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1.  Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis 
PLoS Medicine  2009;6(11):e1000181.
Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause.
Background
Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture.
Methods and Findings
Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.
Conclusions
At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anyone can break a hip but most hip fractures occur in elderly people. As people age, their bones gradually lose minerals and become less dense, which weakens the bones and makes them more susceptible to fracture. Because women lose bone density faster than men as they age and because women constitute the majority of the elderly, three-quarters of hip fractures occur in women. Hip fractures can cause long-term health problems and premature death. Thus, although surgical repair of a broken hip usually only requires a hospital stay of about a week, a quarter of elderly people who were living independently before their fracture have to stay in a nursing home for at least a year after their injury and a fifth of elderly people who break a hip die within the year. Most hip fractures are caused by falls. Regular exercise to improve strength and balance combined with review of medicines (to reduce side effects and interactions), regular eye examinations, and the removal of fall hazards from the home can help to prevent hip fractures in elderly people.
Why Was This Study Done?
Bone density decreases very rapidly in women immediately after menopause—the time when menstruation permanently stops—and then continues to decrease more slowly with age. Most women have their menopause in their early 50s but menopause can occur in younger women. Early menopause is thought to be a risk factor for osteoporosis (thinning of the bones) and fractures later in life but little is known about how menopause influences hip fracture risk as women age. In this prospective study (a type of study in which a group of people is followed for several years to see whether they develop a particular condition), the researchers investigate the incidence of hip fractures in relation to age, menopausal status, and age at menopause among the participants of the Million Women Study. This study, which recruited 1.3 million women aged 50–64 years who attended UK breast cancer screening clinics between 1996 and 2001, has been investigating how reproductive and lifestyle factors affect women's health.
What Did the Researchers Do and Find?
At enrollment and three years later, the study participants provided information about their menopausal status and other health and lifestyle factors likely to affect their fracture risk. From these data, the researchers identified more than half a million women who had never used hormone replacement therapy (which reduces fracture risk) and who had given complete information about their menopausal status. They then looked for statistical associations between the occurrence of a first hip fracture in these women over the next few years and their age, menopausal status, and age at menopause. Among women aged 50–54 years, postmenopausal women were twice as likely to have a hip fracture as premenopausal women. Among postmenopausal women, the incidence of hip fractures increased steeply with age and was seven times higher in 70–74-year olds than in 50–54-year olds. Women who had their menopause before age 45 had a slightly increased risk of hip fracture but any effect of age at menopause on the risk of hip fracture was small compared to the effect of age itself, and the slightly increased risk may have been due to other factors that could not be fully accounted for in the analysis.
What Do These Findings Mean?
These findings indicate that around the time of menopause, although hip fractures are rare, the risk of a fracture in postmenopausal women is twice that in premenopausal women. The findings also show that among postmenopausal women, age is the major determinant of hip fracture risk and that for women of a given age, their age at menopause has little effect on hip fracture risk. Women attending breast cancer screening clinics and completing questionnaires about their health may not be representative of the general population. Furthermore, these findings rely on women self-reporting their menopausal status accurately. Nevertheless, the results of this study suggest that clinicians advising women about hip fracture prevention should probably base their advice on the woman's age and on age-related factors such as frailty rather than on factors related to menopause. Clinicians can also now reassure elderly women who had an early menopause that their risk of hip fracture is unlikely to be higher than that of similar women who had a later menopause.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000181.
The American Academy of Orthopaedic Surgeons has detailed information about hip fractures
The US National Institute of Arthritis and Muscoloskeletal and Skin Diseases has an interactive feature called “Check up on your bones and provides detailed information about osteoporosis, including advice on fall prevention
The US Centers for Disease Control and Prevention has a fact sheet about hip fractures among older adults
MedlinePlus has links to resources about hip fracture, osteoporosis, and menopause (in English and Spanish)
More information on the Million Women Study is available
doi:10.1371/journal.pmed.1000181
PMCID: PMC2766835  PMID: 19901981
2.  Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction? 
PLoS Medicine  2007;4(5):e157.
Background
Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.
Methods and Findings
To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1.
Conclusions
Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
Editors' Summary
Background.
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
  The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040157.
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)
doi:10.1371/journal.pmed.0040157
PMCID: PMC1872041  PMID: 17518513
3.  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
4.  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.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
doi:10.1089/jwh.2012.3479
PMCID: PMC3613168  PMID: 23398127
5.  Progression of female reproductive stages associated with bipolar illness exacerbation 
Bipolar disorders  2012;14(5):515-526.
Objectives
Late perimenopause and early postmenopause confer an increased risk of depression in the population, yet bipolar disorder mood course during these times remains unclear.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1399-5618.2012.01026.x
PMCID: PMC3407285  PMID: 22650986
Bipolar Disorder; Menopause; Depression; Mood Disorders; Women
6.  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
7.  Polymorphic repeat in AIB1 does not alter breast cancer risk 
Breast Cancer Research : BCR  2000;2(5):378-385.
We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population.
Introduction:
A causal association between endogenous and exogenous estrogens and breast cancer has been established. Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development after binding to their respective steroid hormone receptors. Coactivator and corepressor proteins have recently been identified that interact with steroid hormone receptors and modulate transcriptional activation [1]. AIB1 (amplified in breast 1) is a member of the steroid receptor coactivator (SRC) family that interacts with estrogen receptor (ER)α in a ligand-dependent manner, and increases estrogen-dependent transcription [2]. Amplification and overexpression of AIB1 has been observed in breast and ovarian cancer cell lines and in breast tumors [2,3]. A polymorphic stretch of glutamine amino acids, with unknown biologic function, has recently been described in the carboxyl-terminal region of AIB1 [4]. Among women with germline BRCA1 mutations, significant positive associations were observed between AIB1 alleles with 26 or fewer glutamine repeats and breast cancer risk [5]
Aim:
To establish whether AIB1 repeat alleles are associated with breast cancer risk and specific tumor characteristics among Caucasian women.
Patients and methods:
We evaluated associations prospectively between AIB1 alleles and breast cancer risk in the Nurses' Health Study using a nested case-control design. The Nurses' Health Study was initiated in 1976, when 121 700 US-registered nurses between the ages of 30 and 55 years returned an initial questionnaire reporting medical histories and baseline health-related exposures. Between 1989 and 1990 blood samples were collected from 32 826 women. Eligible cases in this study consisted of women with pathologically confirmed incident breast cancer from the subcohort who gave a blood specimen. Cases with a diagnosis anytime after blood collection up to June 1, 1994, with no previously diagnosed cancer except for nonmelanoma skin cancer were included. Controls were randomly selected participants who gave a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the cases were diagnosed, and were matched to cases on year of birth, menopausal status, postmenopausal hormone use, and time of day, month and fasting status at blood sampling. The nested case-control study consisted of 464 incident breast cancer cases and 624 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Womens' Hospital, Boston, Massachusetts USA. Information regarding breast cancer risk factors was obtained from the 1976 baseline questionnaire, subsequent biennial questionnaires, and a questionnaire that was completed at the time of blood sampling. Histopathologic characteristics, such as stage, tumor size and ER and progesterone receptor (PR) status, were ascertained from medical records when available and used in case subgroup analyses.
AIB1 repeat alleles were determined by automated fluorescence-based fragment detection from polymerase chain reaction (PCR)-amplified DNA extracted from peripheral blood lymphocytes. Fluorescent 5' -labeled primers were utilized for PCR amplification, and glutamine repeat number discrimination was performed using the ABI Prism 377 DNA Sequencer (Perkin-Elmer, Foster City, CA, USA). Genotyping was performed by laboratory personnel who were blinded to case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures (n = 110); concordance for the blinded samples was 100%. Methods regarding plasma hormone assays have previously been reported [6]. Conditional and unconditional logistic regression models, including terms for the matching variables and other potential confounders, were used to assess the association of AIB1 alleles and breast cancer characterized by histologic subtype, stage of disease, and ER and PR status. We also evaluated whether breast cancer risk associated with AIB1 genotype differed within strata of established breast cancer risk factors, and whether repeat length in AIB1 indirectly influenced plasma hormone levels.
Results:
The case-control comparisons of established breast cancer risk factors among these women have previously been reported [7], and are generally consistent with expectation. The mean age of the women was 58.3 (standard deviation [SD] 7.1) years, ranging from 43 to 69 years at blood sampling. There were 188 premenopausal and 810 postmenopausal women, with mean ages of 48.1 (SD 2.8) years and 61.4 (SD 5.0) years, respectively, at blood sampling. Women in this study were primarily white; Asians, African-Americans and Hispanics comprised less than 1% of cases or controls.
The distribution of AIB1 glutamine repeat alleles and AIB1 genotypes for cases and controls are presented in Table 1. Women with AIB1 alleles of 26 glutamine repeats or fewer were not at increased risk for breast cancer (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.75-1.36; Table 2). Results were also similar by menopausal status and in analyses additionally adjusting for established breast cancer risk factors. Among premenopausal women, the OR for women with at least one allele with 26 glutamine repeats or fewer was 0.82 (95% Cl 0.37-1.81), and among postmenopausal women the OR was 1.09 (95% Cl 0.78-1.52; Table 2). We did not observe evidence of a positive association between shorter repeat length and advanced breast cancer, defined as women with breast cancer having one or more involved nodes (OR 1.07, 95% Cl 0.64-1.78), or with cancers with a hormone-dependent phenotype (ER-positive: OR 1.16, 95% Cl 0.81-1.65; Table 3). No associations were observed among women who had one or more alleles with 26 glutamine repeats or fewer, with or without a family history of breast cancer (family history: OR 1.09; 95% Cl 0.46-2.58; no family history: OR 0.94; 95% Cl 0.68-1.31; test for interaction P = 0.65). We also did not observe associations with breast cancer risk to be modified by other established breast cancer risk factors. Among postmenopausal controls not using postmenopausal hormones, geometric least-squared mean plasma levels of estrone sulfate and estrone were similar among carriers and noncarriers of AIB1 alleles with 26 glutamine repeats or fewer (both differences: ≤ +3.5%; P >0.50). Mean levels of estradiol were slightly, but nonsignificantly elevated among carriers of alleles with 26 glutamine repeats or fewer (+11.6%; P = 0.08).
Discussion:
In this population-based nested case-control study, women with at most 26 repeating glutamine codons (CAG/CAA) within the carboxyl terminus of AIB1 were not at increased risk for breast cancer. We did not observe shorter repeat alleles to be positively associated with breast cancer grouped by histologic subtype, stage of disease, or by ER and PR status. These data suggest that AIB1 repeat length is not a strong independent risk factor for postmenopausal breast cancer, and does not modify the clinical presentation of the tumor among Caucasian women in the general population.
PMCID: PMC13920  PMID: 11056690
AIB1 polymorphism; breast cancer; genetic susceptibility; molecular epidemiology
8.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
Objective
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Intervention
Digital mammography.
Magnetic resonance imaging.
Comparator
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Sensitivity.
Specificity.
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Intervention
Both MRI and FM.
Comparators
Screening with MRI alone and FM alone.
Outcomes of Interest
Sensitivity.
Specificity.
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
9.  Depressive Symptoms are Increased in the Early Perimenopausal Stage in Ethnically Diverse HIV+ and HIV− Women 
Menopause (New York, N.Y.)  2012;19(11):1215-1223.
Objective
The risk of clinically significant depressive symptoms increases during the perimenopause. With highly active antiretroviral treatment (HAART), more HIV-infected women survive to transition through the menopause. In a cross-sectional analysis, we evaluated the association of menopausal stage and vasomotor symptoms with depressive symptoms in an ethnically diverse, cohort of women with a high prevalence of HIV.
Methods
Participants included 835 HIV-infected women and 335 HIV-uninfected controls from the Women’s Interagency HIV Study (WIHS; 63% African-American). The Center for Epidemiological Studies Depression (CES-D) scale was used to screen for elevated depressive symptoms. Menopausal stages were defined according to standard definitions. Logistic regression analysis was used to identify predictors of elevated depressive symptoms.
Results
Compared to premenopausal women, early perimenopausal (OR 1.74, 95%CI 1.17–2.60), but not late perimenopausal or postmenopausal women were more likely to show elevated depressive symptoms in adjusted analyses. The odds were similar in HIV-infected and HIV-uninfected women. Persistent vasomotor symptoms also predicted elevated depressive symptoms in HIV-infected and uninfected women (OR 1.45, 95%CI 1.02–2.06). In HIV-infected women, menopausal stage interacted with antiretroviral use (p=0.02); the likelihood of elevated depressive symptoms in early perimenopause compared with premenopause was especially high in HAART-untreated women (OR 3.87, 95%CI 1.57–9.55).
Conclusions
In HIV+ and HIV− women, the odds of elevated depressive symptoms were significantly higher during the early perimenopause. Elevated depressive symptoms were associated with nonadherence to HAART, underscoring the importance of screening and treating depressive symptoms in HIV+ women who have experienced a change in the regularity of their menstrual cycles.
doi:10.1097/gme.0b013e318255434d
PMCID: PMC3483358  PMID: 22872013
HIV; Depression; Menopause; Perimenopause; African American; Vasomotor
10.  Presence of vasomotor symptoms is associated with lower bone mineral density 
Menopause (New York, N.Y.)  2009;16(2):239-246.
Objective
To determine whether women with vasomotor symptoms (VMS) have lower bone mineral density (BMD) than women without VMS.
Design
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.
Results
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.
Conclusions
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.
doi:10.1097/gme.0b013e3181857964
PMCID: PMC2695505  PMID: 19002017
Menopause; hot flashes; vasomotor symptoms; bone mineral density
11.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial 
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
12.  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
13.  Association of Menopausal Vasomotor Symptoms With Increased Bone Turnover During the Menopausal Transition 
The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage. We analyzed data from 2283 participants of the Study of Women's Health Across the Nation, a longitudinal community-based cohort study of women aged 42 to 52 years at baseline. At baseline and annually through follow-up visit 8, participants provided questionnaire data, urine samples, serum samples, and anthropometric measurements. Using multivariable repeated-measures mixed models, we examined associations between annually assessed VMS frequency and annual NTX measurements. Our results show that mean adjusted NTX was 1.94 nM of bone collagen equivalents (BCE)/mM of creatinine higher among early perimenopausal women with any VMS than among early perimenopausal women with no VMS (p < .0001). Mean adjusted NTX was 2.44 nM BCE/mM of creatinine higher among late perimenopausal women with any VMS than among late perimenopausal women with no VMS (p = .03). Among premenopausal women, VMS frequency was not significantly associated with NTX level. When NTX values among women with frequent VMS (≥6 days in past 2 weeks) were expressed as percentages of NTX values among women without frequent VMS, the differences were 3% for premenopausal women, 9% for early perimenopausal women, 7% for late perimenopausal women, and 4% for postmenopausal women. Adjustment for serum follicle-stimulating hormone (FSH) level greatly reduced the magnitudes of associations between VMS and NTX level. We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.259
PMCID: PMC3179323  PMID: 20878774
HOT FLASHES; VASOMOTOR SYMPTOMS; BONE TURNOVER; URINARY N-TELOPEPTIDE; NTX
14.  Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study 
PLoS Medicine  2014;11(6):e1001659.
Using data from the Nurses' Health Study, Jiali Han and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk.
Methods and Findings
We followed 74,523 female nurses for 24 y (1986–2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98–1.10 for 1–5 nevi; 1.15, 95% CI, 1.00–1.31 for 6–14 nevi, and 1.35, 95% CI, 1.04–1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%–9.33%) for women with 1–5 nevi, 9.75% (95% CI, 8.48%–11.11%) for women with 6–14 nevi, and 11.4% (95% CI, 8.82%–14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)–positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02–1.16 for ER+/progesterone receptor [PR]–positive tumors; 1.08, 95% CI, 0.94–1.24 for ER+/PR− tumors; and 0.99, 95% CI, 0.86–1.15 for ER−/PR− tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched controls with plasma hormone measurements, the multivariable-adjusted odds ratio for every five nevi attenuated from 1.25 (95% CI, 0.89–1.74) to 1.16 (95% CI, 0.83–1.64) after adjusting for plasma hormone levels. Key limitations in this study are that cutaneous nevi were self-counted in our cohort and that the study was conducted in white individuals, and thus the findings do not necessarily apply to other populations.
Conclusions
Our results suggest that the number of cutaneous nevi may reflect plasma hormone levels and predict breast cancer risk independently of previously known factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
One woman in eight will develop breast cancer during her lifetime. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably (which leads to the formation of a lump in the breast) and to move around the body (metastasize). The treatment of breast cancer, which is diagnosed using mammography (a breast X-ray) or manual breast examination and biopsy, usually involves surgery to remove the lump, or the whole breast (mastectomy) if the cancer has started to metastasize. After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells and may also be given drugs that block the action of estrogen and progesterone, female sex hormones that stimulate the growth of some breast cancer cells. Globally, half a million women die from breast cancer each year. However, in developed countries, nearly 90% of women affected by breast cancer are still alive five years after diagnosis.
Why Was This Study Done?
Several sex hormone–related factors affect breast cancer risk, including at what age a woman has her first child (pregnancy alters sex hormone levels) and her age at menopause, when estrogen levels normally drop. Moreover, postmenopausal women with high circulating levels of estrogen and testosterone (a male sex hormone) have an increased breast cancer risk. Interestingly, moles (nevi)—dark skin blemishes that are a risk factor for the development of melanoma, a type of skin cancer—often darken or enlarge during pregnancy. Might the number of nevi be a marker of hormone levels, and could nevi counts therefore be used to predict an individual's risk of breast cancer? In this prospective cohort study, the researchers look for an association between number of nevi and breast cancer risk among participants in the US Nurses' Health Study (NHS). A prospective cohort study enrolls a group of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of certain diseases. The NHS, which enrolled 121,700 female nurses aged 30–55 years in 1976, is studying risk factors for cancer and other chronic diseases in women.
What Did the Researchers Do and Find?
In 1986, nearly 75,000 NHS participants (all of whom were white) reported how many nevi they had on their left arm. Over the next 24 years, 5,483 invasive breast cancers were diagnosed in these women. Compared to women with no nevi, women with increasing numbers of nevi had a higher risk of breast cancer after adjustment for known breast cancer risk factors. Specifically, among women with 1–5 nevi, the hazard ratio (HR) for breast cancer was 1.04, whereas among women with 15 or more nevi the HR was 1.35. An HR compares how often a particular event occurs in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event. Over 24 years of follow-up, the absolute risk of developing breast cancer was 8.48% in women with no nevi but 11.4% for women with 15 or more nevi. Notably, postmenopausal women with six or more nevi had higher blood levels of estrogen and testosterone than women with no nevi. Finally, in a subgroup analysis, the association between number of nevi and breast cancer risk disappeared after adjustment for hormone levels.
What Do These Findings Mean?
These findings support the hypothesis that the number of nevi reflects sex hormone levels in women and may predict breast cancer risk. Notably, they show that the association between breast cancer risk and nevus number was independent of known risk factors for breast cancer, and that the risk of breast cancer increased with the number of nevi in a dose-dependent manner. These findings also suggest that a hormonal mechanism underlies the association between nevus number and breast cancer risk. Because this study involved only white participants, these findings may not apply to non-white women. Moreover, the use of self-reported data on nevus numbers may affect the accuracy of these findings. Finally, because this study is observational, these findings are insufficient to support any changes in clinical recommendations for breast cancer screening or diagnosis. Nevertheless, these data and those in an independent PLOS Medicine Research Article by Kvaskoff et al. support the need for further investigation of the association between nevi and breast cancer risk and of the mechanisms underlying this relationship.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001659.
An independent PLOS Medicine Research Article by Kvaskoff et al. also investigates the relationship between nevi and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the Nurses' Health Study is available
doi:10.1371/journal.pmed.1001659
PMCID: PMC4051600  PMID: 24915186
15.  Menopausal symptoms 
Clinical Evidence  2010;2010:0804.
Introduction
Menopause is a physiological event. In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time, although they can persist for decades in some women.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menopausal symptoms? What are the effects of non-prescribed treatments for menopausal symptoms? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 68 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: agnus castus, antidepressants, black cohosh, clonidine, oestrogens, phyto-oestrogens, progestogens, testosterone, and tibolone.
Key Points
In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Symptoms associated with the menopause include vasomotor symptoms, sleeplessness, mood changes, reduced energy levels, loss of libido, vaginal dryness, and urinary symptoms.Many symptoms, such as hot flushes, are temporary, but those resulting from reduced hormone levels, such as genital atrophy, may be permanent.
Progestogens reduce menopausal vasomotor symptoms compared with placebo. However, the clinical usefulness of progestogens given alone for menopausal symptoms is limited by the unwanted adverse effects of the relatively high doses need to achieve relief of menopausal symptoms. Progestogens used alone or with oestrogens reduce vasomotor symptoms in perimenopausal women.
Oestrogens reduce vasomotor and sexual symptoms, but, like progestogens, increase the risk of serious adverse effects. Oestrogens, used alone or with progestogens, reduce vasomotor, urogenital, and psychological symptoms, and improve quality of life compared with placebo over 3 to 6 months.However, oestrogens increase the risk of breast cancer, endometrial cancer, stroke, and venous thromboembolism.Oestrogens, used alone or with progestogens, do not seem to increase the risk of coronary heart disease.We don't know whether phyto-oestrogens, such as those in soy flour, reduce menopausal symptoms. Phyto-oestrogens have not been shown consistently to improve symptoms, and they may increase the risk of endometrial hyperplasia in perimenopausal women.
CAUTION: Women with an intact uterus who are prescribed oestrogen replacement therapy should also take continuous or cyclical progestogens.
Tibolone reduces vasomotor symptoms in postmenopausal women compared with placebo. Tibolone may improve sexual function compared with placebo or compared with combined oestrogens plus progestogens.However, we don't know if tibolone is more effective in reducing vasomotor symptoms than oestrogen and progestogen combined treatment.Tibolone may be associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer compared with placebo.
Testosterone reduces sexual symptoms in postmenopausal women but does not seem to reduce vasomotor symptoms, compared with oestrogen HRT alone.
Antidepressants may be more effective than placebo at relieving vasomotor symptoms in postmenopausal women in the short term. However, we don't know whether they are effective in the long term.
We don't know whether clonidine, black cohosh, or agnus castus reduce menopausal symptoms.
PMCID: PMC2907604  PMID: 21718582
16.  Worse Renal Disease in Postmenopausal F2[Dahl S x R]-Intercross Rats: Detection of Novel QTLs Affecting Hypertensive Kidney Disease 
PLoS ONE  2013;8(2):e56096.
The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of ovarian hormones. Furthermore, the detection of distinct GIS-QTLs in postmenopausal intercross female rats suggests that distinct genetic mechanisms underlie hypertensive glomerulosclerosis in premenopausal and postmenopausal states.
doi:10.1371/journal.pone.0056096
PMCID: PMC3564915  PMID: 23393608
17.  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.
doi:10.7860/JCDR/2012/4910.2688
PMCID: PMC3576769  PMID: 23450244
Menopause; Quality of life; Menopausal transition; Early post menopausal women; Late post menopausal women
18.  Prevalence of Bacterial Vaginosis and Vaginal Flora Changes in Peri- and Postmenopausal Women 
Journal of Clinical Microbiology  2002;40(6):2147-2152.
Our aim was to evaluate the prevalence of bacterial vaginosis and decrease in lactobacillus colonization in women 40 years old or older in relation to menopausal status by evaluation of Gram-stained smears. A total of 1,486 smears from Italian Caucasian women aged 40 to 79 years were examined. Women were classified as follows: fertile (regular cycles) (n = 328), perimenopausal (irregular cycles) (n = 237), and postmenopausal (n = 921), including 331 women on estroprogestinic hormone replacement therapy (HRT). The prevalences of bacterial vaginosis (assessed as a Nugent score of ≥7) in fertile (9.8%) and perimenopausal (11.0%) women were not statistically different, whereas the prevalence was significantly lower overall in postmenopausal women (6.0%) (P = 0.02). Specifically, 6.3% of postmenopausal women without HRT and 5.4% of postmenopausal women with HRT were positive for bacterial vaginosis. The Nugent score system was not adequate for evaluating the normal and intermediate vaginal flora in women over the age of 40 years. High numbers of peri- and postmenopausal women had no lactobacilli and no bacterial-vaginosis-associated microorganisms. This nonpathological absence of lactobacilli in women with a Nugent score of 4 was scored as 4∗, and this group was considered separately from the intermediate flora group. A score of 4∗ was obtained for 2.1% of fertile women, 11.4% of perimenopausal women, 44.1% of postmenopausal women without HRT, and 6.9% of postmenopausal women with HRT. The physiological reduction in lactobacillus colonization of the vagina in postmenopausal women does not cause an increase in bacterial-vaginosis prevalence. Reversion of lactobacillus flora to premenopausal levels due to HRT does not increase the prevalence of bacterial vaginosis in postmenopausal women.
doi:10.1128/JCM.40.6.2147-2152.2002
PMCID: PMC130764  PMID: 12037079
19.  The relationship between mood and sleep in different female reproductive states 
BMC Psychiatry  2014;14:177.
Background
Sleep is disrupted in depressed subjects, but it also deteriorates with age and possibly with the transition to menopause. The nature of interaction between mood, sleep, age and reproductive state is not well-defined. The aim of this study was to evaluate the relationship between mood and sleep among healthy women in different reproductive states.
Methods
We analyzed data from 11 younger (20–26 years), 21 perimenopausal (43–51 years) and 29 postmenopausal (58–71 years) healthy women who participated in a study on menopause, sleep and cognition. The 21-item Beck Depression Inventory (BDI) was administered to assess mood. Subjective sleep quality was assessed with the Basic Nordic Sleep Questionnaire (BNSQ). Objective sleep was measured with all-night polysomnography (PSG) recordings. Perimenopausal and younger women were examined during the first days of their menstrual cycle at the follicular phase.
Results
Among younger women, less arousals associated with higher BDI total scores (p = 0.026), and higher SWS percentages with more dissatisfaction (p = 0.001) and depressive-somatic symptoms (p = 0.025), but with less depressive-emotional symptoms (p = 0.001). In specific, less awakenings either from REM sleep or SWS, respectively, associated with more punishment (p = 0.005; p = 0.036), more dissatisfaction (p < 0.001; p = 0.001) and more depressive-somatic symptoms (p = 0.001; p = 0.009), but with less depressive-emotional symptoms (p = 0.002; p = 0.003). In perimenopausal women, higher BNSQ insomnia scores (p = 0.005), lower sleep efficiencies (p = 0.022) and shorter total sleep times (p = 0.024) associated with higher BDI scores, longer sleep latencies with more depressive-somatic symptoms (p = 0.032) and longer REM latencies with more dissatisfaction (p = 0.017). In postmenopausal women, higher REM percentages associated with higher BDI total scores (p = 0.019) and more depressive-somatic symptoms (p = 0.005), and longer SWS latencies with more depressive-somatic symptoms (p = 0.030).
Conclusions
Depressive symptoms measured with the total BDI scores associated with sleep impairment in both perimenopausal and postmenopausal women. In younger women, specific BDI factors revealed minor associations, suggesting that the type of sleep impairment can vary in relation to different depressive features. Our data indicate that associations between sleep and depressed mood may change in conjunction with hormonal milestones.
doi:10.1186/1471-244X-14-177
PMCID: PMC4071019  PMID: 24935559
Perimenopause; Postmenopause; Reproduction; Sleep stage
20.  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
21.  Menopause and the Metabolic Syndrome 
Archives of internal medicine  2008;168(14):1568-1575.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1001/archinte.168.14.1568
PMCID: PMC2894539  PMID: 18663170
22.  Menopausal symptoms 
Clinical Evidence  2011;2011:0804.
Introduction
Menopause is a physiological event. In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time, although they can persist for decades in some women.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menopausal symptoms? What are the effects of non-prescribed treatments for menopausal symptoms? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: agnus castus, antidepressants, black cohosh, clonidine, oestrogens, phyto-oestrogens, progestogens, testosterone, and tibolone.
Key Points
In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Symptoms associated with the menopause include vasomotor symptoms, sleeplessness, mood changes, reduced energy levels, loss of libido, vaginal dryness, and urinary symptoms.Many symptoms, such as hot flushes, are temporary, but those resulting from reduced hormone levels, such as genital atrophy, may be permanent.
Progestogens reduce menopausal vasomotor symptoms compared with placebo. However, the clinical usefulness of progestogens given alone for menopausal symptoms is limited by the unwanted adverse effects of the relatively high doses needed to achieve relief of menopausal symptoms.
Oestrogens reduce vasomotor and sexual symptoms but, like progestogens, they increase the risk of serious adverse effects. Oestrogens, used alone or with progestogens, reduce vasomotor and urogenital symptoms, and improve quality of life compared with placebo over 3 to 6 months.However, oestrogens increase the risk of breast cancer, endometrial cancer, stroke, and venous thromboembolism.We don't know whether phyto-oestrogens, such as those in soy flour, reduce menopausal symptoms. Phyto-oestrogens have not been shown consistently to improve symptoms, and they may increase the risk of endometrial hyperplasia in perimenopausal women.
CAUTION: Women with an intact uterus who are prescribed oestrogen replacement therapy should also take continuous or cyclical progestogens.
Tibolone reduces vasomotor symptoms in postmenopausal women compared with placebo. Tibolone may improve sexual function compared with placebo or compared with combined oestrogens plus progestogens.We don't know if tibolone is more effective than oestrogen and progestogen combined treatment in reducing vasomotor symptoms.Tibolone may be associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer.
We don't know whether testosterone alone reduces menopausal symptoms, as we found no RCTs. Testosterone plus oestrogen-based HRT reduces sexual symptoms in postmenopausal women but does not seem to reduce vasomotor symptoms, compared with oestrogen HRT alone.
Antidepressants may be more effective than placebo at relieving vasomotor symptoms in postmenopausal women in the short term. However, we don't know whether they are effective in the long term.
We don't know whether clonidine, black cohosh, or agnus castus reduce menopausal symptoms.
PMCID: PMC3275139  PMID: 21696644
23.  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
24.  Frequency of symptoms, determinants of severe symptoms, validity of and cut-off score for Menopause Rating Scale (MRS) as a screening tool: A cross-sectional survey among midlife Nepalese women 
BMC Women's Health  2011;11:30.
Background
Majority of Nepalese women live in remote rural areas, where health services are not easily accessible. We determined the validity of Menopause Rating Scale (MRS) as a screening tool for identification of women with severe menopausal symptoms and cut-off MRS score for referral.
Methods
A cross-sectional survey was carried out between February and August, 2008. Trained health workers administered MRS and a questionnaire to 729 women (40 to 65 years) attending health screening camps in Kaski district of Western Development Region of Nepal. Information about demographics, menopausal status, and use of hormone replacement therapy (HRT), chronic disease, self-perceived general health and reproductive history was also collected. Menopausal status was classified according to the Staging of Reproductive Ageing Workshop (STRAW). We calculated rates of menopausal symptoms, sensitivity, and specificity and likelihood ratios of MRS scores for referral to a gynaecologist. We also carried out multivariate analyses to identify the predictors for referral to a gynaecologist for severe symptoms.
Results
A total 729 women were interviewed. Mean age at menopause was 49.9 years (SD 5.6). Most frequently reported symptoms were, sleeping problems (574, 78.7%), physical and mental exhaustion (73.5%), hot flushes (508, 69.7%), joint and muscular discomfort (500, 68.6%) and dryness of vagina (449, 61.6%). Postmenopausal women (247, 33.9%) and perimenopausal (215, 29.5%) women together experienced significantly higher prevalence of all symptoms than the premenopausal (267, 36.6%) women. MRS score of ≥16 had highest ratio for (sensitivity + specificity)/2. Women who reported urogenital symptoms [OR 5.29, 95% CI 2.59, 10.78], and self perceived general health as poor [OR 1.29, 95% CI 1.11, 1.53] were more likely to be referred to a gynaecologist for severe menopausal symptoms. While women reporting somatic [OR 0.72, 95% CI 0.63, 0.82] and psychological [OR 0.86, 95% CI 0.74, 0.99] symptoms were less likely to be referred.
Conclusion
MRS may be used as a screening tool at a cut-off score of ≥16 with least misclassification rate. However, its utility may be limited by woman's general health status and occurrence of urogenital symptoms.
doi:10.1186/1472-6874-11-30
PMCID: PMC3126771  PMID: 21672198
25.  Effects of the menopause transition and hormone use on cognitive performance in midlife women 
Neurology  2009;72(21):1850-1857.
Background:
There is almost no longitudinal information about measured cognitive performance during the menopause transition (MT).
Methods:
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).
Results:
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.
Conclusions:
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.
GLOSSARY
= 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.
doi:10.1212/WNL.0b013e3181a71193
PMCID: PMC2690984  PMID: 19470968

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