Changes in collagen type I C-telopeptide and procollagen type I N-terminal propeptide during the menopause transition.

CONTEXT: Collagen type I C-telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP) are reference bone resorption and formation markers, respectively. OBJECTIVE: To characterize CTX and PINP trajectories across the menopause transition (MT). DESIGN: 18-year longitudinal analysis from the Study of Women's Health Across the Nation. SETTING: Community-based cohort. PARTICIPANTS: 541 women (126 Black, 90 Chinese, 87 Japanese, 238 White) who transitioned from pre- to postmenopause. MAIN OUTCOME MEASURES: CTX and PINP. RESULTS: Multivariable mixed effects regression fit piecewise linear models of CTX or PINP relative to years from final menstrual period (FMP); covariates were race/ethnicity, body mass index (BMI), and age at FMP. In the referent participant (White, 52.46 years at FMP, BMI 27.12 kg/m2), CTX and PINP were stable until 3 years pre- FMP (premenopause). During the MT (3 years before to 3 years after the FMP), CTX and PINP increased 10.3% (p<0.0001) and 7.5% (p<0.0001) per year, respectively; MT-related gains totaled 61.9% for CTX and 45.2% for PINP. Starting 3 years post-FMP (postmenopause), CTX and PINP decreased 3.1% (p<0.0001) and 2.9% (p<0.0001) per year, respectively. Compared to White women, during the MT, Chinese participants had larger gains in CTX (p=0.01), and Japanese women experienced greater increases in CTX (p<0.0001) and PINP (p=0.02). In postmenopause, CTX (p=0.01) and PINP (p=0.01) rose more in Japanese relative to White women. CONCLUSIONS: CTX and PINP are stable in premenopause, increase during the MT, and decrease in postmenopause. During the MT and postmenopause, bone turnover change rates vary by race/ethnicity.

Prediabetes and Fracture Risk Among Midlife Women in the Study of Women's Health Across the Nation.

Importance: Whether prediabetes is associated with fracture is uncertain. Objective: To evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT. Design, Setting, and Participants: This cohort study used data collected between January 6, 1996, and February 28, 2018, in the Study of Women's Health Across the Nation cohort study, an ongoing, US-based, multicenter, longitudinal study of the MT in diverse ambulatory women. The study included 1690 midlife women in premenopause or early perimenopause at study inception (who have since transitioned to postmenopause) who did not have type 2 diabetes before the MT and who did not take bone-beneficial medications before the MT. Start of the MT was defined as the first visit in late perimenopause (or first postmenopausal visit if participants transitioned directly from premenopause or early perimenopause to postmenopause). Mean (SD) follow-up was 12 (6) years. Statistical analysis was conducted from January to May 2022. Exposure: Proportion of visits before the MT that women had prediabetes (fasting glucose, 100-125 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), with values ranging from 0 (prediabetes at no visits) to 1 (prediabetes at all visits). Main Outcomes and Measures: Time to first fracture after the start of the MT, with censoring at first diagnosis of type 2 diabetes, initiation of bone-beneficial medication, or last follow-up. Cox proportional hazards regression was used to examine the association (before and after adjustment for bone mineral density) of prediabetes before the MT with fracture during the MT and after menopause. Results: This analysis included 1690 women (mean [SD] age, 49.7 [3.1] years; 437 Black women [25.9%], 197 Chinese women [11.7%], 215 Japanese women [12.7%], and 841 White women [49.8%]; mean [SD] body mass index [BMI] at the start of the MT, 27.6 [6.6]). A total of 225 women (13.3%) had prediabetes at 1 or more study visits before the MT, and 1465 women (86.7%) did not have prediabetes before the MT. Of the 225 women with prediabetes, 25 (11.1%) sustained a fracture, while 111 of the 1465 women without prediabetes (7.6%) sustained a fracture. After adjustment for age, BMI, and cigarette use at the start of the MT; fracture before the MT; use of bone-detrimental medications; race and ethnicity; and study site, prediabetes before the MT was associated with more subsequent fractures (hazard ratio for fracture with prediabetes at all vs no pre-MT visits, 2.20 [95% CI, 1.11-4.37]; P = .02). This association was essentially unchanged after controlling for BMD at the start of the MT. Conclusions and Relevance: This cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.

Leisure time physical activity and bone mineral density preservation during the menopause transition and postmenopause: a longitudinal cohort analysis from the Study of Women's Health Across the Nation (SWAN).

Background: Whether greater leisure time physical activity (LTPA) is associated with less bone mineral density (BMD) loss during the menopause transition (MT) remains an open question. We hypothesized that: 1) larger increases in LTPA from pre-/early perimenopause (period 1) to late perimenopause/postmenopause (period 2) would be associated with a slower period 2 BMD loss rate; and 2) greater entire-study LTPA levels would be associated with better final absolute BMD (g/cm2). Methods: Data were from of the Study of Women's Health Across the Nation (1996-2017). Exclusions were: bone beneficial medications, inability to identify start of the MT, and extreme BMD change rates. LTPA measures were a validated ordinal scale and number of metabolic equivalents per hour per week (MET hr wk-1) from sport/exercise. Multiply adjusted, linear regression models estimated: 1) BMD decline rate (annualized %) as a function of LTPA change; and 2) final BMD as a function of entire-study LTPA. Findings: Median [p25, p75] MET hr wk-1 were 4.2 [0.9, 10.1] and 4.9 [1.4, 11.2] in periods 1 and 2, respectively; walking was the commonest activity. In adjusted models (N = 875), greater increases in LTPA ordinal score and MET hr wk-1 were statistically significantly associated with a slower decline in femoral neck (FN) BMD. Larger entire-study averages of each LTPA measure were statistically significantly related to better final FN and lumbar spine BMD levels. Interpretation: Findings suggest that LTPA, at modest levels, mitigate MT-related BMD decline and even small increases in intensity, duration or frequency of common activities may lessen bone loss at the population level. Funding: US-NIH.

Dietary Inflammatory Index and Fractures in Midlife Women: Study of Women's Health Across the Nation.

CONTEXT: While evidence suggests that chronic, low-grade inflammation is a risk factor for bone loss and fractures, the potential relation between an inflammatory dietary profile and greater fracture risk is uncertain. OBJECTIVE: We examined whether a more inflammatory diet, consumed during pre- and early perimenopause, is associated with more incident fractures starting in the menopause transition (MT) and continuing into postmenopause. METHODS: Dietary inflammatory potential was quantified using 2 energy-adjusted dietary inflammatory index scores: one for diet only (E-DII), and one for diet plus supplements (E-DII-S). We included 1559 women from the Study of Women's Health Across the Nation, with E-DII and E-DII-S scores from the baseline visit (during pre- or early perimenopausal), and up to 20 years of follow-up. We excluded women using bone-beneficial medications at baseline; subsequent initiators were censored at first use. The associations of E-DII or E-DII-S (each tested as separate exposures) with incident fracture were examined using Cox proportional hazards regression. RESULTS: Adjusted for age, BMI, cigarette use, diabetes, MT stage, race/ethnicity, prior fracture, bone-detrimental medication use, aspirin or nonsteroidal anti-inflammatory drug use, and study site, greater E-DII and E-DII-S (tested separately) were associated with more future fractures. Each SD increment in E-DII and E-DII-S predicted 28% (P = .005) and 21% (P = .02) greater fracture hazard, respectively. Associations were essentially unchanged after controlling for bone mineral density. CONCLUSION: A more pro-inflammatory diet in pre- and early perimenopause is a risk factor for incident fracture. Future studies should consider whether reducing dietary inflammation in midlife diminishes fracture risk.

Sexual functioning among breast cancer survivors and non-cancer controls over 5 years post diagnosis: Pink SWAN.

PURPOSE: To compare sexual functioning from diagnosis to 5 years post diagnosis among breast cancer survivors (BCS) and women without cancer (controls). PATIENTS AND METHODS: Analyses included 118 BCS and 1765 controls from 20 years of the longitudinal Study of Women's Health Across the Nation (SWAN), a multiracial/ethnic cohort of mid-life women assessed approximately annually from 1995 to 2015. Pink SWAN participants reported no cancer at SWAN enrollment and developed (BCS) or did not develop (controls) incident breast cancer after enrollment. Outcomes included: being sexually active or not, intercourse frequency, sexual desire, vaginal dryness, and pain with intercourse. Using longitudinal logistic regression, we compared BCS and controls on prevalence of sexual functioning outcomes with respect to years since diagnosis. In addition, we examined whether menopause transition stage, depressive symptoms, relationship satisfaction, vaginal dryness, or pain with intercourse modified the relation between breast cancer and sexual functioning outcomes. RESULTS: Adjusting for partner status, both BCS and controls reported similar declines over time in being sexually active, sexual intercourse frequency, and sexual desire. Among sexually active women, more BCS than controls consistently reported vaginal dryness with significant differences between 2 and 4 years post-diagnosis, and pain with intercourse, with statistically significant differences between 0.5 years post-diagnosis to 2 years post-diagnosis. Being post-menopausal and reporting depressive symptoms were significant effect modifiers for pain with intercourse with both variables having positive and stronger associations with pain among the controls than among BCS. CONCLUSION: Except for more reporting of vaginal dryness and pain with intercourse among BCS, negative changes in sexual function during mid-life were similar in those with and without breast cancer.

Menopause-Related Changes in Body Composition Are Associated With Subsequent Bone Mineral Density and Fractures: Study of Women's Health Across the Nation.

During the menopause transition (MT), lean mass decreases and fat mass increases. We examined the associations of these body composition changes during the MT (2 years before to 2 years after the final menstrual period) with bone mineral density (BMD) at the end of the MT and fracture after the MT. We included 539 participants from the Study of Women's Health Across the Nation who were not taking bone-beneficial or bone-detrimental medications before or during the MT. Using multivariable linear regression, we assessed the independent associations of % lean mass loss and % fat mass gain during the MT (mutually adjusted) with femoral neck (FN) and lumbar spine (LS) BMD at the end of the MT, adjusted for pre-MT BMD, pre-MT lean and fat mass, race/ethnicity, Study of Women's Health Across the Nation (SWAN) study site, age, and cigarette use. We used Cox proportional hazards regression to quantify the relations of % lean loss and % fat gain during the MT with fracture after the MT. The Cox model was adjusted for the covariates above plus post-MT use of bone-detrimental medications, and censored at the first use of bone-beneficial medications; we further controlled for FN or LS BMD at the end of the MT. Adjusted for covariates, each standard deviation (SD) (6.9%) increment in lean mass loss was associated with 0.010 g/cm2 lower FN BMD (p < 0.0001); each SD (19.9%) increment in fat mass gain was related to 0.026 g/cm2 greater FN (p = 0.009) and LS (p = 0.03) BMD. Each SD increment in lean mass loss and fat mass gain was associated with 63% (p = 0.001) and 28% (p = 0.05) greater fracture hazard after the MT; associations were essentially unchanged by BMD adjustment. MT-related lean mass loss and fat mass gain were associated differentially with BMD; both were independently related to more fractures. Mitigating MT-related body composition changes may reduce fracture risk. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Longitudinal associations of insulin resistance with change in bone mineral density in midlife women.

BACKGROUNDThe effects of insulin resistance on bone mineral density (BMD) are unclear.METHODSIn Study of Women's Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTSThe relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSIONWhen it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDINGThe SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women's Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

Anti-Müllerian hormone levels and breast cancer risk in the study of women's health across the nation.

PURPOSE: The relation of premenopausal anti-Müllerian hormone (AMH) levels with breast cancer risk has been evaluated in a few studies, but primarily in non-Hispanic White women. METHODS: We evaluated the association of AMH levels with breast cancer risk in Study of Women's Health Across the Nation (SWAN), a multi-ethnic cohort of women. At enrollment, participants had an intact uterus and ≥ 1 ovary, and ≥ 1 menstrual period in the last 3 months. AMH at first measurement was assessed in 1,529 pre- or perimenopausal women using a high-sensitivity ELISA assay; values were natural log transformed. Breast cancer diagnoses were assessed at enrollment and subsequent follow-up visits through 2018 (median 6.1 years). RESULTS: In total, 84 women reported an incident breast cancer diagnosis. In multivariable Cox regression models adjusting for age, race and ethnicity, body mass index, and other factors, higher AMH levels were associated with a non-significant increased breast cancer risk. Compared to women in the 1st quartile, the hazard ratio (95% confidence interval) for women in the 4th quartile was 1.77 (0.87-3.60). CONCLUSION: Our results did not suggest a significant association between AMH and breast cancer risk; however, estimates were consistent with prior studies that reported positive associations.

Anti-Mullerian Hormone as Predictor of Future and Ongoing Bone Loss During the Menopause Transition.

The menopause transition in women is a period of significant bone loss, with rapid declines in bone mineral density (BMD) commencing a year before the final menstrual period (FMP). Changes in menstrual bleeding patterns cannot reliably tell us if this rapid bone loss has begun or is imminent. We hypothesized that low circulating levels of anti-Mullerian hormone (AMH), which decline as women approach the FMP, would be associated with future and ongoing rapid bone loss. We used data from The Study of Women's Health Across the Nation, a multisite, multi-ethnic, prospective cohort study of the menopause transition to test this hypothesis. Adjusted for age, body mass index, race/ethnicity, and study site, every 50% decrement in AMH level in premenopause and early perimenopause was associated with 0.14% per year faster decline over the following 3 to 4 years in lumbar spine BMD and 0.11% per year faster decline in femoral neck BMD (p < 0.001 for both). AMH in late perimenopause was not associated with the rate of future BMD decline. AMH was also associated with the magnitude of ongoing bone loss, measured as percent of peak BMD lost by the end of the next 2 to 3 years. Every 50% decrement in AMH level was associated with 0.22% additional loss in spine BMD in premenopause, 0.43% additional loss in early perimenopause, and 0.50% additional loss in late perimenopause (p < 0.001 for all three). If a woman will lose more of her peak BMD than the site-specific least significant change (LSC) at either the lumbar spine or femoral neck by the next 2 to 3 years, then AMH below 100 pg/mL will detect it with sensitivity of 50% in premenopause, 80% in early perimenopause, and 98% in late perimenopause. These findings suggest that AMH measurement can help flag women at the brink of significant bone loss for early intervention. © 2022 American Society for Bone and Mineral Research (ASBMR).

Disparities in Reproductive Aging and Midlife Health between Black and White women: The Study of Women's Health Across the Nation (SWAN).

This paper reviews differences in the experience of the menopause transition and midlife health outcomes between Black and White women who participated in the Study of Women's Health Across the Nation (SWAN), a 25-year, longitudinal, multi-racial/ethnic cohort study. We identify health disparities, i.e., instances in which Black women's outcomes are less favorable than those of White women, and consider whether structural racism may underlie these disparities. Although SWAN did not explicitly assess structural racism, Black women in SWAN grew up during the Jim Crow era in the United States, during which time racism was legally sanctioned. We consider how we might gain insight into structural racism by examining proxy exposures such as socioeconomic characteristics, reports of everyday discrimination, and a range of life stressors, which likely reflect the longstanding, pervasive and persistent inequities that have roots in systemic racism in the US. Thus, this paper reviews the presence, magnitude, and longitudinal patterns of racial disparities observed in SWAN in six areas of women's health - menopause symptoms, sleep, mental health, health related quality of life, cardio-metabolic health, and physical function -and elucidates the contextual factors that are likely influencing these disparities. We review the strengths and weaknesses of SWAN's design and approach to analysis of racial disparities and use this as a springboard to offer recommendations for future cohort studies.

Prediabetes and insulin resistance are associated with lower trabecular bone score (TBS): cross-sectional results from the Study of Women's Health Across the Nation TBS Study.

In pre- and early perimenopausal women, prediabetes (with blood glucose ≥ 110 mg/dL) and greater insulin resistance are associated with worse trabecular bone quality (as assessed by trabecular bone score). PURPOSE: Diabetes mellitus (DM) is associated with lower trabecular bone score (TBS) and fracture; less certain is whether the precursor states of prediabetes and increased insulin resistance are also related to adverse bone outcomes. We examined, in women who do not have DM, the associations of glycemic status (prediabetes vs. normal) and insulin resistance with TBS. METHODS: This was a cross-sectional analysis of baseline data collected from 42- to 52-year-old, pre- and perimenopausal participants in the Study of Women's Health Across the Nation (SWAN) TBS Study. Women with prediabetes were categorized as having either high prediabetes if their fasting glucose was between 110 and 125 mg/dL or low prediabetes if their fasting glucose was between 100 and 109 mg/dL. Normoglycemia was defined as a fasting glucose below 100 mg/dL. RESULTS: In multivariable linear regression, adjusted for age, race/ethnicity, menopause transition stage, cigarette use, calcium and vitamin D supplementation, lumbar spine bone mineral density, and study site, women with high prediabetes had 0.21 (p < 0.0001) standard deviations (SD) lower TBS than those with normoglycemia. Low prediabetes was not associated with lower TBS. When HOMA-IR levels were ≥ 1.62, each doubling of HOMA-IR was associated with a 0.11 SD decrement in TBS (p = 0.0001). CONCLUSION: Similar to diabetics, high prediabetics have lower TBS than normoglycemic individuals. Women with greater insulin resistance have lower TBS even in the absence of DM. Future studies should examine the associations of high prediabetes and insulin resistance with incident fracture.

Associations of Age at Menopause With Postmenopausal Bone Mineral Density and Fracture Risk in Women.

CONTEXT: Menopause before age 45 is a risk factor for fractures, but menopause occurs at age ≥45 in ~90% of women. OBJECTIVE: To determine, in women with menopause at age ≥45, whether (1) years since the final menstrual period (FMP) is more strongly associated with postmenopausal bone mineral density (BMD) than chronological age and (2) lower age at FMP is related to more fractures. DESIGN AND SETTING: The Study of Women's Health Across the Nation, a longitudinal cohort study of the menopause transition (MT). PARTICIPANTS: A diverse cohort of ambulatory women (pre- or early perimenopausal at baseline, with 15 near-annual follow-up assessments). MAIN OUTCOME MEASURES: Postmenopausal lumbar spine (LS) or femoral neck (FN) BMD (n = 1038) and time to fracture (n = 1554). RESULTS: Adjusted for age, body mass index (BMI), cigarette use, alcohol intake, baseline LS or FN BMD, baseline MT stage, and study site using multivariable linear regression, each additional year after the FMP was associated with 0.006 g/cm2 (P < 0.0001) and 0.004 g/cm2 (P < 0.0001) lower postmenopausal LS and FN BMD, respectively. Age was not related to FN BMD independent of years since FMP. In Cox proportional hazards regression, accounting for race/ethnicity, BMI, cigarette use, alcohol intake, prior fracture, diabetes status, exposure to bone-modifying medications/supplements, and study site, the hazard for incident fracture was 5% greater for each 1-year decrement in age at FMP (P = 0.02). CONCLUSIONS: Years since the FMP is more strongly associated with postmenopausal BMD than chronological age, and earlier menopause is associated with more fractures.

Changes in Regional Fat Distribution and Anthropometric Measures Across the Menopause Transition.

CONTEXT: The relation between the menopause transition (MT) and changes in regional fat distribution is uncertain. OBJECTIVE: To determine whether the MT is associated with the development of central adiposity. DESIGN: Longitudinal analysis from the Study of Women's Health Across the Nation, spanning 1996-2013 (median follow-up 11.8 years). SETTING: Community-based. PARTICIPANTS: 380 women with regional body composition measures by dual energy X-ray absorptiometry. Mean baseline age was 45.7 years; racial/ethnic composition was 16% Black, 41% Japanese and 43% White. OUTCOMES: Changes in android, gynoid and visceral fat and waist and hip circumferences. RESULTS: Android fat increased by 1.21% per year (py) and 5.54% py during premenopause and the MT, respectively (each P < 0.05). Visceral and gynoid fat began increasing at the MT, annualized changes were 6.24% and 2.03%, respectively (each P < 0.05). Postmenopausal annual trajectories decelerated to 1.47% (visceral), 0.90% (android), and -0.87% (gynoid), (all non-zero, P < 0.05). Waist girth grew during premenopause (0.55% py), the MT (0.96% py), and postmenopause (0.55% py) (all non-zero, P < 0.05; not statistically different from each other). Hip girth grew during premenopause (0.20% py) and the MT (0.35% py) (each non-zero, P < 0.05; not statistically different from each other) and decelerated to zero slope in postmenopause. Results are for the White referent; there were statistically significant differences in some trajectories in Black and Japanese women. CONCLUSIONS: The MT is associated with the development of central adiposity. Waist or hip circumferences are less sensitive to changes in fat distribution.

Race/ethnic difference in trabecular bone score in midlife women: The Study of Women's Health Across the Nation (SWAN).

There was no difference in Trabecular Bone Score (TBS) comparing White and Black women after adjusting for body mass index (BMI) and diabetes status. Japanese women had lower TBS than White women. Our results diverge from established differences in fracture rates by race/ethnicity. INTRODUCTION: The TBS was developed as an indirect measure of vertebral bone microarchitecture derived from texture analysis of lumbar spine DXA scans. There is little information on race/ethnic differences in TBS. METHODS: We compared TBS in 656 White, 492 Black, and 268 Japanese pre- and early perimenopausal women. We used a beta version of TBS that accounts for tissue thickness using DXA measured soft tissue thickness rather than BMI. The relation between BMI and tissue thickness corrected TBS differed by BMI; we used a three-segment linear spline to adjust for BMI. RESULTS: The women were, on average, 46.5 years of age; 50% were premenopausal. In BMI and diabetes adjusted models, there was no difference in TBS between White and Black women. TBS was modestly (2%) lower in the Japanese women compared to White women, p = 0.04. In a sensitivity analysis, restricting the analysis to those with BMI 24-31 kg/m2, results were similar. CONCLUSIONS: TBS was similar in Black and White women after accounting for tissue thickness and adjusting for BMI, diabetes, and other covariates. The Japanese women had modestly lower TBS. These results diverge from established race/ethnic differences in fracture rates and areal bone mineral density, underscoring the need for further studies.

Increase in C-Reactive Protein Predicts Increase in Rate of Bone Mineral Density Loss: The Study of Women's Health Across the Nation.

This longitudinal cohort study's aim was to detect whether larger increases in C-reactive protein (CRP) predict greater amounts of subsequent bone loss in women transitioning from premenopause to postmenopause. Participants were initially 42 to 52 years of age and premenopausal or early perimenopausal. The sample included 1431 women who were not using hormone therapy and whose CRP values were not consistent with acute inflammation. Individual fixed effects (IFE) models estimated the association of log2 CRP with subsequent bone mineral density (BMD) decline rate, adjusted for menopause transition (MT) stage (1: premenopausal or early perimenopausal; 2: late perimenopausal or early postmenopausal; or 3: late postmenopausal), body mass index, diabetes, smoking, alcohol, bone active medications, and anti-inflammatory medications. BMD decline at both the lumbar spine (LS) and femoral neck (FN) was faster for observations made in MT stage 2 than that during other stages (all p < .001). In adjusted IFE models, MT stage modified the relation between increase in CRP and BMD decline rate (interaction p values <.05). Each within-woman doubling of CRP was associated with a 0.09% faster yearly decline in FN BMD in MT stages 1 (p = .006) and 3 (p = .03), and 0.10% faster decline in LS BMD in MT stage 3 only (p = .007). Within-woman increases in CRP in premenopause and early perimenopause and in late postmenopause predict faster BMD decline in the next ~2 years, but the magnitude of CRP's effect is small. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Faster Lumbar Spine Bone Loss in Midlife Predicts Subsequent Fracture Independent of Starting Bone Mineral Density.

CONTEXT: Bone mineral density (BMD) decreases rapidly during menopause transition (MT), and continues to decline in postmenopause. OBJECTIVE: This work aims to examine whether faster BMD loss during the combined MT and early postmenopause is associated with incident fracture, independent of starting BMD, before the MT. METHODS: The Study of Women's Health Across the Nation, a longitudinal cohort study, included 451 women, initially premenopausal or early perimenopausal, and those transitioned to postmenopause. Main outcome measures included time to first fracture after early postmenopause. RESULTS: In Cox proportional hazards regression, adjusted for age, body mass index, race/ethnicity, study site, use of vitamin D and calcium supplements, and use of bone-detrimental or -beneficial medications, each SD decrement in lumbar spine (LS) BMD before MT was associated with a 78% increment in fracture hazard (P = .007). Each 1% per year faster decline in LS BMD was related to a 56% greater fracture hazard (P = .04). Rate of LS BMD decline predicted future fracture, independent of starting BMD. Women with a starting LS BMD below the sample median, and an LS BMD decline rate faster than the sample median had a 2.7-fold greater fracture hazard (P = .03). At the femoral neck, neither starting BMD nor rate of BMD decline was associated with fracture. CONCLUSION: At the LS, starting BMD before the MT and rate of decline during the combined MT and early postmenopause are independent risk factors for fracture. Women with a below-median starting LS BMD and a faster-than-median LS BMD decline have the greatest fracture risk.

Lowered progesterone metabolite excretion and a variable LH excretion pattern are associated with vasomotor symptoms but not negative mood in the early perimenopausal transition: Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition. STUDY DESIGN: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy. OUTCOME MEASURES: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C). RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood. CONCLUSION: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

Longitudinal Assessment of Physical Activity and Cognitive Outcomes Among Women at Midlife.

Importance: The increasing prevalence of cognitive decline, impairment, and dementia spurs intense interest in cognitive preservation strategies. Objective: To explore the longitudinal association between physical activity (PA) and cognitive performance among women at midlife. Design, Setting, and Participants: This cohort study is an analysis from the Study of Women's Health Across the Nation. Enrollment occurred from 1996 through 1997, and follow-up extended into 2017. Included individuals were those who had undergone cognitive measures during the first 3 cognitive test visits and had at least 1 additional cognitive measurement. Stroke prior to baseline was an exclusion, and observations were censored for subsequent stroke. Data were analyzed from June 2018 through August 2019. Exposures: Engaging in sport or exercise PA (self-reported). Main Outcomes and Measures: The Symbol Digit Modalities Test (SDMT) was used to assess cognitive processing speed. The East Boston Memory Test-Delayed (EBMT-D) was used to measure verbal episodic memory. The digit span backwards (DSB) test was used to evaluate working memory. Results: Among 1718 women with a median (range) observation time of 11.9 (0.60-13.5) years, the mean (SD) baseline age was 45.7 (2.5) years. From baseline through age 61 years, mean change in SDMT score was -0.20 annually (95% CI, -0.26 to -0.15; P < .001). After age 61 years, the mean change in SDMT was -0.51 yearly (95% CI, -0.54 to -0.41; P < .001). Beginning at age 58 years of the mean change in EBMT was -0.03 yearly (95% CI, -0.04 to -0.02; P < .001). Starting at age 61 years, mean (SD) change in DSB was -0.03 annually (95% CI, -0.04 to -0.01; P = .001). When adjusted for attrition and practice effect, PA was associated with higher concurrent SDMT and EBMT scores and a smaller decrease in SDMT score. For each unit increment in PA, there was a 0.36 increment in concurrent SDMT score (95% CI, 0.14 to 0.59; P = .002) and a 0.10 increment in concurrent EBMT score (95% CI, 0.05 to 0.15; P < .001). Greater PA was associated with a smaller annual mean decrease in SDMT score (0.06 yearly; 95% CI, 0.02 to 0.09; P = .001). After additional adjustment for demographic characteristics, menopause symptoms, hormone therapy use, and the presence of diabetes and hypertension, PA was not associated with trajectories (ie, levels or slopes) of any cognitive outcome. Conclusions and Relevance: This cohort study found no association between greater PA levels and cognitive outcomes among women in midlife, unlike cohort studies that begin observations at later ages, which may be associated with confounding by reverse causation (ie, cognitive decline associated with an outcome of lower PA levels).

Hormones and bone loss across the menopause transition.

The menopause transition is a critical period for bone health in women, with rapid losses in bone mass and strength occurring over an approximately 3-year window bracketing the date of the final menstrual period. The onset of the rapid bone loss phase is preceded by large changes in sex steroid hormones, measurements of which may be clinically useful in predicting the onset of the rapid loss phase and identifying the women who will lose the most bone mass during this rapid bone loss phase. Here we summarize recent and new findings related to the ability of sex hormone levels to (1) determine if a woman in her 5th decade of life is about to enter or has already entered the rapid phase of bone loss, and (2) if she will lose more than the average amount of bone mass over the menopause transition.