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A prospective study of inflammatory biomarker levels and risk of early menopause.

ABSTRACT: OBJECTIVE:Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated. METHODS:We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, interleukin-6 (IL6) levels with incident early menopause among Nurses' Health Study II participants who provided a premenopausal blood sample in 1996 to 1999. Cases (n?=?328) were women reporting natural menopause between blood collection and age 45.Controls (n?=?492) included (1) 328 women with menopause after age 47, matched 1:1 with cases on age at blood collection and other factors; and (2) 164 additional women with menopause after age 45. RESULTS:In multivariable models comparing cases and n?=?492 controls, we observed a significant association of sTNFR2 levels and risk of early menopause (P?=?0.002). Compared with women with the lowest sTNFR2 levels, odds ratios (95% CIs) for quartiles 2 to 4 were 0.60 (0.38-0.95), 0.93 (0.61-1.43), and 1.40 (0.93-2.11). Results further adjusting for antimüllerian hormone levels were similar in magnitude, as were results from sensitivity analyses of matched cases and controls (n?=?328 pairs), nonsmokers, and leaner women. C-reactive protein and IL6 levels were unrelated to risk. CONCLUSIONS:The observation of lower risk of early menopause among women with moderate sTNFR2 levels compared with women with lower and higher levels warrants further prospective study.

SUBMITTER: Bertone-Johnson ER

PROVIDER: S-EPMC6309942 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A prospective study of inflammatory biomarker levels and risk of early menopause.

Bertone-Johnson Elizabeth R ER Manson JoAnn E JE Purdue-Smithe Alexandra C AC Hankinson Susan E SE Rosner Bernard A BA Whitcomb Brian W BW

Menopause (New York, N.Y.) 20190101 1

<h4>Objective</h4>Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated.<h4>Methods</h4>We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, inter ...[more]

PMID: 29994968

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Project description:STUDY QUESTION:Are anti-Müllerian hormone (AMH) levels assessed in women aged 32-44 associated with risk of incident early natural menopause? SUMMARY ANSWER:We observed strong, significant associations between lower AMH levels and higher risk of early menopause. WHAT IS KNOWN ALREADY:The ability to predict risk early menopause, defined as menopause before age 45, prior to fertility decline would improve options for family planning and cardiovascular disease prevention. Though AMH is an established marker of menopause timing in older reproductive-aged women, whether AMH is associated with risk of early menopause has not been evaluated. STUDY DESIGN, SIZE, DURATION:We assessed these relations in a nested case-control study within the prospective Nurses' Health Study II cohort. Premenopausal blood samples were collected in 1996-1999. Participants were followed until 2011 for early natural menopause, with follow-up rates >94%. PARTICIPANTS/MATERIALS, SETTING, METHODS:Early menopause cases (n = 327) were women reporting natural menopause between blood collection and age 45. Controls (n = 491) experienced menopause after age 45 and included 327 cases matched to controls on the basis of age at blood draw (±4 months) and other factors. AMH levels up to 12 years before early menopause were assayed in 2016. MAIN RESULTS AND THE ROLE OF CHANCE:In multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/ml decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). In polynomial regression models including linear and quadratic terms for AMH, odds ratios for early menopause for women with AMH levels of 1.5, 1.0 and 0.5 ng/ml compared to 2.0 ng/ml were 2.6, 7.5 and 23 (all P < 0.001). Significant associations were observed irrespective of smoking status, adiposity, infertility history and menstrual cycle characteristics. Furthermore, models assessing the predictive ability of AMH showed high concordance, and C-statistics were high, ranging from 0.68 (age ?35) to 0.93 (age 42). LIMITATIONS, REASONS FOR CAUTION:Our population was relatively homogenous with respect to race/ethnicity. Further work in more ethnically diverse populations is needed. WIDE IMPLICATION OF THE FINDINGS:To our knowledge, this is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women. STUDY FUNDING/COMPETING INTEREST(S):This project was supported by UM1CA176726, R01CA67262, and R01HD078517 from the U.S. Department of Health and Human Services, National Institutes of Health. No competing interests declared.

Project description:STUDY QUESTION:Is adult adiposity associated with early menopause? SUMMARY ANSWER:Overall and abdominal adiposity were non-linearly associated with odds for early natural menopause with elevated odds observed among women who were underweight in early or mid-adulthood compared to lean-normal weight women. WHAT IS KNOWN ALREADY:High and low adiposity have been associated with reproductive function and may potentially impact timing of menopause. It is unclear whether various aspects of adiposity are associated with risk of early menopause. STUDY DESIGN, SIZE, DURATION:Prospective cohort study that examined data from 78 759 premenopausal women from the Nurses' Health Study II who were followed from 1989 to 2011 for incidence of early natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS:Participants were aged 25-42 years and premenopausal at baseline in 1989, when information on menopausal status, height and weight was reported via questionnaire. Information on menopausal status, type of menopause (natural, surgical, radiation/chemotherapy), hormone therapy use and weight was updated every two years along with information on smoking, physical activity and other behavioral and health-related factors. Multivariable logistic regression was used to estimate odds ratios for early menopause, defined as natural menopause before age 45 years, by aspects of adiposity. MAIN RESULTS AND THE ROLE OF CHANCE:Early natural menopause was reported by 2804 participants. Body mass index (BMI) was non-linearly associated with risk for early menopause. Compared to women with BMI = 18.5-22.4 kg/m2, those with BMI < 18.5 kg/m2 had a significant 30% higher odds of early menopause (95% confidence interval (CI) = 1.08, 1.57), while women with BMIs between 25.0-29.9 kg/m2 had significant 21-30% lower odds. Odds were not higher in women with BMI ? 35.0 kg/m2 in fully adjusted analysis. Non-linear associations with higher odds in underweight women were also observed for age 18 and age 35 BMI, though lower odds for overweight women was only observed for age 35 BMI. Odds were highest among women with age 18 BMI < 18.5 kg/m2 reporting severe weight cycling. LIMITATIONS, REASONS FOR CAUTION:Though weight and early menopause status were self-reported, validation studies conducted among Nurses' Health Study participants suggest that self-reported weight is highly correlated with directly measured weight, and prospective self-reported menopausal status is highly reproducible. It is possible that underweight women may have been misclassified with an earlier age at menopause if being underweight led to amenorrhea. WIDER IMPLICATIONS OF THE FINDINGS:In one of the few studies to prospectively examine a variety of adiposity measures and risk for early menopause, our findings that women who were underweight in early or mid-adulthood had elevated risk for early menopause can assist in efforts to better understand the etiology of early menopause. Additional prospective research is needed to understand how low adiposity may physiologically impact timing of menopause. STUDY FUNDING/COMPETING INTEREST(S):This study was conducted with funding from NIH UM1CA176726 and R01HD078517. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER:Not applicable.

Project description:Background Low-grade inflammation in the young may contribute to the early development of cardiovascular disease. We assessed whether circulating levels of glycoprotein acetyls (GlycA) were better able to predict the development of adverse cardiovascular disease risk profiles compared with the more commonly used biomarker high-sensitivity CRP (C-reactive protein). Methods and Results A total of 3306 adolescents and young adults from the Avon Longitudinal Study of Parents and Children (mean age, 15.4±0.3; n=1750) and Cardiovascular Risk in Young Finns Study (mean age, 32.1±5.0; n=1556) were included. Baseline associations between inflammatory biomarkers, body composition, cardiovascular risk factors, and subclinical measures of vascular dysfunction were assessed cross-sectionally in both cohorts. Prospective risk of developing hypertension and metabolic syndrome during 9-to-10-year follow-up were also assessed as surrogate markers for future cardiovascular risk. GlycA showed greater within-subject correlation over 9-to-10-year follow-up in both cohorts compared with CRP, particularly in the younger adolescent group (r=0.36 versus 0.07). In multivariable analyses, GlycA was found to associate with multiple lifestyle-related cardiovascular disease risk factors, cardiometabolic risk factor burden, and vascular dysfunction (eg, mean difference in flow-mediated dilation=-1.2 [-1.8, -0.7]% per z-score increase). In contrast, CRP levels appeared predominantly driven by body mass index and showed little relationship to any measured cardiovascular risk factors or phenotypes. In both cohorts, only GlycA predicted future risk of both hypertension (risk ratio [RR], ≈1.1 per z-score increase for both cohorts) and metabolic syndrome (RR, ≈1.2-1.3 per z-score increase for both cohorts) in 9-to-10-year follow-up. Conclusions Low-grade inflammation captured by the novel biomarker GlycA is associated with adverse cardiovascular risk profiles from as early as adolescence and predicts future risk of hypertension and metabolic syndrome in up to 10-year follow-up. GlycA is a stable inflammatory biomarker which may capture distinct sources of inflammation in the young and may provide a more sensitive measure than CRP for detecting early cardiovascular risk.

Project description:BackgroundObesity disproportionately affects more women than men. The loss of ovarian function during the menopause transition coincides with weight gain, increases in abdominal adiposity, and impaired metabolic health. Racial differences in obesity prevalence that results from the menopause transition are not well understood.ObjectiveThe purpose of the study was to assess longitudinal changes in body composition and cardiometabolic risk among black and white women during the menopausal transition.Study designIn a secondary analysis of a prospective, observational cohort study (the Healthy Transitions study), 161 women ≥43 years old with a body mass index of 20-40 kg/m2 and who had not yet transitioned through menopause were enrolled at Pennington Biomedical Research Center. Women were seen annually for body composition by dual-energy X-ray absorptiometry, for abdominal adipose tissue distribution by computed tomography, for sex steroid hormones, and for cardiometabolic risk factors that include fasting glucose, insulin, and lipids. Surrogate measures of insulin sensitivity were also calculated.ResultsNinety-four women (25 black, 69 white) transitioned through menopause and were included within the analyses. At menopause onset, black women weighed more (77.8±3.0 vs 70.8±1.8 kg) and had a higher systolic (125±16 vs 118±14 mm Hg) and diastolic (80±8 vs 74±7 mm Hg) blood pressure compared with white women (all P≤.05). No other differences in body composition, sex steroid hormones, or cardiometabolic risk factors were observed at menopause onset. Before menopause, white women gained significant weight (3 kg), total body adiposity (6% percent body fat, 9% fat mass, 12% trunk fat mass) and abdominal adipose tissue (19% subcutaneous fat, 15% visceral fat, 19% total adipose tissue), which coincided with significant decreases in estradiol, sex hormone-binding globulin, and estrone sulfate and increases in follicle-stimulating hormone, total cholesterol, and low-density lipoprotein cholesterol. Conversely, black women had more abdominal adipose tissue before menopause, which was maintained across the menopause transition. Black women also had significant decreases in estrone sulfate and total testosterone and increases in follicle-stimulating hormone before menopause. In the postmenopausal years, abdominal subcutaneous adipose tissue, total adipose tissue, follicle-stimulating hormone, total cholesterol, and low-density and high-density lipoprotein cholesterol increased only in white women.ConclusionWhite women gained more abdominal adiposity during the menopause transition compared with black women, which, in part, may be due to differences in the pattern of sex steroid hormone changes between women of different racial backgrounds. The gains in abdominal adiposity in white women were observed in tandem with increased cardiometabolic risk factors. Future studies should consider comprehensive lifestyle approaches to target these increased gains in abdominal adiposity (ie, nutrition and physical activity coaching), while taking into account the potential interactions of race, body adiposity, sex steroid hormones, and their influence on cardiometabolic risk.

Dataset Information

A prospective study of inflammatory biomarker levels and risk of early menopause.

Publications

A prospective study of inflammatory biomarker levels and risk of early menopause.

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