the menopausal transition than when they are premenopausal.
PMCID: PMC3584692  PMID: 21306662
3.  Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study 
Journal of Women's Health  2013;22(2):121-131.
Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score.
Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
PMCID: PMC3613168  PMID: 23398127
4.  Effects of the Transition from Premenopause to Postmenopause on Lipids and Lipoproteins: Quantification and Related Parameters 
The aim of this study was to quantitatively measure changes in lipids and lipoproteins during perimenopause and to identify variables related to these changes.
Among women who had three regular health evaluations over a span of 2-4 years, 34 women remained in the premenopausal state, 34 premenopausal women transitioned to the postmenopausal state, and 36 postmenopausal women were enrolled. The menopausal state was determined not only by a history of amenorrhea but also by levels of female sex hormones. Yearly changes in lipids were calculated using a linear regression of the three measurements.
The transition from premenopause to postmenopause was associated with increased total cholesterol and low-density lipoprotein (LDL) cholesterol levels by 7.4 ± 8.0 mg/dL (4.2 ± 4.9%) and 6.9 ± 6.5 mg/dL (6.8 ± 7.0%) over one year, resulting in an elevation of 19.6 ± 22.6 mg/dL (10.9 ± 13.0%) and 18.9 ± 19.5 mg/dL (18.6 ± 20.3%), respectively, during perimenopause. There were no changes observed in premenopausal and postmenopausal women. Body weight, blood pressure, high-density lipoprotein (HDL) cholesterol, and triglycerides did not change in any of the three groups. In all women, changes in both total cholesterol and LDL cholesterol were associated with changes in follicle stimulating hormone (r = 0.40, p < 0.001 and r = 0.38, p < 0.001, respectively). Changes in triglycerides were associated with changes in body weight (r = 0.28, p = 0.005).
During perimenopause, total and LDL cholesterol levels increase and these changes in cholesterol are mainly dependent on changes in female sex hormones.
PMCID: PMC3056255  PMID: 21437162
Lipids; Lipoproteins; Menopause; Gonadal steroid hormones
5.  Summary of the NIA-sponsored Conference on Depressive Symptoms and Cognitive Complaints in the Menopausal Transition 
Menopause (New York, N.Y.)  2010;17(4):815-822.
This NIA-sponsored workshop was aimed at understanding the impact of the menopausal transition on mood symptoms and cognitive disorders during the menopausal transition and identifying research priorities for further investigation. Longitudinal studies provide insights into the frequency of these problems in representative samples of midlife women. The majority of women do not experience serious depressive symptoms during the transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen alone therapy in younger postmenopausal women, and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger and older women. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally menopausal women is an important goal for future research. Pharmacological challenge studies bridge the basic science and clinical literatures to provide insights into the extent to which changes in endogenous and exogenous hormones and other neurotransmitter systems contribute to cognitive and mood problems. Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available on-line and free of charge.
PMCID: PMC2901893  PMID: 20616668
Menopause; Cognition; Mood; Perimenopause; Depression
6.  The Severity of Depressive Symptoms vs. Serum Mg and Zn Levels in Postmenopausal Women 
The aim of this study was to assess the severity of depressive symptoms in postmenopausal women, depending on serum Mg and Zn levels. The study involved 171 postmenopausal women from Poland, who were not using menopausal hormone therapy (MHT). The intensity of depressive symptoms was evaluated using a standard research technique, the Beck Depression Inventory (BDI). The plasma Mg and Zn concentrations were measured. Depressive symptoms of different severity levels were diagnosed in 36.8 % of the women. The mean serum Mg level was 1.53 ± 0.28 mg/dL, and Zn level was 72 ±14 μg/dL. The women with higher serum Mg and Zn levels had less depressive symptoms, and this observation is a precious information which can be used when planning depressive disorder prevention programmes.
PMCID: PMC3895221  PMID: 24271492
Depressive disorder; Postmenopause; Magnesium; Zinc
7.  Lipids, Menopause and Early Atherosclerosis in SWAN Heart Women 
Menopause (New York, N.Y.)  2011;18(4):376-384.
The risk of cardiovascular disease increases after menopause. Recent evidence suggests that it is possible for HDL to become proatherogenic or dysfunctional in certain situations. Our objective was to evaluate whether the relationship of HDL-C to subclinical cardiovascular disease differed across the menopausal transition, which would provide insight for this increased risk.
Aortic calcification (AC), coronary artery calcification (CAC), carotid plaque and intima media thickness (IMT) were measured in the Study of Women’s Health Across the Nation (SWAN Heart). Women, not using hormone therapy, were stratified into premenopausal or early-perimenopausal (Pre/EP, n=316) and late-perimenopausal or postmenopausal (LP/Post, n=224).
The inverse relationship of HDL-C to subclinical atherosclerosis measures among Pre/EP women was weaker or reversed among LP/post women, adjusted for age, site, race, SBP, glucose, BMI, smoking, menopausal status and LDL-C. Specifically: Multivariable modeling demonstrated an inverse association between HDL-C and AC and IMT, among Pre/EP women; however, the protective effect of HDL-C for AC, left main CAC, carotid plaque and IMT was not seen in LP/Post women. In a small subset (n=53), LP/Post women had more total and small HDL particles, higher triglycerides and more total LDL particles compared to Pre/EP women (p<0.05).
These results suggest that the protective effect of HDL may be diminished as women transition the menopause. Future studies should examine whether this may be due to changes in HDL size, functionality, or related changes in other lipids or lipoproteins.
PMCID: PMC3123389  PMID: 21107300
subclinical cardiovascular disease; lipids; lipoproteins; menopause
8.  Study Protocol: effects of acupuncture on hot flushes in perimenopausal and postmenopausal women – a multicenter randomized clinical trial 
Trials  2008;9:70.
Hot flushes are the most frequent climacteric symptom and a major cause of suffering among menopausal women. The condition negatively influences many aspects of women's lives. To date, conventional hormone replacement therapy (HRT) is considered the most effective treatment for hot flushes. However, HRT is associated with a host of negative side effects. Complementary and alternative medical (CAM) approaches have been employed to relieve symptoms and to avoid these side effects. Acupuncture is one of the most strongly preferred CAM treatments for many diseases, causing few serious adverse effects, and is frequently used in Korea.
We aim to evaluate the effectiveness of Traditional Korean Acupuncture (TKA) in conjunction with usual care, compared to usual care alone, on hot flushes in perimenopausal and postmenopausal women in Korea.
This study consists of a multi-center randomized controlled trial with 2 parallel arms. Participants included in the study will meet the following criteria: 1) a documented daily average hot flush score ≥ 10 for one week prior to the screening visit 2) not taking HRT and other pharmaceutical therapies which might affect hot flushes or other vasomotor symptoms.
While maintaining usual care, the treatment group will receive acupuncture 3 times a week, for a total of 12 sessions over 4 weeks. The control group will receive usual care alone during the same period. Post-treatment follow-up will be performed one month after completing 12 sessions of acupuncture.
This trial will provide evidence for the effectiveness of acupuncture as a treatment for hot flushes. The primary endpoint in both groups is a change in hot flush score from baseline to week 4 and/or week 8. As the secondary endpoint, we will employ the Menopause Rating Scale (MRS), a health-related quality of life questionnaire. Further analysis will examine the frequency, severity and difference in symptoms for daytime vs. nighttime hot flushes, sub-domain analysis of MRS, and participants' expectations of acupuncture treatment.
Trial registration
Current Controlled Trials ISRCTN49335612
PMCID: PMC2631496  PMID: 19055763
9.  Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population 
Thorax  2001;56(8):613-616.
BACKGROUND—Recent evidence suggests a role for hormonal factors in the aetiology of asthma.
METHODS—Data from a large study of women selected from the general population were used to relate treatment with oral hormonal contraceptives (OCP) and postmenopausal hormone replacement therapy (HRT) to the following asthma indicators: self-reported asthma, wheezing, cough at exertion, and use of medication for asthma. The study sample comprised 1536 premenopausal and 3016 postmenopausal women who participated in the third round of the Copenhagen City Heart Study in 1991-4. A total of 377 women were taking OCP (24.5% of premenopausal women) and 458 were on HRT (15.2% of postmenopausal women).
RESULTS—In premenopausal women 4.8% reported having asthma. The prevalence of self-reported asthma, wheeze, use of asthma medication, and cough at exertion was not significantly related to use of OCP. In postmenopausal women the prevalence of self-reported asthma was 6.2%. A weak but consistent association was observed between HRT and self-reported asthma (OR 1.42 (95% CI 0.95 to 2.12)), wheeze (OR 1.29 (95% CI 1.02 to 1.64)), cough at exertion (OR 1.34 (95% CI 1.01 to 1.77)), and use of asthma medication (OR 1.45 (95% CI 0.97 to 2.18)).
CONCLUSIONS—In this study of the general population no relationship was found between the use of OCP and asthma. Although an association was observed between HRT and asthma and asthma-like symptoms, this was relatively weak and it is concluded that there is no necessity to change present prescription practice.

PMCID: PMC1746111  PMID: 11462063
10.  Effects of the menopause transition and hormone use on cognitive performance in midlife women 
Neurology  2009;72(21):1850-1857.
There is almost no longitudinal information about measured cognitive performance during the menopause transition (MT).
We studied 2,362 participants from the Study of Women's Health Across the Nation for 4 years. Major exposures were time spent in MT stages, hormone use prior to the final menstrual period, and postmenopausal current hormone use. Outcomes were longitudinal performance in three domains: processing speed (Symbol Digit Modalities Test [SDMT]), verbal memory (East Boston Memory Test [EBMT]), and working memory (Digit Span Backward).
Premenopausal, early perimenopausal, and postmenopausal women scored higher with repeated SDMT administration (p ≤ 0.0008), but scores of late perimenopausal women did not improve over time (p = 0.2). EBMT delayed recall scores climbed during premenopause and postmenopause (p ≤ 0.01), but did not increase during early or late perimenopause (p ≥ 0.14). Initial SDMT, EBMT-immediate, and EBMT-delayed tests were 4%–6% higher among prior hormone users (p ≤ 0.001). On the SDMT and EBMT, compared to the premenopausal referent, postmenopausal current hormone users demonstrated poorer cognitive performance (p ≤ 0.05) but performance of postmenopausal nonhormone users was indistinguishable from that of premenopausal women.
Consistent with transitioning women's perceived memory difficulties, perimenopause was associated with a decrement in cognitive performance, characterized by women not being able to learn as well as they had during premenopause. Improvement rebounded to premenopausal levels in postmenopause, suggesting that menopause transition–related cognitive difficulties may be time-limited. Hormone initiation prior to the final menstrual period had a beneficial effect whereas initiation after the final menstrual period had a detrimental effect on cognitive performance.
= cardiovascular disease;
= Digit Span Backward;
= East Boston Memory Test;
= final menstrual period;
= menopause transition;
= Symbol Digit Modalities Test;
= Study of Women's Health Across the Nation.
PMCID: PMC2690984  PMID: 19470968
11.  Associations of Estrogen and Testosterone With Insulin Resistance in Pre- and Postmenopausal Women With and Without Hormone Therapy 
Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. Testosterone and sex hormone–binding globulin (SHBG) as well as estrogen are also associated with insulin resistance in women. However, to date, the associations of estradiol, testosterone and SHBG with insulin resistance according to estrogen level have not been clarified.
We examined the associations of estradiol, testosterone and SHBG with insulin resistance in pre- and in postmenopausal women and postmenopausal women who had received hormone therapy to clarify whether the associations differ depending on the estrogen status.
Patients and Methods
Twenty premenopausal women and thirty-two postmenopausal women were enrolled in this study. Fifteen postmenopausal women received oral conjugated equine estrogen (CEE) (0.625 mg) everyday for 12 months. Serum levels of estradiol, testosterone, SHBG and insulin and plasma levels of glucose were measured.
Serum estradiol levels tended to have a negative correlation with homeostasis model assessment of insulin resistance (HOMA-IR) in premenopausal women but not in postmenopausal women. On the other hand, free testosterone levels tended to have a positive correlation with HOMA-IR in postmenopausal women but not in premenopausal women. Serum SHBG levels showed significant negative correlations with HOMA-IR in both pre- and postmenopausal women. SHBG level was significantly increased, free testosterone level was significantly decreased and HOMA-IR was significantly decreased at 12 months after CEE administration. However, there were no significant correlations of changes between estradiol, SHBG or free testosterone and HOMA-IR.
The associations of sex steroid hormones with insulin resistance are different depending on the estrogen status.
PMCID: PMC3693666  PMID: 23825975
Estradiol; Testosterone; Sex Hormone-Binding Globulin; HOMA-IR
12.  Influence of menopause on high density lipoprotein-cholesterol and lipids. 
Journal of Korean Medical Science  2000;15(4):380-386.
It has been generally accepted that high density lipoprotein cholesterol (HDL-C) level decreases with menopause in women. However, recent reports show different results. There is very little data concerning perimenopausal women. To verify these findings, lipids and lipoprotein(a) [Lp(a)] levels were compared among pre-, peri- and postmenopausal women of similar mean ages. Postmenopausal women had higher HDL-C levels than premenopausal women (p<0.001) and there was no difference between peri- and postmenopausal women. LDL-C level in perimenopausal women was lower than in postmenopausal women (p<0.001) and higher than in premenopausal women with borderline significance (p=.051). Total cholesterol levels showed stepwise elevation from premenopause to postmenopause. Perimenopausal women had lower Lp(a) levels than postmenopausal women (p<0.0005) and similar levels to premenopausal women. Lp(a) levels between 0.1 to 10.0 mg/dL were the most prevalent in pre- and perimenopausal women, and those between 10.1 to 20.0 mg/dL in postmenopausal women. In conclusion, menopause itself is associated with the elevation of HDL-C level, and the postmenopausal increase of coronary artery disease is not related to postmenopausal change of HDL-C level. Perimenopausal status, although transient, may favor Lp(a) and lipid profiles for delaying atherosclerosis.
PMCID: PMC3054669  PMID: 10983684
13.  Can depression be a menopause-associated risk? 
BMC Medicine  2010;8:79.
There is little doubt that women experience a heightened psychiatric morbidity compared to men. A growing body of evidence suggests that, for some women, the menopausal transition and early postmenopausal years may represent a period of vulnerability associated with an increased risk of experiencing symptoms of depression, or for the development of an episode of major depressive disorder. Recent research has begun to shed some light on potential mechanisms that influence this vulnerability. At the same time, a number of studies and clinical trials conducted over the past decade have provided important data regarding efficacy and safety of preventative measures and treatment strategies for midlife women; some of these studies have caused a shift in the current thinking of how menopausal symptoms should be appropriately managed.
Essentially, most women will progress from premenopausal into postmenopausal years without developing significant depressive symptoms. However, those with prior history of depression may face a re-emergence of depression during this transition while others may experience a first episode of depression in their lives. Here I provide an overview of what is known about risk factors for depression and the risk posed by the menopausal transition, its associated symptoms, and the underlying changes in the reproductive hormonal milieu, discussing the evidence for the occurrence of mood symptoms in midlife women and the challenges that face clinicians and health professionals who care for this population.
PMCID: PMC3003619  PMID: 21122126
14.  Associations of Endogenous Sex Hormones with the Vasculature in Menopausal Women: The Study of Women’s Health Across the Nation (SWAN) 
Menopause (New York, N.Y.)  2008;15(3):414-421.
As associations between endogenous sex hormones and the vasculature are not well characterized, the objective was to examine the cross-sectional associations of menopausal status and endogenous sex hormones with vascular characteristics.
Common carotid artery adventitial diameter and intima-media thickness were determined using B-mode ultrasound among 483 middle-aged women enrolled in the Pittsburgh and Chicago sites of the Study of Women’s Health Across the Nation.
Sixty-two percent of women were pre- or early perimenopausal (<3 months amenorrhea), 12% were late perimenopausal (3-12 months amenhorrhea), and 27% were postmenopausal (≥12 months amenorrhea). After adjustment for age, compared to pre-/early perimenopause, late perimenopause was associated with a 0.28 mm larger adventitial diameter (p=0.001), while postmenopause was associated with a 0.15 mm larger adventitial diameter (p=0.040). Adjustment for traditional cardiovascular risk factors slightly attenuated these associations, but the association with late perimenopause remained statistically significant (p=0.001). Each standard deviation lower log estradiol value was associated with a 0.07 mm larger adventitial diameter after adjustment for traditional cardiovascular risk factors (p=0.023), while other endogenous hormones showed no associations. Intima-media thickness values were not significantly associated with menopausal status or endogenous sex hormones after adjustment for age.
The menopausal transition and declining estrogen levels are associated with alterations of the peripheral vasculature, which may help to explain the increased risk of cardiovascular disease with postmenopause.
PMCID: PMC2874195  PMID: 18209686
estradiol; endogenous sex hormones; menopause; arteriosclerosis
15.  A Cross Sectional Evaluation of Perimenopausal Depression 
Overall, the clinical spectrum of depression during the perimenopause is not well characterized. This cross-sectional study examined the following: 1) clinical characteristics of women who presented to the NIMH midlife mood disorders clinic (between March 1990 and January 2004) with perimenopausal major and minor depressions; 2) the impact on these measures of either a prior episode of depression or the presence of hot flushes.
Historical variables, reproductive status, symptom ratings, and plasma hormone measures were examined in 116 women who met research criteria for perimenopause-related depression (a current episode of major or minor depression according to the Structured Clinical Interview for DSM-IV or Primary Care Evaluation of Mental Disorders supplemented with a past history form).
Clinical characteristics did not differ in those women with first onset (39%) versus recurrent depressions or in those with (57%) and without hot flushes. Depressive episodes clustered in the later stages of the menopause transition and the first year postmenopause. Seven (6%) women reported a past postpartum major depression, and 55% of women reported a history of premenstrual dysphoria (PMD).
We found no evidence that either hot flushes or a previous episode of depression conveys a distinct clinical profile in these women. The clustering of onsets of depression suggests that the hormone events that characterize the late menopause transition may be relevant to the onset of this form of depression. Finally, although we observed a high rate of PMD, neither postpartum depression nor PMD are consistent accompaniments of perimenopausal depression.
PMCID: PMC2727626  PMID: 18505304
perimenopause; major depression; minor depression; hot flushes
16.  Predictors of first lifetime episodes of major depression in midlife women 
Psychological medicine  2008;39(1):55-64.
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.
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.
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.
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.
PMCID: PMC2905863  PMID: 18377672
Incident major depression; longitudinal study; menopause; midlife women
17.  Menopause and the Metabolic Syndrome 
Archives of internal medicine  2008;168(14):1568-1575.
Cross-sectional studies suggest that prevalence of the metabolic syndrome (MetS) increases from premenopause to postmenopause in women, independent of age. Little is known about why. We hypothesized that the incidence of the MetS increases with progression through menopause and that this increase is explained by the progressive androgenicity of the hormonal milieu.
This longitudinal, 9-year study of 949 participants in the Study of Women’s Health Across the Nation investigates the natural history of the menopausal transition. Participants of 5 ethnicities at 7 geographic sites were recruited when they were premenopausal or early perimenopausal and were eligible for this study if they (1) reached menopause during the study; (2) had never taken hormone therapy, and (3) did not have diabetes mellitus or the MetS at baseline. The primary outcome was the presence of MetS using National Cholesterol Education Program Adult Treatment Panel III criteria. Secondary outcomes were the components of the MetS.
By the final menstrual period, 13.7% of the women had new-onset MetS. Longitudinal analyses, centered at the final menstrual period, were adjusted for age at menopause, ethnicity, study site, marital status, education, body mass index, smoking, and aging. Odds of developing the MetS per year in perimenopause were 1.45 (95% confidence interval, 1.35-1.56); after menopause, 1.24 (95% confidence interval, 1.18-1.30). These odds were significantly different (P<.001). An increase in bioavailable testosterone or a decrease in sex hormone–binding globulin levels increased the odds.
As testosterone progressively dominates the hormonal milieu during the menopausal transition, the prevalence of MetS increases, independent of aging and other important covariates. This may be a pathway by which cardiovascular disease increases during menopause.
PMCID: PMC2894539  PMID: 18663170
18.  Perimenopausal and Postmenopausal Health 
BMC Women's Health  2004;4(Suppl 1):S23.
Health Issue
The average age of natural menopause in Western societies is estimated to be 51 years; women in Canada can therefore expect to live, on average, a third of their lives in post-menopausal years. During these years women are at increased risk of chronic diseases such as osteoporosis and cardiovascular disease.
Key Findings
Clinical and epidemiological data on women in perimenopause are limited. There are no adequate Canadian data on symptom severity and prevalence among perimenopausal and postmenopausal women. Scientific evidence is lacking to support or refute claims that commonly used botanical products can offer therapeutic relief of menopausal symptoms.
Recent data from the Women's Health Initiative suggest that combined estrogen plus therapy increases the risk of stroke, coronary artery disease and breast cancer. Hormone therapy is no longer recommended for the prevention of chronic diseases for asymptomatic women. Stroke is an important issue for perimenopausal and postmenopausal women and sex differences may exist in the progestin treatment of stroke. Osteoporosis affects an estimated one in six women over the age of 50.
Data Gaps and Recommendations
There is a need to conduct clinical and epidemiological research aimed at better understanding the menopausal transition and defining its clinical phases. Investigations aimed at alternative combinations and doses of hormone therapy and non-pharmaceutical alternatives in light of known risks and benefits are also necessary. Health care practitioners and women need to be educated on the risks and effective treatment related to cardiovascular disease so they can present for treatment more quickly and receive the most effective therapies.
PMCID: PMC2096694  PMID: 15345086
19.  Sex Hormones and Mood in the Perimenopause 
The focus of this chapter is the relationship between the onset of depression in women and the reproductive events of the menopause transition. Epidemiologic studies have documented that the majority of women do not become depressed during the menopause transition. However, recent longitudinal studies suggest that in some women, the reproductive events related to the menopause transition could play a role in the onset of depression. No abnormality of ovarian hormones has been identified that distinguishes women with depression from those who remain asymptomatic during the menopause transition. Nonetheless, several findings suggest a role of ovarian hormones in the onset of these depressions. First, episodes of depression cluster during the stage of the menopause transition that is accompanied by estradiol withdrawal. Second, randomized controlled trials have documented the short-term (3–6 weeks) antidepressant efficacy of estradiol in depressed perimenopausal women. Third, experimentally induced estradiol withdrawal triggers mood symptoms in some women. Thus, although depression is not a uniform accompaniment of the menopause transition, in some women, age-related changes in ovarian estrogen production may alter central nervous system function and predispose them to develop depression.
PMCID: PMC2891531  PMID: 19906233
menopause transition; depression; estrogen
20.  The Quality of Life During and After Menopause Among Rural Women 
Introduction: The overall health and well-being of middle-aged women has become a major public health concern around the world. More than 80% of the women experience physical or psychological symptoms in the years when they approach menopause, with various distresses and disturbances in their lives, leading to a decrease in the quality of life. The aim of our study was to assess the quality of life and the impact of hormonal changes in perimenopausal and postmenopausal women and to correlate the prevalence of the symptoms with their duration since menopause.
Material and Methods: A cross- sectional study was done at Sri Manakula Vinayagar Medical College and Hospital, Puducherry, from January 2012 to April 2012. Five hundred women who were in the age group of 40-65 years, who came from rural areas to our hospital, were included in the study. The women who were receiving hormonal treatment and those who refused to participate in the study were excluded. The data such as the socio-demographic information and the menstruation status, which were based on the reported length of time since the last menstrual period and the experience of the symptoms, as were tested in the Menopause Specific Quality of Life (MENQOL) questionnaire, were collected from each patient. The women who were included in the study were divided into three groups as the menopause transition, early postmenopausal and the late postmenopausal groups. All the data which were gathered were analyzed by using SAS 9.2. The Chi square test and the relative risk and the confidence interval calculations were applied to compare the frequencies of the symptoms among the women with different menopausal statuses. A p-value of less than 0.05 was considered to be statistically significant.
Results: Mean menopausal age in the study group was 45 years. The most common symptom within study subjects were low back ache (79%) and muscle-joint pain (77.2%). The least frequent symptoms were increase in facial hair (15%) and feeling of dryness during intimacy (10.8%). Scores of vasomotor domain were significantly more in menopause transition group. Scores of physical domain were significantly more in late postmenopausal group.
Conclusion: The menopause related symptoms had a negative effect on the quality of life of the perimenopausal and the postmenopausal women. Such regional studies can help in creating awareness and in educating women on the early identification of the common menopausal symptoms.
PMCID: PMC3576769  PMID: 23450244
Menopause; Quality of life; Menopausal transition; Early post menopausal women; Late post menopausal women
21.  Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study 
BMJ : British Medical Journal  2002;325(7358):239.
To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17β-oestradiol and 1 mg norethisterone acetate on endometrial histology in postmenopausal women.
Follow up study in postmenopausal women.
31 menopause clinics in the United Kingdom.
534 postmenopausal women, all with an intact uterus, who had completed nine months of treatment with oral continuous combined 2 mg 17β-oestradiol and 1 mg norethisterone acetate agreed to take part in a long term follow up study. Women were assigned to different groups on the basis of the treatment status immediately before entering the original study: 360 women had taken sequential oestrogen-progestogen hormone replacement therapy, 164 had taken no hormone replacement therapy, and 10 had taken unopposed oestrogen therapy.
Endometrial aspiration specimens were taken before the women started the continuous combined regimen, after 9 and 24-36 months, and at the end of the five year treatment period or on withdrawal from the study.
Main outcome measure
Results of endometrial histology.
The duration of treatment with continuous combined hormone replacement therapy was 4.4 (range 1.1-5.9) years. Data on endometrial specimens were available for 526 women after nine months of treatment, 465 women after 24-36 months of treatment, and 398 women who completed the five years treatment (345 women) or were withdrawn between the two latter visits for biopsies (53 women). No cases of endometrial hyperplasia or malignancy were detected at biopsy; 69% of women had an endometrium classified as atrophic or unassessable on completion of the study or withdrawal from it. Before the continuous combined therapy was started, complex hyperplasia was detected in 21 women who had taken sequential hormone replacement therapy before the study and in one who had taken unopposed oestrogen. All of these women had normal results on histological examination of endometrial tissue after nine months of treatment with continuous combined hormone replacement therapy, and hyperplasia did not recur after up to five years of treatment.
Long term treatment (for up to five years) with continuous combined hormone replacement therapy containing oestradiol 2 mg and norethisterone 1 mg daily was associated with neither endometrial hyperplasia nor malignancy. In women who had complex hyperplasia during previous sequential or unopposed regimens, the endometrium returned to normal during treatment with continuous combined hormone replacement therapy. These findings provide reassurance about the long term safety of this continuous combined regimen in terms of the endometrium.
What is already known on this topicLong term use of sequential oestrogen-progestogen hormone replacement therapy increases the risk of endometrial cancerContinuous combined hormone replacement therapy regimens are safe and effective in the short term treatment of postmenopausal womenPrevious trials have involved small numbers of patients (<100) or short durations of treatment (2-3 years), or bothWhat this study addsAll women who had complex hyperplasia while taking sequential or unopposed hormone replacement therapies reverted to normal endometrial patternsContinuous combined hormone replacement therapies that include continuous progestogen improve endometrial safety when used in the long term (up to five years)
PMCID: PMC117635  PMID: 12153918
22.  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
23.  Soy use and vasomotor symptoms: Soy Estrogen Alternative follow-up study 
To evaluate vasomotor symptoms and soy and hormone therapy use in women who had previously participated in the Soy Estrogen Alternative (SEA) study, a trial conducted to compare the effects of soy protein supplements containing differing levels of isoflavones on menopausal symptoms, chronic disease risk factors, and health-related quality of life in perimenopausal and postmenopausal women.
Participants and methods
Two years after the SEA study ended participants were recontacted to complete questionnaires to quantify their health status, medications, menopausal symptoms, and their use of hormone therapy and soy-based foods and supplements. Participants were also asked to record vasomotor symptoms for seven days.
Surveys were collected from 182 of the 241 participants who had been enrolled in the SEA study (76% response rate). Women were 55 ± 2.8 years of age, well educated (80% more than high school), and 93% reported good to excellent health. All but six reported experiencing at least one menopausal symptom, and 56% reported one or more hot flashes on one or more days. Eighty-one women (45%) continued to use soy for menopausal symptom relief, and 58 (32%) were using hormone therapy. Women taking hormone therapy were experiencing fewer and less severe hot flashes than those who were not taking hormone therapy (P < 0.001); hot flash frequency and severity did not differ significantly between those who did and did not use soy, after controlling for hormone therapy use.
Most participants reported they were still experiencing menopausal symptoms. Additionally, half of the most symptomatic women (not taking hormone therapy) were still consuming soy products for vasomotor symptoms.
PMCID: PMC2990907  PMID: 21151685
menopause; vasomotor symptoms; soy consumption; survey
24.  Hemodynamic effect of angiotensin II receptor blockade in postmenopausal women on a high-sodium diet: A double-blind, randomized, placebo-controlled study 
Background: Hypertension becomes increasingly prevalent after menopause. Postmenopausal women are more responsive to salt than premenopausal women, and they have been reported to develop marked renal vasoconstriction on a high-sodium diet.
Objective: The aim of this study was to assess whether angiotensin II receptor blockade can restore a normal pattern of renal response to salt in postmenopausal women on a high-sodium diet. We also assessed segmental renal sodium handling in that population.
Methods: Normotensive and hypertensive postmenopausal women not receiving hormone replacement therapy were enrolled in this prospective, double-blind, placebo-controlled, crossover study. They were assigned to receive irbesartan 150 mg or placebo for 6 weeks; the sequence in which they received irbesartan or placebo was randomized. During the last week of treatment, they received a high-sodium diet (250 mmol/d). Ambulatory blood pressure (ABP), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) were measured using sinistrin and para-amino-hippurate clearances. Renal sodium handling was assessed by measuring endogenous lithium clearance on day 7 of the high-salt diet.
Results: Nineteen women (mean age, 54.7 years; range, 43–72 years; 7 normotensive subjects [mean age, 53.4 years; range, 47–61 years] and 12 hypertensive subjects [mean age, 55.4 years; range, 43–72 years]) were included in the study. When the data for all 19 subjects were pooled, ABP was significantly lower with irbesartan than placebo both during the day (120 [3]/79 [2] vs 127 [3]/85 [2] mm Hg; both, P < 0.01) and at night (systolic BP, 107 [4] vs 111 [4] mm Hg [P < 0.01] and diastolic BP, 71 [2] vs 75 [2] mm Hg [P < 0.05]). Compared with placebo, irbesartan was not associated with a significant change in GFR in either the normotensive or the hypertensive women. When the data for all 19 subjects were pooled, irbesartan was associated with a significant increase in ERPF compared with placebo (372 [21] vs324 [18] mL/min · 1.73 m2; P < 0.05). When the hypertensive and normotensive women were considered separately, the effect was more pronounced in the hypertensive women than in the normotensive women, but the changes did not reach statistical significance. When the data for all subjects were pooled, irbesartan was associated with a significant increase in daytime urinary sodium excretion compared with placebo (135 [13] vs 106 [13] μmol/min; P < 0.05) and a significant decrease at night (109 [13] vs 136 [19] μmol/min; P < 0.05). Fractional excretion of lithium (FELi), an inverse marker of proximal sodium reabsorption, increased significantly during the daytime with irbesartan compared with placebo (47% [6.5%] vs 35% [4.7%]; P < 0.05). At nighttime, FELi was significantly higher in the hypertensive subjects receiving irbesartan compared with placebo (43% [7.2%] vs 29% [6.5%]; P < 0.05). The fractional distal reabsorption of sodium did not change significantly with irbesartan compared with placebo.
Conclusions: The results from this study suggest that angiotensin II receptor blockade had a favorable impact on BP, renal hemodynamics, and renal sodium handling in these salt-replete postmenopausal women. Blockade of the renin-angiotensin system restored the normal pattern of renal response to high sodium intake in these women.
PMCID: PMC3969927
blood pressure; lithium; renal hemodynamics; gender; angiotensin II receptor blockade
25.  Effectiveness of a modified version of the applied relaxation technique in treatment of perimenopausal and postmenopausal symptoms 
Awareness of the risks associated with hormone therapy for menopausal symptoms has sparked a global decline in this treatment. Alternative treatments to relieve menopausal symptoms are therefore required. The applied relaxation (AR) technique has proven to be successful for symptom amelioration, but requires participation in 12 weekly classes. The purpose of this study was to determine the effectiveness of a modified relaxation version (MR) of AR for treatment of hot flashes, night sweats, and sleep disturbances.
We conducted a12-week, randomized, parallel, open-label, controlled trial in perimenopausal and postmenopausal women visiting the menopausal clinic. Participants were randomly assigned to an MR or AR group. The MR group (n=36) received a single session of (MR) training and the AR group (n=35) received conventional 12-week training. Participants were instructed to practice the techniques daily at home for 12 weeks. The main outcome was the measure on the severity scale and frequency of hot flashes, night sweats, and sleep disturbances.
All participants completed the study. Total severity scores in both groups decreased after 12 weeks, but there was no difference between the groups (P=0.93). The severity score for hot flashes in the MR group decreased more than in the AR group (P=0.02). The severity scores for night sweats and sleep disturbances decreased in both groups. The frequency of hot flashes, night sweats, and sleep disturbances were also decreased in both groups.
A shorter, modified version of the AR was equally effective or slightly better than the conventional AR for the relief of hot flashes, night sweats, and sleep disturbances in perimenopausal and postmenopausal women. Recommendations for future research include confirmatory studies and trials with larger samples.
PMCID: PMC3821752  PMID: 24235848
alternative treatments; applied relaxation; menopausal symptoms; hot flashes

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