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1.  Progestogen levels, Progesterone Receptor Gene polymorphisms, and mammographic density changes: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study (PEPI-MDS) 
Menopause (New York, N.Y.)  2012;19(3):302-310.
Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy (ET) alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestin Interventions (PEPI) trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of post-treatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density.
We measured percent mammographic density and serum progestogen levels in 280 PEPI participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how increase in progestogen levels and PGR genetic variations influenced mammographic density change following EPT.
The increase in post-treatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P-trend=0.044). Compared to women in the lowest quartile of serum progestogen, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P=0.046). We did not find a strong indication that genetic variations in PGR were associated with mammographic density increase, or modified the association with serum progestogen, however confidence in these null findings is constrained by our small sample size.
Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density.
PMCID: PMC4497814  PMID: 22105149
progestogen level; progesterone receptor gene; hormone therapy; mammographic density
2.  Osteoporosis Screening in Postmenopausal Women 50-64 years-old: Comparison of U.S. Preventive Services Task Force Strategy and Two Traditional Strategies in the Women's Health Initiative 
The U.S. Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture is ≥ 9.3%. For identifying screening candidates among women aged 50-64 years, it is uncertain how the USPSTF strategy compares with the Osteoporosis Self-Assessment Tool (OST) and the Simple Calculated Osteoporosis Risk Estimate (SCORE). We examined data (1994-2012) from 5165 Women's Health Initiative participants aged 50-64. For the USPSTF (FRAX major fracture risk ≥ 9.3% calculated without BMD), OST (score <2), and SCORE (score >7) strategies, we assessed sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to discriminate between those with and without femoral neck (FN) T-score ≤ −2.5. Sensitivity, specificity, and AUC for identifying FN T-score ≤ −2.5 were 34.1%, 85.8%, and 0.60 for USPSTF (FRAX), 74.0%, 70.8%, and 0.72 for SCORE, and 79.8%, 66.3%, and 0.73 for OST. The USPSTF strategy identified about 1/3rd of women aged 50-64 with FN T-scores ≤ −2.5. Among women aged 50-64 years, the USPSTF strategy was modestly better than chance alone and inferior to conventional SCORE and OST strategies in discriminating between women with and without FN T-score ≤ −2.5.
PMCID: PMC4117254  PMID: 24431262
osteoporosis; fracture; bone mineral density; Fracture Risk Assessment Tool; USPSTF; OST; SCORE; FRAX
While several studies have noted increased fracture risk in individuals with type 2 DM (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength.
Data came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). Homeostasis model assessment of insulin resistance (HOMAIR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual-energy X-ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA-IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site.
Greater HOMA-IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA-IR was associated with 0.34 to 0.40 standard deviations (SD) decrement in the strength indices (p<0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength.
Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross-sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load.
PMCID: PMC3935990  PMID: 23983216
Insulin resistance; bone strength
4.  Childhood Socioeconomic Status and Adult Femoral Neck Bone Strength: Findings from The Midlife in the United States Study 
Bone  2013;56(2):320-326.
Bone acquisition in childhood impacts adult bone mass, and can be influenced by childhood socioeconomic conditions. Socioeconomic status is also associated with body weight which affects the load that bone is exposed to in a fall. We hypothesized that socioeconomic advantage in childhood is associated with greater bone strength relative to load in adulthood.
Hip dual x-ray absorptiometry scans from 722 participants in the Midlife in the United States Study were used to measure femoral neck size and bone mineral density, and combined with body weight and height to create composite indices of femoral neck strength relative to load in different failure modes: compression, bending, and impact. A childhood socioeconomic advantage score was created for the same participants from parental education, self-rated financial status relative to others, and not being on welfare. Multiple linear regression was used to determine the association of childhood socioeconomic advantage score with femoral neck composite strength indices, stratified by gender and race (white/non-white), and adjusted for study site, age, menopause status in women, education, and current financial advantage.
Childhood socioeconomic advantage was independently associated with higher indices of all three composite strength indices in white men (adjusted standardized effect sizes, 0.19 to 0.27, all p values <0.01), but not in the other three race/gender groups. Additional adjustment for adult obesity, physical activity in different life stages, smoking, and heavy drinking over the life-course significantly attenuated the associations in white men.
Socioeconomic disadvantage in childhood is associated with lower hip strength relative to load in white men, and these influences are dampened by healthy lifestyle choices.
PMCID: PMC3784306  PMID: 23810840
bone strength; femoral neck; childhood socioeconomic advantage; health behaviors
5.  Factors Related to Age at Natural Menopause: Longitudinal Analyses From SWAN 
American Journal of Epidemiology  2013;178(1):70-83.
Early age at the natural final menstrual period (FMP) or menopause has been associated with numerous health outcomes and might be a marker of future ill health. However, potentially modifiable factors affecting age at menopause have not been examined longitudinally in large, diverse populations. The Study of Women's Health Across the Nation (SWAN) followed 3,302 initially premenopausal and early perimenopausal women from 7 US sites and 5 racial/ethnic groups, using annual data (1996–2007) and Cox proportional hazards models to assess the relation of time-invariant and time-varying sociodemographic, lifestyle, and health factors to age at natural FMP. Median age at the FMP was 52.54 years (n = 1,483 observed natural FMPs). Controlling for sociodemographic, lifestyle, and health factors, we found that racial/ethnic groups did not differ in age at the FMP. Higher educational level, prior oral contraceptive use, and higher weight at baseline, as well as being employed, not smoking, consuming alcohol, having less physical activity, and having better self-rated health over follow-up, were significantly associated with later age at the FMP. These results suggest that age at the natural FMP reflects a complex interrelation of health and socioeconomic factors, which could partially explain the relation of late age at FMP to reduced morbidity and mortality.
PMCID: PMC3698989  PMID: 23788671
age; education; ethnicity; menopause; oral contraceptives; race; smoking; weight
6.  C-Reactive Protein, Bone Strength, and Nine-Year Fracture Risk: Data From the Study of Women’s Health Across the Nation (SWAN) 
Higher levels of C-reactive protein (CRP), an inflammatory marker, are associated with increased fracture risk, although previous studies on CRP and bone mineral density (BMD) have yielded conflicting results. We aimed to test the hypotheses that composite indices of femoral neck strength relative to load, which are inversely associated with fracture risk, would also be inversely associated with CRP, and would explain part of the association between CRP and fracture risk. We analyzed data from a multisite, multiethnic prospective cohort of 1872 community-dwelling women, premenopausal or early perimenopausal at baseline. Femoral neck composite strength indices in three failure modes were calculated using dual-energy X-ray absorptiometry (DXA)-derived femoral neck width (FNW), femoral neck axis length (FNAL), femoral neck BMD and body size at baseline, as BMD*FNW/weight for compression strength, BMD*(FNW)2/(FNAL*weight) for bending strength, and BMD*FNW*FNAL/(height*weight) for impact strength. Incident nondigital, noncraniofacial fractures were ascertained annually over a median follow-up of 9 years. In analyses adjusted for age, race/ethnicity, diabetes, menopause transition stage, body mass index, smoking, alcohol use, physical activity, medications, prior fracture, and study site, CRP was associated inversely with each composite strength index (0.035–0.041 SD decrement per doubling of CRP, all p< 0.001), but not associated with femoral neck or lumbar spine BMD. During the follow-up, 194 women (10.4%) had fractures. In Cox proportional hazards analyses, fracture hazard increased linearly with loge(CRP), only for CRP levels ≥ 3 mg/L. Addition of femoral neck or lumbar spine BMD to the model did not attenuate the CRP-fracture association. However, addition of any of the composite strength indices attenuated the CRP-fracture association and made it statistically nonsignificant. We conclude that fracture risk increases with increasing CRP, only above the threshold of 3 mg/L. Unlike BMD, composite strength indices are inversely related to CRP levels, and partially explain the increased fracture risk associated with inflammation.
PMCID: PMC3880424  PMID: 23456822
7.  Physical Activity as Determinant of Femoral Neck Strength Relative to Load in Adult Women: Findings from the Hip Strength Across the Menopause Transition Study 
Our objective was to examine the associations of physical activity in different life domains with peak femoral neck strength relative to load in adult women. Composite indices of femoral neck strength integrate body size with femoral neck size and bone mineral density to gauge bone strength relative to load during a fall, and are inversely associated with incident fracture risk.
Participants were 1919 pre- and early perimenopausal women from the Study of Women’s Health Across the Nation. Composite indices of femoral neck strength relative to load in three failure modes (compression, bending, and impact) were created from hip DXA scans and body size. Usual physical activity within the past year was assessed with the Kaiser Physical Activity Survey in four domains: sport, home, active living, and work. We used multiple linear regression to examine the associations.
Greater physical activity in each of the four domains was independently associated with higher composite indices, adjusted for age, menopausal transition stage, race/ethnicity, SWAN study site, smoking status, smoking pack-years, alcohol consumption level, current use of supplementary calcium, current use of supplementary vitamin D, current use of bone-adverse medications, prior use of any sex steroid hormone pills or patch, prior use of depo-provera injections, history of hyperthyroidism, history of previous adult fracture, and employment status: standardized effect sizes ranged from 0.04 (p<0.05) to 0.20 (p<0.0001).
Physical activity in each domain examined was associated with higher peak femoral neck strength relative to load in pre- and early perimenopausal women.
PMCID: PMC3877714  PMID: 23812598
Physical Activity; Peak Bone Strength; Composite Strength Indices; Femoral Neck Strength Relative to Load; Active Living
8.  Bone resorption and fracture across the menopausal transition: the Study of Women’s Health Across the Nation 
Menopause (New York, N.Y.)  2012;19(11):1200-1207.
Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women.
Women attended up to nine clinic visits for an average of 7.6 ± 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs.
Women who fractured (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.55; 95% CI, 1.32–1.73). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.45; 95% CI, 1.04–2.23). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61–6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08–2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD.
A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.
PMCID: PMC3483443  PMID: 22850443
Bone resorption; Fracture; Menopause; Osteoporosis; Bone mineral density
9.  Socioeconomic status over the life-course and adult bone mineral density: The Midlife in the U.S. Study 
Bone  2012;51(1):107-113.
Adult bone mass depends on acquisition in childhood and decline in adulthood, and may be influenced by socioeconomic conditions over the entire life course.
We examined associations of bone mineral density (BMD) in adulthood with life course socioeconomic status in 729 participants in the Midlife in the United States Biomarker Project, adjusting for age, menopausal transition stage, race, gender, body weight, smoking, physical activity in several life stages, and research site. Primary predictors were a) childhood socioeconomic advantage score (including parental education, self-rated financial status relative to others, not being on welfare), b) adult education level (no college vs. some college vs. college graduate), and c) adult current financial advantage score (including family-adjusted poverty to income ratio, self-assessed current financial situation, having enough money to meet needs, ease in paying bills).
Mean age was 56.9 (range 34–85) years. After adjustment for covariates, childhood socioeconomic advantage and adult education level were positively associated with lumbar spine BMD: 0.27 standard deviations (SD) higher at 90th compared to 10th percentile of childhood advantage score (P = 0.009), and 0.24 SD higher in college graduates compared to participants without college education (P = 0.01). Adult current financial advantage was not associated with lumbar spine BMD. None of the three socioeconomic indicators was significantly associated with femoral neck BMD.
Childhood socioeconomic advantage and adult education level were associated with higher adult lumbar spine BMD. Current financial advantage was not associated with BMD. Childhood socioeconomic factors may influence acquisition of lumbar BMD.
PMCID: PMC3371160  PMID: 22543227
bone mineral density; socioeconomic status; poverty; education; income
10.  Breast Tenderness and Breast Cancer Risk in the Estrogen plus Progestin and Estrogen-Alone Women’s Health Initiative Clinical Trials 
The associations between breast tenderness during use of conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) therapy and subsequent breast cancer risk are unknown.
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin (N = 16,608, 5.6 years intervention) and Estrogen-Alone (N = 10,739, 6.8 years intervention) clinical trials until trial close-out (Spring 2005). At baseline and annually, participants underwent mammography and clinical breast exam. Self-reported breast tenderness was assessed at baseline and 12 months. Invasive breast cancer was confirmed by medical record review.
The risk of new-onset breast tenderness after 12 months was significantly higher among women assigned to active therapy than placebo (CEE alone vs. placebo risk ratio [RR] 2.15, 95% confidence interval [CI] 1.97–2.35; CEE + MPA vs. placebo RR 3.07, 95% CI 2.85–3.30). CEE + MPA doubled the risk of invasive breast cancer among women with baseline breast tenderness (hazard ratio [HR] 2.16, 95% CI 1.29–3.74), but had a smaller effect among women without baseline breast tenderness (HR 1.17; 95%CI 0.97–1.41). New-onset breast tenderness was associated with a higher risk of breast cancer among women assigned to CEE + MPA (HR 1.33, 95% CI 1.02–1.72, P=0.03), but not among women assigned to CEE alone (HR 0.98, 95% CI 0.62–1.53).
New-onset breast tenderness during use of CEE + MPA was associated with increased subsequent breast cancer risk. The association of CEE + MPA therapy with increased breast cancer risk was especially pronounced among women with baseline breast tenderness.
PMCID: PMC3697872  PMID: 22042371
breast tenderness; breast cancer; menopausal hormone therapy; conjugated equine estrogens; medroxyprogesterone acetate
11.  Breast Tenderness after Initiation of Conjugated Equine Estrogens and Mammographic Density Change 
We examined the association between new-onset breast tenderness and change in mammographic density after initiation of conjugated equine estrogens (CEE).
We analyzed baseline, year 1, and year 2 data from 695 participants of the Women's Health Initiative Estrogen + Progestin (daily CEE 0.625 mg + medroxyprogesterone acetate 2.5 mg [MPA] or placebo) and Estrogen-Alone (CEE 0.625 mg or placebo) trials who participated in the Mammogram Density Ancillary Study. Using multivariable repeated measures models, we analyzed the association between new-onset breast tenderness (i.e. absence of baseline tenderness and presence of tenderness at year 1 follow-up) and change from baseline in percent mammographic density.
Active therapy increased the odds of new-onset breast tenderness (CEE + MPA vs. placebo risk ratio [RR] 3.01, 95% confidence interval [95% CI] 1.96-4.62; CEE vs. placebo RR 1.70, 95% CI 1.14-2.53). Among women assigned to CEE + MPA, mean increase in mammographic density was greater among participants reporting new-onset of breast tenderness than among participants without new-onset breast tenderness (11.3% vs. 3.9% at year 1, 9.4% vs. 3.2% at year 2, P < 0.001). Among women assigned to CEE alone, increase in mammographic density at year 1 follow-up was not significantly different in women with new-onset breast tenderness compared to women without new-onset breast tenderness (2.4% vs. 0.6% at year 1, 2.2% vs. 1.0% at year 2, P = 0.30).
The new-onset of breast tenderness after initiation of CEE + MPA, but not CEE alone, is associated with greater increases in mammographic density.
PMCID: PMC3685488  PMID: 21979747
Mammographic density; breast density; breast tenderness; mastalgia; mastodynia; conjugated equine estrogen; medroxyprogesterone acetate
12.  New-onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk 
Archives of internal medicine  2009;169(18):1684-1691.
The use of estrogen plus progestin therapy increases both breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain.
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin Clinical Trial, which randomized postmenopausal women with an intact uterus to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily (CEE + MPA, N=8506) or placebo (N=8102). At baseline and annually, participants underwent mammography and clinical breast exam. Self-report of breast tenderness was assessed at baseline and 12 months. Invasive breast cancer incidence was confirmed by medical record review (mean 5.6 years of follow-up).
Among women without baseline breast tenderness (N=14538), significantly more women assigned to CEE + MPA than placebo experienced new-onset breast tenderness after 12 months (36.1% vs. 11.8%, P<0.001). Among women in the CEE + MPA group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared to those without new-onset breast tenderness (Hazard Ratio 1.48, 95% confidence interval 1.08–2.03, P=0.02). Among women in the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness.
New-onset breast tenderness during use of CEE + MPA was associated with increased breast cancer risk. The sensitivity and specificity for the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model.
PMCID: PMC3670683  PMID: 19822825
13.  Socioeconomic Status, Race, and Bone Turnover in the Midlife in the U.S. Study 
Osteoporosis International  2011;23(5):1503-1512.
To determine socioeconomic status (SES) and race differences in levels of bone turnover.
Using data from the Biomarker Substudy of the Midlife in the U.S. (MIDUS) study (491 men, 449 women), we examined cross-sectional associations of SES and race with serum levels of bone turnover markers (bone-specific alkaline phosphatase [BSAP], procollagen type I N-terminal propeptide [PINP], and N-telopeptide [Ntx]) separately in men and women. Linear multivariable regression was used to control for body weight, menopausal transition stage, and age.
Among men, low family poverty-to-income ratio (FPIR) was associated with higher turnover, but neither education nor race was associated with turnover. Men with FPIR <3 had 1.808 nM BCE higher Ntx (P = 0.05), 3.366 U/L higher BSAP (P = 0.02), and 7.066 higher PINP (P = 0.02). Among women, neither education nor FPIR was associated with bone turnover, but Black women had 3.688 nM BCE higher Ntx (P = 0.001), 5.267 U/L higher BSAP (P=0.005), and 11.906 μg/L higher PINP (P=0.008) compared to non-Black women.
Economic adversity was associated with higher bone turnover in men, and minority race status was associated with higher bone turnover in women, consistent with the hypothesis that higher levels of social stresses cause increased bone turnover. The magnitude of these associations was comparable to the effects of some osteoporosis medications on levels of turnover.
PMCID: PMC3257365  PMID: 21811862
bone turnover; bone resorption; socioeconomic status; SES; N-telopeptide; bone-specific alkaline phosphatase; procollagen type I N-terminal propeptide; poverty; income; Ntx; PINP; BSAP
14.  Vasomotor Symptoms and Lipid Profiles in Women Transitioning Through Menopause 
Obstetrics and Gynecology  2012;119(4):753-761.
To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol (E2) and follicle-stimulating hormone (FSH).
Study of Women’s Health Across the Nation participants (N=3201), aged 42–52 at entry, completed interviews on frequency of hot flushes and night sweats (none, 1–5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoproteinA-1, apolipoprotein B [apoB], lipoprotein(a), trigycerides, serum E2, FSH) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones.
Compared to no flushes, experiencing hot flushes was associated with significantly higher LDL [1–5 days: beta (β) (standard error (SE)) =1.48(.47), p<0.01; 6 days or more: β(SE)=2.13(.62), p<.001], HDL [1–5 days: β(SE)=.30(.18),; 6 days or more: β(SE)=.77(.24), p<.01], apolipoproteinA-1 [1–5 days: β(SE)=.92(.47), p<.10; 6 days or more: β(SE)=1.97(.62), p<.01], apolipoproteinB [1–5 days: β(SE)=1.41(.41), p<.001; 6 days or more: β(SE)=2.51(.54), p<.001], and triglycerides [1–5 days: percent change(95%CI)=2.91(1.41–4.43), p<.001; 6 days or more: percent change(95%CI)=5.90(3.86–7.97), p<.001] in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences between hot flashes 6 days or more compared with no days ranged from less than 1 (HDL) to 10 mg/dL (triglycerides). Night sweats were similar. Associations were strongest for lean women.
Vasomotor symptoms were associated with higher LDL, HDL, apolipoproteinA-1, apolipoproteinB, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk.
PMCID: PMC3343636  PMID: 22433339
15.  Bone Mineral Density Loss in Relation to the Final Menstrual Period in a Multi-ethic Cohort: Results from the Study of Women’s Health Across the Nation (SWAN) 
The objective of this study was to describe: the time of onset and offset of bone mineral density (BMD) loss relative to the date of the final menstrual period (FMP); the rate and amount of BMD decline during the 5 years before and the 5 years after the FMP; and the independent associations between age at final menstrual period (FMP), body mass index (BMI) and race/ethnicity with rates of BMD loss during this time interval. The sample included 242 African-American, 384 Caucasian, 117 Chinese and 119 Japanese women, pre- or early perimenopausal at baseline, who had experienced their FMP and for whom an FMP date could be determined. Loess-smoothed curves showed that BMD loss began 1 year before the FMP and decelerated (but did not cease) 2 years after the FMP, at both the lumbar spine (LS) and femoral neck (FN) sites. Piece-wise, linear, mixed effects regression models demonstrated that during the 10-year observation period, at each bone site, the rates and cumulative amounts of bone loss were greatest from 1 year before through 2 years after the FMP, termed the transmenopause. Postmenopausal loss rates, those occurring between 2 and 5 years after the FMP, were less than those observed during transmenopause. Cumulative, 10-year LS BMD loss was 10.6%; 7.38% was lost during the transmenopause. Cumulative FN loss was 9.1%; 5.8% was lost during the transmenopause. Greater BMI and African American heritage were related to slower loss rates, while the opposite was true of Japanese and Chinese ancestry.
PMCID: PMC3378821  PMID: 21976317
Menopause; perimenopause; bone mineral density; ethnic differences; longitudinal cohort
16.  History of Socioeconomic Disadvantage and Allostatic Load in Later Life 
There is a growing interest in understanding how the experience of socioeconomic status (SES) adversity across the life course may accumulate to negatively affect the functioning of biological regulatory systems important to functioning and health in later adulthood. The goal of the present analyses was to examine whether greater life course SES adversity experience would be associated with higher scores on a multi-system allostatic load (AL) index of physiological function in adulthood. Data for these analyses are from 1,008 participants (92.2% White) from the Biomarker Substudy of the Study of Midlife in the US (MIDUS). Multiple indicators of SES adversity in childhood (parent educational attainment, welfare status, financial situation) and two points in adulthood (educational attainment, household income, difficulty paying bills, availability of money to meet basic needs, current financial situation) were used to construct SES adversity measures for each life course phase. An AL score was constructed using information on 24 biomarkers from 7 different physiological systems (sympathetic and parasympathetic nervous systems, hypothalamic-pituitary-adrenal axis, cardiovascular, lipid metabolism, glucose metabolism, inflammatory immune activity). Analyses indicate higher AL as a function of greater SES adversity at each phase of, and cumulatively across, the life course. Associations were only moderately attenuated when accounting for a wide array of health status, behavioral and psychosocial factors. Findings suggest that SES adversity experience may cumulate across the life course to have a negative impact on multiple biological systems in adulthood. An important aim of future research is the replication of current findings in this predominantly White sample in more ethnically diverse populations.
PMCID: PMC3264490  PMID: 22115943
socioeconomic status; SES; allostatic load; biomarkers; health inequalities; life course; USA
17.  Are Vasomotor Symptoms Associated with Alterations in Hemostatic and Inflammatory Markers? Findings from the Study of Women’s Health Across the Nation 
Menopause (New York, N.Y.)  2011;18(10):1044-1051.
Emerging research suggests links between menopausal hot flashes and cardiovascular risk. The mechanisms underlying these associations are unclear, due in part to the incomplete understanding of the physiology of hot flashes. We aimed to examine the longitudinal associations between hot flashes/night sweats and both inflammatory and hemostatic markers, controlling for cardiovascular risk factors and estradiol concentrations.
Participants in the Study of Women’s Health Across the Nation (SWAN) (N=3199), a longitudinal cohort study, were ages 42–52 years at cohort entry. Women completed interviews (hot flashes, night sweats: none, 1–5, 6 days in past 2 weeks), physical measures (blood pressure; height; weight), and a blood draw (C-reactive protein, high sensitivity; plasminogen activator inhibitor-1; Factor VIIc, tissue plasminogen activator antigen (tPA-ag); fibrinogen; glucose; serum estradiol) yearly for 8 years. Hot flashes/night sweats were examined in relation to each inflammatory/hemostatic marker in linear mixed models adjusting for demographic factors, cardiovascular risk factors, and medication use, and additionally serum estradiol.
Compared to experiencing no flashes, reporting hot flashes was associated with higher tPA-aglog (hot flashes 1–5 days: % change (95%CI): 3.88(2.22–5.58), p<0.0001; ≥6 days: % change (95%CI): 4.11(1.95–6.32), p<0.001) and higher Factor VIIclog (hot flashes ≥6 days: % change (95%CI): 2.13(0.80–3.47), p<0.01) in multivariable models. Findings persisted after adjusting for estradiol. Findings for night sweats were similar but attenuated with adjustment.
Frequent hot flashes were associated with higher Factor VIIc and tPA-ag. Hemostatic pathways may be relevant to understanding hot flashes physiology and links between hot flashes and cardiovascular risk.
PMCID: PMC3183159  PMID: 21926929
Menopause; vasomotor symptoms; hot flashes; inflammation; coagulation; hemostasis
18.  Genetic polymorphisms and obesity influence estradiol decline during the menopause 
Clinical Endocrinology  2011;74(5):618-623.
Obesity and genetic variation in aromatase and type 1 17-β hydroxysteroid dehydrogenase (HSD) could influence the E2 trajectory of decline during the menopause transition.
Design and participants
E2 trajectories during the menopause transition (phenotype) were identified using 5934 data points acquired annually from 681 women in Study of Women’s Health across the Nation (SWAN), a multiethnic study of the mid-life. E2 trajectories were related to CYP19 and type I 17-βHSD single-nucleotide polymorphisms (SNPs) and obesity.
logE2 trajectories began to decline precipitously 2 years before the final menstrual period (FMP). The trajectory of the logE2 decline varied with genotypes and obesity. logE2 rates of decline were greater in nonobese women than in obese women, P < 0.05. Women with the CYP19rs936306 CT variant had logE2 rate of decline that was 54% as rapid as the rate of decline of women with the TT variant, P < 0.05. logE2 rate of decline in women with the CYP19rs749292 GG variant was two-thirds the rate of logE2 decline in women with the AG variant, P < 0.05. logRates of E2 decline with 17-βHSD SNPs (rs2830, rs592389, and rs615942) varied according to genotype within obesity groups. Within each obesity group, logE2 rate of decline was greater in heterozygous variants and much less in homozygotes (P < 0.05). Obese women with selected CYP19 and 17-β HSD gene variants had remarkably different E2 trajectories around the FMP, resulting in different postmenopausal E2 levels. The rate of the E2 decline and the subsequent postmenopausal E2 levels may be relevant to oestrogen-sensitive chronic diseases including cancers.
PMCID: PMC3357071  PMID: 21198743
19.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
20.  Association of Menopausal Vasomotor Symptoms With Increased Bone Turnover During the Menopausal Transition 
The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage. We analyzed data from 2283 participants of the Study of Women's Health Across the Nation, a longitudinal community-based cohort study of women aged 42 to 52 years at baseline. At baseline and annually through follow-up visit 8, participants provided questionnaire data, urine samples, serum samples, and anthropometric measurements. Using multivariable repeated-measures mixed models, we examined associations between annually assessed VMS frequency and annual NTX measurements. Our results show that mean adjusted NTX was 1.94 nM of bone collagen equivalents (BCE)/mM of creatinine higher among early perimenopausal women with any VMS than among early perimenopausal women with no VMS (p < .0001). Mean adjusted NTX was 2.44 nM BCE/mM of creatinine higher among late perimenopausal women with any VMS than among late perimenopausal women with no VMS (p = .03). Among premenopausal women, VMS frequency was not significantly associated with NTX level. When NTX values among women with frequent VMS (≥6 days in past 2 weeks) were expressed as percentages of NTX values among women without frequent VMS, the differences were 3% for premenopausal women, 9% for early perimenopausal women, 7% for late perimenopausal women, and 4% for postmenopausal women. Adjustment for serum follicle-stimulating hormone (FSH) level greatly reduced the magnitudes of associations between VMS and NTX level. We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179323  PMID: 20878774
21.  Predictors of Breast Discomfort among Women Initiating Menopausal Hormone Therapy 
Menopause (New York, N.Y.)  2010;17(3):462-470.
To study the determinants of breast discomfort among postmenopausal women initiating menopausal hormone therapy (HT).
We analyzed questionnaire, anthropometric, and serum estrone data from the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI), a randomized trial comparing placebo, conjugated equine estrogen (CEE) alone, or CEE with a progestogen (continuous or cyclical medroxyprogesterone acetate or cyclical micronized progesterone) among postmenopausal women. HT users could join PEPI after stopping HT for 2 months. We modeled the relation between smoking, body weight, alcohol consumption, age, quitting HT to join PEPI, physical activity and alpha-tocopherol consumption and new-onset breast discomfort at 12-month follow-up among 662 participants without baseline breast discomfort.
The associations of new-onset breast discomfort with weight and with strenuous exercise varied by treatment assignment. Among women assigned to CEE + progestogen, strenuous exercise was associated with a 49% lower odds of new-onset breast discomfort (OR 0.51, 95% CI 0.29–0.89, P = 0.02), whereas among women assigned to placebo or CEE alone, strenuous exercise was not significantly associated with new-onset breast discomfort. Surprisingly, among women taking CEE alone, each kilogram higher weight was associated with 6% lower odds of new-onset breast discomfort (P=0.04), whereas among women taking placebo, the association was in the opposite direction (P=0.04). Adjustment for estrone level had neglible effects on odds ratios. Alpha-tocopherol intake, age, smoking, and alcohol intake were not significantly associated with new-onset breast discomfort in adjusted analyses.
Strenuous exercise and higher body weight may decrease the odds of new-onset breast discomfort among postmenopausal women initiating HT.
PMCID: PMC2866780  PMID: 20009961
mastodynia; mastalgia; menopausal hormone therapy; estrogen therapy; breast pain
22.  Gains in Body Fat and Vasomotor Symptom Reporting Over the Menopausal Transition 
American Journal of Epidemiology  2009;170(6):766-774.
Although most women report vasomotor symptoms (hot flashes, night sweats) during midlife, their etiology and risk factors are incompletely understood. Body fat is positively associated with vasomotor symptoms cross-sectionally, but the longitudinal relation between changes in body fat and vasomotor symptoms is uncharacterized. The study aim was to examine whether gains in body fat were related to vasomotor symptom reporting over time. Measures of bioelectrical impedance for body fat, reproductive hormones, and reported vasomotor symptoms were assessed annually over 4 years from 2002 to 2006 among 1,659 women aged 47–59 years participating in the Study of Women's Health Across the Nation. Body fat change was examined in relation to vasomotor symptoms by using generalized estimating equations. Body fat gains were associated with greater odds of reporting hot flashes in models adjusted for age, site, race/ethnicity, education, smoking, parity, anxiety, and menopausal status (relative to stable body fat, gain: odds ratio = 1.23, 95% confidence interval: 1.02, 1.48; P = 0.03; loss: odds ratio = 1.07, 95% confidence interval: 0.89, 1.29; P = 0.45). Findings persisted controlling for estradiol, the free estradiol index, or follicle-stimulating hormone concentrations. The relations between body fat changes and night sweats were not statistically significant. Body fat gains are associated with greater hot flash reporting during the menopausal transition.
PMCID: PMC2768523  PMID: 19675142
adipose tissue; adiposity; body composition; body fat distribution; climacteric; hot flashes; menopause
23.  Quality indicators for multiple sclerosis 
Determining whether persons with multiple sclerosis (MS) receive appropriate, comprehensive healthcare requires tools for measuring quality. The objective of this study was to develop quality indicators for the care of persons with MS. We used a modified version of the RAND/UCLA Appropriateness Method in a two-stage process to identify relevant MS care domains and to assess the validity of indicators within high-ranking care domains. Based on a literature review, interviews with persons with MS, and discussions with MS providers, 25 MS symptom domains and 14 general health domains of MS care were identified. A multidisciplinary panel of 15 stakeholders of MS care, including 4 persons with MS, rated these 39 domains in a two-round modified Delphi process. The research team performed an expanded literature review for 26 highly ranked domains to draft 86 MS care indicators. Through another two-round modified Delphi process, a second panel of 18 stakeholders rated these indicators using a nine-point response scale. Indicators with a median rating in the highest tertile were considered valid. Among the most highly rated MS care domains were appropriateness and timeliness of the diagnostic work-up, bladder dysfunction, cognition dysfunction, depression, disease-modifying agent usage, fatigue, integration of care, and spasticity. Of the 86 preliminary indicators, 76 were rated highly enough to meet predetermined thresholds for validity. Following a widely accepted methodology, we developed a comprehensive set of quality indicators for MS care that can be used to assess quality of care and guide the design of interventions to improve care among persons with MS.
PMCID: PMC2921149  PMID: 20562162
health services research; multiple sclerosis; outcome research; quality indicators
24.  Beyond frequency: who is most bothered by vasomotor symptoms? 
Menopause (New York, N.Y.)  2008;15(5):841-847.
Most menopausal women report vasomotor symptoms (hot flashes, night sweats). However, not all women with vasomotor symptoms, including frequent symptoms, are bothered by them. The primary aim was to identify correlates of vasomotor symptom bother beyond symptom frequency.
The Study of Women’s Health Across the Nation participants reporting vasomotor symptoms at annual visit 7 comprised the sample (N = 1,042). Assessments included hot flash and night sweats frequency (number per week) and bother (1, not at all– 4, very much). Negative affect (index of depressive symptoms, anxiety, perceived stress, negative mood), symptom sensitivity, sleep problems, and vasomotor symptom duration (number of years) were examined cross-sectionally in relation to bother in ordinal logistic regression models with symptom frequency and covariates. Hot flashes and night sweats were considered separately.
In multivariable models controlling for hot flash frequency, negative affect (odds ratio [OR] = 1.27, 95% CI: 1.08–1.51), symptom sensitivity (OR = 1.18, 95% CI: 1.03–1.37), sleep problems (OR = 1.38, 95% CI: 1.04–1.85), poorer health (OR = 1.24, 95% CI: 1.03–1.48), duration of hot flashes (OR = 1.14, 95% CI: 1.06–1.23), younger age (OR = 0.94, 95% CI: 0.89–0.99), and African American race (vs white, OR = 1.59, 95% CI: 1.12–2.26) were associated with hot flash bother. After controlling for night sweats frequency and covariates, sleep problems (OR = 1.84, 95% CI: 1.33–2.55) and night sweats duration (OR = 1.10, 95% CI: 1.02–1.20) were associated with night sweats bother.
Beyond frequency, factors associated with bothersome hot flashes include mood, symptom sensitivity, symptom duration, sleep problems, age, and race. Correlates of bothersome night sweats include sleep problems and symptom duration. In addition to reducing frequency, interventions for vasomotor symptoms might consider addressing modifiable factors related to symptom bother.
PMCID: PMC2866103  PMID: 18521049
Vasomotor symptoms; Hot flashes; Hot flushes; Night sweats; Mood; Sleep
25.  Presence of vasomotor symptoms is associated with lower bone mineral density 
Menopause (New York, N.Y.)  2009;16(2):239-246.
To determine whether women with vasomotor symptoms (VMS) have lower bone mineral density (BMD) than women without VMS.
We analyzed data from baseline to annual follow-up visit 5 for 2213 participants in the bone substudy of the Study of Women’s Health Across the Nation. At baseline, women were aged 42 to 52 years, had intact uterus and ≥1 ovary, were not using exogenous hormones, were not pregnant or lactating, and were pre- or early perimenopausal. Menopausal stage and VMS were assessed by annual questionnaire. Menopausal stages were premenopausal, early perimenopausal, late perimenopausal, and postmenopausal. Using repeated measures mixed models, we determined the association between VMS (any vs. none) and BMD (by dual x-ray absorptiometry) within each menopause status category.
After controlling for age, time within each menopausal stage, race/ethnicity, study site, and baseline menopause stage, postmenopausal women with any VMS had lower lumbar (0.008g/cm2 lower, P=0.001) and lower total hip (0.005 g/cm2 lower, P=0.04) BMD than postmenopausal women without VMS. Compared to early perimenopausal women without VMS, early perimenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.0001). Premenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.03), compared to premenopausal women without VMS.
Even in the earliest menopause transition stages, women with VMS had lower BMD than women without VMS. Effects varied by anatomical site, being most evident in postmenopausal women at the lumbar spine and total hip, and among premenopausal and early perimenopausal women at the femoral neck.
PMCID: PMC2695505  PMID: 19002017
Menopause; hot flashes; vasomotor symptoms; bone mineral density

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