Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study.

BACKGROUND: Although the association between menopause and cardiovascular disease (CVD) risk has been studied extensively, the simultaneous role of chronological aging herein remains underexposed. This study aims to disentangle the relationships of menopausal status and chronological aging with CVD risk factors in the largest study population to date. METHODS: In this cross-sectional study, CVD risk factors were compared between women with a different menopausal status within the same yearly age strata. The study population comprised female participants of the baseline visit of the population-based LifeLines Cohort Study. A total of 63,466 women, aged between 18 and 65 years, was included. Of them, 39,379 women were considered to be premenopausal, 8669 were perimenopausal, 14,514 were naturally postmenopausal, and 904 were surgically postmenopausal. RESULTS: Compared to postmenopausal women aged 45 years, average total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) were 0.5 and 0.4 mmol/L higher, respectively, in postmenopausal women aged 50. Systolic and diastolic blood pressure levels were 4 and 1 mmHg higher, respectively. At all ages between 46 and 55 years, and after adjustment for confounders, naturally postmenopausal women had 0.2 to 0.4 mmol/L higher TC and 0.1 to 0.3 mmol/L higher LDL-c levels compared to premenopausal women in the same age range. Systolic blood pressure levels were up to 4 mmHg lower in naturally post- compared to premenopausal women at all ages between 29 and 52 years. Body mass index levels were up to 3.2 kg/m2 higher in women with surgical menopause compared to all other women between the ages 32 and 52 years. All aforementioned results were statistically significant. CONCLUSIONS: Chronological age and menopausal status are both independently associated with CVD risk factors. Based on the comparatively smaller observed differences associated with menopausal status than with chronological aging, the significance of a more unfavorable lipid profile in a later reproductive stage may be less obvious than previously thought.

Back to the basics of ovarian aging: a population-based study on longitudinal anti-Müllerian hormone decline.

BACKGROUND: Anti-Müllerian hormone (AMH) is currently used as an ovarian reserve marker for individualized fertility counseling, but very little is known of individual AMH decline in women. This study assessed whether the decline trajectory of AMH is uniform for all women, and whether baseline age-specific AMH levels remain consistently high or low during this trajectory. METHODS: A total of 3326 female participants from the population-based Doetinchem Cohort Study were followed with five visits over a 20-year period. Baseline age was 40 ± 10 years with a range of 20-59 years. AMH was measured in 12,929 stored plasma samples using the picoAMH assay (AnshLabs). Decline trajectories of AMH were studied with both chronological age and reproductive age, i.e., time to menopause. Multivariable linear mixed effects models characterized the individual AMH decline trajectories. RESULTS: The overall rate of AMH decline accelerated after 40 years of age. Mixed models with varying age-specific AMH levels and decline rates provided the significantly best fit to the data, indicating that the fall in AMH levels over time does not follow a fixed pattern for individual women. AMH levels remained consistent along individual trajectories of age, with an intraclass correlation coefficient (ICC) of 0.87. The ICC of 0.32 for AMH trajectories with time to menopause expressed the large variation in AMH levels at a given time before the menopause. The differences between low and high age-specific AMH levels remained distinguishable, but became increasingly smaller with increasing chronological and reproductive age. CONCLUSIONS: This is the first study to characterize individual AMH decline over a long time period and broad age range. The varying AMH decline rates do not support the premise of a uniform AMH decline trajectory. Although age-specific AMH levels remain consistently high or low with increasing age, the converging trajectories and variance of AMH levels at a given time before menopause shed doubt on the added value of AMH to represent individualized reproductive age.

The association of low ovarian reserve with cardiovascular disease risk: a cross-sectional population-based study.

STUDY QUESTION: Is there a relationship between serum anti-Müllerian hormone (AMH) level and cardiovascular disease (CVD) risk in premenopausal women? SUMMARY ANSWER: There are indications that premenopausal women with very low ovarian reserve may have an unfavorable CVD risk profile. WHAT IS KNOWN ALREADY: Age at menopause is frequently linked to CVD occurrence. AMH is produced by ovarian antral follicles and provides a measure of remaining ovarian reserve Literature on whether AMH is related to CVD risk is still scarce and heterogeneous. STUDY DESIGN, SIZE, DURATION: Cross-sectional study in 2338 women (age range of 20-57 years) from the general population, participating in the Doetinchem Cohort Study between 1993 and 1997. PARTICIPANTS/MATERIALS, SETTING, METHODS: CVD risk was compared between 2338 premenopausal women in different AMH level-categories, with adjustment for confounders. CVD risk was assessed through levels of systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose, in addition to a summed score of CVD risk factors. Among other factors, analyses were corrected for smoking, oral contraceptive use and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: The relationship of serum AMH levels with CVD risk factor outcomes was nonlinear. Women with AMH levels <0.16 µg/l had 0.11 (95% confidence intervals (CIs) 0.01; 0.21) more metabolic risk factors compared with women with AMH levels ≥0.16 µg/l. There was no association of individual risk factor levels with AMH levels, besides a tendency towards lower total cholesterol levels of 0.11 mmol/l (95% CI -0.23; 0.01) in women with AMH levels <0.002 µg/l compared with women with AMH levels ≥0.16 µg/l. Although not statistically significant, these effect sizes were larger in women below 40 years of age. LIMITATIONS, REASONS FOR CAUTION: Causality and temporality of the studied association cannot be addressed here. Moreover, the clinical and statistical significance of the results of this exploratory study should be interpreted with caution due to the absence of adjustment for multiple statistical testing. WIDER IMPLICATIONS OF THE FINDINGS: This population-based study supports previous findings that premenopausal women with very low AMH levels may have an increased CVD risk. It lays the groundwork for future research to focus on this group of women. Longitudinal studies with more sensitive AMH assays may furthermore help better understand the implications of these results. STUDY FUNDING/COMPETING INTEREST: No financial support was received for this research or manuscript. The Doetinchem Cohort Study is conducted and funded by the Dutch National Institute for Public Health and the Environment F.J.M.B. has received fees and grant support from Merck Serono, Gedeon Richter, Ferring BV and Roche. TRIAL REGISTRATION NUMBER: N/A.

Age-specific anti-Müllerian hormone and electrocardiographic silent coronary artery disease.

OBJECTIVE: To explore the relationship between age-specific anti-Müllerian hormone level, as a predictor of ovarian reserve status, and electrocardiographic silent coronary artery disease in a population-based, prospective cohort, the Tehran Lipid and Glucose Study. METHODS: For the present study, 1015 reproductive-aged participants in the Tehran Lipid and Glucose Study met our eligibility criteria. According to the Whitehall criteria, silent coronary artery disease was defined as an electrocardiogram showing possible or probable coronary heart disease using Minnesota codes. By excluding those with a history of coronary heart disease and silent coronary artery disease at the initiation of the study (n = 49), there were 108 events of silent coronary artery disease at electrocardiograms among 752 women followed for 9.5 ± 0.9 years (missing data: n = 214); the association between this outcome with age-specific anti-Müllerian hormone levels was explored after adjustment for confounding variables using logistic regression analysis. Cardiovascular disease risk scores were assessed for all participants using the guidelines of the American College of Cardiology and the American Heart Association. RESULTS: There were 108 events of silent coronary artery disease over the 10-year follow-up. Logistic regression analysis, considering age-specific anti-Müllerian hormone and atherosclerotic cardiovascular disease risk score as independent variables, revealed an odds ratio of 1.146 (95% confidence interval 1.008-1.303) for cardiovascular disease risk score (p = 0.038) and odds ratio of 1.002 (95% confidence interval 0.996-1.009) for age-specific anti-Müllerian hormone (p = 0.526). CONCLUSION: No association has been found between age-specific anti-Müllerian hormone levels and events of silent coronary artery disease in a 10-year follow-up of reproductive-aged women.

A quantitative comparison of anti-Müllerian hormone measurement and its shifting boundaries between two assays.

OBJECTIVE: Anti-Müllerian hormone (AMH), a quantitative marker of ovarian reserve, is used for both clinical and research purposes in the field of reproductive medicine. Numerous AMH assays have been developed. Among other factors, the lack of large-scale comparisons of the various assays hinders the universal interpretation of AMH levels. Moreover, little is known of the practical performance of highly sensitive assays compared with conventional assays with regard to the very low AMH levels found in women nearing menopause. This study aimed to compare the measurements of the Gen II (Beckman Coulter) assay with those of the highly sensitive picoAMH (AnshLabs) assay. METHODS: This cross-sectional study included 1985 premenopausal women who completed the second visit of the population-based Doetinchem Cohort Study, with a mean age of 42±7years. AMH levels were measured with the Gen II and picoAMH assays. Passing-Bablok and Bland Altman analyses were performed and differences in the proportion of detectable samples were assessed. RESULTS: The results from the Gen II and picoAMH assays were highly correlated, with a Spearman correlation coefficient of 0.91. The Passing-Bablok regression formula was picoAMH=0.01+1.69*GenII, meaning that on average picoAMH levels were 69% higher than Gen II levels. Of the 670 samples with an undetectable AMH value with the Gen II assay, AMH could be detected in 78% with the picoAMH assay, at a median concentration [interquartile range] of 0.05 [0.01-0.14] ng/mL. CONCLUSION: These results indicate that, despite a high correlation, there is a large relative difference between results of the Gen II and picoAMH assays. The use of a highly sensitive AMH assay is likely to result in a large increase in the proportion of samples with detectable levels. This may enable research into women's health across the menopausal transition and research into the potential clinical benefits of distinguishing between women with very low ovarian reserve.