Low-density lipoprotein subclasses over the menopausal transition and risk of coronary calcification and carotid atherosclerosis: the SWAN Heart and HDL ancillary studies.

OBJECTIVE: Perimenopausal women experience a steep increase in low-density lipoprotein cholesterol (LDL-C) that is related to a higher risk of carotid plaque later in life. Low-density lipoprotein subclasses have been linked to cardiovascular diseases beyond LDL-C, promising a better risk stratification. We aim to characterize changes in LDL subclasses and assess their associations with presence of coronary artery calcium (CAC score ≥10) and carotid intima-media thickness (cIMT) over the menopausal transition (MT) and by menopause stage. METHODS: Nuclear magnetic resonance spectroscopy LDL subclasses were measured for a maximum of five time points. Coronary artery calcification and cIMT were measured for a maximum of two time points. LOESS (locally weighted regression with scatter smoothing) plots, linear mixed-effects models, and generalized estimating equations were used for analyses. RESULTS: The study included 471 women (baseline: age, 50.2 ± 2.7 years; 79.0% premenopausal/early perimenopausal), of whom 221 had data on CAC or cIMT. Low-density lipoprotein subclasses increased over the MT, whereas intermediate density-lipoprotein particles declined. In adjusted models, higher total LDL particles (LDL-P) and apolipoprotein B were associated with greater CAC prevalence and greater cIMT. Although none of the associations were modified by menopause stage, higher LDL-C, apolipoprotein B, and total LDL-P were associated with greater cIMT during the perimenopause or postmenopause stages, whereas higher LDL-C and small LDL-P were associated with greater CAC prevalence, mainly during perimenopause. CONCLUSIONS: During the MT, women experience significant increases in LDL subclasses found to be related to greater cIMT levels and CAC prevalence. Whether these changes could better predict future risk of hard cardiovascular disease events beyond LDL-C remains a research question to address.

Lipoprotein subfractions and subclinical vascular health in middle aged women: does menopause status matter?

OBJECTIVE: During midlife, women experience changes in lipoprotein profiles and deterioration in vascular health measures. We analyzed the associations of groups of lipoprotein subfractions as determined by principal component analysis (PCA) with subclinical vascular health measures in midlife women and tested if these associations were modified by menopause status. METHODS: PCA was used to generate principal components (PCs) from 12 lipoprotein subfractions quantified among 545 midlife women. The associations of the identified PCs and concurrent vascular health measures were assessed using linear or logistic regressions among participants with carotid intima-media thickness (cIMT; n = 259), coronary artery calcium (n = 249), or aortic calcium (n = 248) scores. RESULTS: PCA generated four PCs representing groups of (1) small, medium, and large very low-density lipoproteins subclasses-very low-density lipoprotein PC; (2) very small, small, and medium low-density lipoprotein (LDL) subclasses-small-medium LDL-PC; (3) large and small high-density lipoproteins subclasses and midzone particles-high-density lipoprotein PC; and (4) large LDL and small intermediate-density lipoproteins-large LDL-PC. Small-medium LDL-PC was positively associated with cIMT, coronary artery calcium, and aortic calcium in unadjusted but not in adjusted models. Menopause status modified the positive association of the small-medium LDL-PC with cIMT (interaction P = 0.02) such that this association was stronger after versus before menopause ( P = 0.01). CONCLUSIONS: Carotid intimal medial thickening is positively and independently associated with small- and medium-sized LDL particles after menopause. Monitoring levels of specific lipoprotein fractions may have value in identifying midlife women at risk for developing atherosclerotic vascular disease.

Patterns of menstrual cycle length over the menopause transition are associated with subclinical atherosclerosis after menopause.

OBJECTIVE: Longer menstrual cycles have been associated with greater risk of cardiovascular disease, supporting a contribution of abnormal ovarian function. We aimed to characterize trajectories of menstrual cycle length over the menopause transition (MT) and test whether these trajectories are associated with postmenopausal markers of subclinical atherosclerosis. METHODS: Women from the Study of Women's Health Across the Nation Daily Hormone Study were included if they had an observed date of the final menstrual period (FMP), recorded cycle lengths from ≥2 annual menstrual cycles (mean±SD: 4.22 ± 1.91 cycles), and had measurements of postmenopausal carotid intima-media thickness (cIMT) and/or brachial-ankle pulse wave velocity (baPWV). Trajectories of cycle length over the MT were identified using group-based trajectory modeling and linked with cIMT and baPWV using linear regression. RESULTS: We studied 428 women who had 1,808 cycles over the MT (45.1 ± 2.3 y old at baseline visit), and of whom 263 had cIMT, and 213 had baPWV measured postmenopausally (after 13.88 ±â€Š0.42 and 15.25 ±â€Š0.70 y since baseline visit, respectively). Three distinct trajectories of cycle length were identified: stable (no changes in cycle length over the MT among 62.1% of women), late increase (a late increase 2 y before the FMP among 21.8%), and early-increase (an early increase 5 y before the FMP among 16.2%). Women with the late-increase pattern had significantly lower postmenopausal cIMT (0.72 mm) and baPWV (1392 cm/s) levels than the stable group (0.77 mm and 1508 cm/s, respectively) adjusting for race, concurrent age, socioeconomic status, physical activity level, and premenopausal cardiovascular risk profile. CONCLUSIONS: Patterns of cycle length over the MT seem to be a marker of future vascular health that may help identify groups at greater or lesser risk of atherosclerosis after menopause.

HDL (High-Density Lipoprotein) Subclasses, Lipid Content, and Function Trajectories Across the Menopause Transition: SWAN-HDL Study.

OBJECTIVE: The cardioprotective capacity of HDL (high-density lipoprotein) cholesterol postmenopause has been challenged. HDL subclasses, lipid contents, and function might be better predictors of cardiovascular risk than HDL cholesterol. Changes in these measures have not been characterized over the menopause transition (MT) with respect to timing relative to the final menstrual period. Approach and Results: Four hundred seventy-one women with HDL particle (HDL-P) subclasses (nuclear magnetic resonance spectroscopy total, large, medium, and small HDL-P and HDL size), HDL lipid content (HDL phospholipids and triglycerides), and HDL function (cholesterol efflux capacity [HDL-CEC]) measured for a maximum of 5 time points across the MT were included. HDL cholesterol and total HDL-P increased across the MT. Within the 1 to 2 years bracketing the final menstrual period, large HDL-P and HDL size declined while small HDL-P and HDL-triglyceride increased. Although overall HDL-CEC increased across the MT, HDL-CEC per HDL-P declined. Higher concentrations of total, large, and medium HDL-P and greater HDL size were associated with greater HDL-CEC while of small HDL-P were associated with lower HDL-CEC. Associations of large HDL-P and HDL size with HDL-CEC varied significantly across the MT such that higher large HDL-P concentrations and greater HDL size were associated with lower HDL-CEC within the 1 to 2 years around the final menstrual period. CONCLUSIONS: Although HDL cholesterol increased over the MT, HDL subclasses and lipid content showed adverse changes. While overall HDL-CEC increased, HDL-CEC per HDL-P declined, consistent with reduced function per particle. Large HDL-P may become less efficient in promoting HDL-CEC during the MT.

Identifying women who share patterns of reproductive hormones, vasomotor symptoms, and sleep maintenance problems across the menopause transition: group-based multi-trajectory modeling in the Study of Women's Health Across the Nation.

OBJECTIVE: To identify groups of women who share levels and patterns of change in follicle-stimulating hormone (FSH), self-reported sleep maintenance problems, and frequent vasomotor symptoms (VMS) up to 10 years before and after their final menstrual period and to evaluate their premenopausal characteristics. METHOD: Group-based multi-trajectory modeling grouped 1,407 women from the Study of Women's Health Across the Nation who had an observed natural menopause and did not use hormone therapy, based on repeated measures of FSH, sleep maintenance problems, and frequent VMS relative to final menstrual period. Multivariable analyses assessed race/ethnicity, body mass index, smoking, and depressive symptoms as predictors of group membership. RESULTS: Women formed five distinct groups: (1) low symptoms (low VMS/sleep problems)/high FSH rise (N = 552; 39.2%); (2) moderate VMS and sleep problems/low FSH rise (N = 169; 12.0%); (3) dominant sleep problems (lower VMS/high sleep problems)/high FSH rise (N = 203; 14.4%); (4) dominant VMS (high VMS/lower sleep problems)/high FSH rise (N = 297; 21.1%)); and (5) high symptoms (high VMS/high sleep problems)/intermediate FSH rise (N = 186; 13.2%)). Multivariate analyses showed that race/ethnicity, premenopausal body mass index and depressive symptoms, and increasing depressive symptoms during the early phase of the transition predicted group membership. CONCLUSIONS: Women can be classified based on shared levels and patterns of FSH, sleep maintenance problems, and frequent VMS across the menopause transition. Either VMS or sleep maintenance problems can be dominant in the face of high FSH. Experiencing one menopause-related symptom or hormone profile does not automatically imply that another is also being experienced.

Daily luteal serum and urinary hormone profiles in the menopause transition: Study of Women's Health Across the Nation.

OBJECTIVE: To further characterize the endocrinology of the menopause transition, we sought to determine: whether relationships between urine and serum hormones are maintained as women enter their sixth decade; whether a single luteal phase serum progesterone (P) is reflective of integrated-luteal urinary pregnanediol glucuronide (uPdg); and whether serum P, like luteal uPdg, declines as women approach their final menses (FMP). METHODS: The Study of Women's Health Across the Nation (SWAN) Daily Hormone Study's (DHS) is a community-based observational study. A subset of participants underwent a timed, luteal blood draw planned for cycle days 16 to 24 during the same month of DHS collection. Serum-luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and P, and urine LH, FSH, estrone conjugates (E1c), and daily and integrated luteal uPdg were measured in 268 samples from 170 women. Serum/urine hormone associations were determined using Pearson's correlation and linear regression, adjusted for concurrent age, body mass index, smoking status, and race/ethnicity. RESULTS: Pearson's r ranged from 0.573 (for LH) to 0.843 (for FSH) for serum/urine correlations. Integrated luteal uPdg weakly correlated with serum P (Pearson's r = 0.26, P = 0.004) and explained 7% of the variability in serum P in adjusted linear regression (total R 0.09, P = 0.002). Serum P demonstrated a marginally significant decline with approaching FMP in adjusted analysis (P = 0.04). CONCLUSIONS: Urine and serum hormones maintain a close relationship in women into their sixth decade of life. Serum luteal P was weakly reflective of luteal Pdg excretion.

The menopause transition and women's health at midlife: a progress report from the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: Our initial understanding of the menopause transition (MT) has been framed by clinical samples of women seeking treatment rather than by population-based studies. The Study of Women's Health Across the Nation (SWAN) initiated in 1996 with an overall goal to define the MT, to characterize its biological and psychosocial antecedents and sequelae in an ethnically and racially diverse sample of midlife women. METHODS: This review summarizes the central findings of SWAN to date that can inform women and their healthcare providers about the impact of the MT and midlife aging on overall health and well-being. RESULTS: SWAN characterized changes in reproductive axis and menstrual cycle patterns that informed the development of the reproductive aging staging system Staging of Reproductive Aging Workshop+10; MT-related symptoms and mental health (vasomotor symptoms, sleep complaints, psychological symptoms, cognitive performance, and urogenital and sexual health); and physiological systems and functions (cardiovascular and cardiometabolic health, bone health, physical function performance) that are influenced by the MT. SWAN demonstrated substantial interrelations among these changes and significant racial/ethnic differences in the rate and magnitude of change in multiple health indictors in midlife women. The findings point to midlife as a critical stage for adopting healthy behavior and preventive strategies. CONCLUSIONS: Over the past 23 years, SWAN has advanced our understanding of the impact of the MT and midlife aging on health and well-being in women. SWAN will be instrumental to determine whether MT-related changes during midlife are related to unfavorable health and well-being in early old age.

Consistent ovulation may not be enough to make women healthy when approaching menopause: an update from the Study of Women's Health Across the Nation.

OBJECTIVE: This study aims to test the hypothesis that consistently ovulatory premenopausal/perimenopausal women have a more favorable cardiometabolic profile than anovulatory women. METHODS: The first four collections from the Study of Women's Health Across the Nation Daily Hormone Study (DHS) were used. DHS enrollees annually completed a daily collection of first morning voided urine for an entire menstrual cycle or up to 50 days (whichever comes first). A woman was categorized as consistently ovulatory annually (COA) if four ovulatory cycles or two to three ovulatory cycles followed by the final menstrual period (FMP) were observed. A woman was categorized as not consistently ovulatory annually (nCOA) if at least one anovulatory year was observed. Cross-sectional and longitudinal differences were compared between COA and nCOA women. Data were centered at FMP and adjusted for age and body mass index (BMI). RESULTS: Six hundred thirty-six DHS participants (mean [SD] age, 47.3 [2.5] y; mean [SD] BMI, 27.4 [7.1] kg/m(2)) were included. Thirty-six percent of the DHS participants were COA women. On the fourth follow-up collection, COA women had lower high-density lipoprotein than nCOA women (mean [95% CI], 55.7 [54.0-57.4] vs 59.5 [57.9-61.0] mg/dL, P = 0.002, respectively), which persisted after adjustment. Among 460 women with FMP, 39% were COA women. COA women were slightly older (52.9 vs 52.0 y, P = 0.002) and had lower BMI (geometric mean, 26.1 vs 27.5 kg/m(2), P = 0.06) than nCOA women at FMP. Other cardiometabolic factors did not significantly differ by COA status through FMP. CONCLUSIONS: Consistent ovulation across the menopausal transition does not seem to reflect superior cardiometabolic health.

Gestational angiogenic biomarker patterns in high risk preeclampsia groups.

OBJECTIVE: Several conditions are associated with increased preeclampsia (PE) risk. Whether altered maternal angiogenic factor levels contribute to risk in these conditions is unknown. Our objective was to compare angiogenic biomarker patterns in high-risk pregnancies and low-risk controls. STUDY DESIGN: We conducted a planned secondary analysis of a 2-center observational study of angiogenic biomarkers in high-risk women. A total of 156 pregnant women with a PE risk factor and 59 low-risk controls were studied. Serial maternal serum samples were collected during 3 gestational windows: 23-27 weeks, 28-31 weeks, and 32-35 weeks. Soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) were measured by enzyme-linked immunosorbent assay. Geometric mean angiogenic biomarker levels and angiogenic ratio (sFlt1 + sEng):PlGF were compared with low-risk controls for each risk group, at each gestational window. RESULTS: Gestational biomarker patterns differed in PE risk groups as compared with low-risk controls. Women with multiple gestations had markedly higher sFlt1 and sEng at all gestational windows. Women with prior PE had higher sFlt1 and angiogenic ratio, and lower PlGF, from 28 weeks onward. Women with chronic hypertension had significantly higher angiogenic ratio for all 3 gestational windows, but differences disappeared when women with PE were excluded. Obese and nulliparous women had significantly lower PlGF, but no differences in the angiogenic ratio. CONCLUSION: High-risk groups have altered angiogenic biomarker patterns compared with controls, suggesting that altered production or metabolism of these factors may contribute to PE risk, particularly in women with multiple gestations and prior PE.