The effect of six-month oral vitamin K supplementation on calcification propensity time in individuals with type 2 diabetes mellitus: A post hoc analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Experimental studies suggested that vitamin K supplementation may retard arterial calcification. Recently, serum calcification propensity time (T50) has been suggested as a functional biomarker for arterial wall calcification propensity. In this post-hoc analysis of a clinical trial, we evaluated the effect of six-month oral vitamin K supplementation on T50 and assessed the correlation between T50 and imaging arterial calcification parameters in people with type 2 diabetes (T2DM). METHODS: This double-blind, randomized, placebo-controlled trial included 68 participants (age = 69 ± 8 years, 76% male) with T2DM. Participants were assigned to menaquinone-7 (360 µg/day; n = 35) or placebo (n = 33). T50 was measured via nephelometry in serum collected at baseline, three and six months. Arterial calcification was measured at baseline and six months via 18F-Na PET-CT and conventional CT using Target-to-Background ratio (TBR) and Agatston score. Longitudinal analysis of covariance adjusted for baseline T50 was used to study the treatment effect. Spearman's correlation was used to assess the correlation between T50 and imaging calcification parameters. RESULTS: Median baseline T50 was similar in the vitamin K (350 [321-394] minutes) and placebo groups (363 [320-398]). There was no significant difference in T50 between treatment arms over time (ẞ = 1.00, 95%C.I. = 0.94-1.07, p = 0.982). The correlation coefficient of T50 with TBR and Agatston score at baseline were -0.185 (p = 0.156) and -0.121 (p = 0.358), respectively. CONCLUSIONS: No effect of vitamin K supplementation on T50 was observed in T2DM. Moreover, T50 did not correlate with TBR and Agatston score. Further research on vitamin K in arterial calcification and on the validity of T50 as arterial calcification marker is warranted.

Is early menopause a potential criterion for cardiovascular risk screening to detect high risk in a multi-ethnic population? The Helius study.

BACKGROUND: Women at risk of cardiovascular disease (CVD) may be missed with current eligibility criteria for CVD risk screening, particularly those from ethnic minority groups, among whom high risk is prevalent at a younger age. Early menopause (EM; menopause before 45 years) is associated with increased risk of CVD, and may be a potential eligibility criterion for CVD risk screening. AIMS AND OBJECTIVES: To determine the contribution of EM to current criteria from patient history (having a family history of CVD, current smoking, obesity and age over 50 years) for identifying women eligible for CVD risk screening in a multi-ethnic population. METHODS AND RESULTS: We used baseline data (2011-2015) from 4512 women aged 45-70 years of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan ethnic origin from the HELIUS study (Amsterdam, Netherlands). Models based on current eligibility criteria with and without EM were compared on area under the curve (AUC) with regard to estimated 10-year CVD risk using the Dutch SCORE. Overall, models with EM had a higher AUC, but changes were not statistically significant. In our total sample of women aged between 45 and 70 years, the AUC changed from 0.70 (95%CI 0.69-0.72) to 0.71 (95%CI 0.69-0.72). Among women aged 45-50 years the AUC changed from 0.66 (95%CI 0.58-0.74) to 0.68 (95%CI 0.59-0.74). Results were consistent across ethnic groups. CONCLUSIONS: The addition of EM to current eligibility criteria did not improve the detection of women at high CVD risk in a multi-ethnic sample of women aged 45-70 years.

Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.

BACKGROUND: Higher dairy consumption has been associated with lower type 2 diabetes (T2D) risk, whereas dairy product subtypes appear to differ in their T2D risk association. We investigated whether replacing one type of milk or yogurt product with another is associated with T2D incidence. METHODS: Participants of the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort (n = 35 982) were included in the present study. Information on milk and yogurt consumption at baseline was obtained by a validated food frequency questionnaire. T2D cases were identified by self-report or linkage to the hospital discharge registry, and validated by consulting the general practitioner. Multivariable Cox proportional hazard models were used to estimate associations. RESULTS: During a mean of 15 years of follow-up, 1467 indecent T2D cases were validated. Median total milk and yogurt intake was 1.5 servings (25th percentile to 75th percentile: 0.8-2.4). After adjustment for demographic and cardiovascular risk factors, replacement of one serving (200 g) of whole-fat milk [hazard ratio (HR) = 0.93, 95% confidence interval (CI) = 0.60-1.44], buttermilk (HR = 0.88, 95% CI = 0.58-1.34), skimmed milk (HR = 0.87, 95% CI = 0.57-1.32) or skimmed fermented milk (HR = 0.99, 95% CI = 0.63-1.54) with whole-fat yogurt was not associated with T2D risk. Substitutions among other milk and yogurt products were also not associated with T2D risk. Sensitivity analysis investigating T2D risk halfway follow-up suggested a lower risk for substitutions with whole-fat yogurt. CONCLUSIONS: No evidence was found for the association between substitutions among milk and yogurt products and the risk of incident T2D, although we cannot exclude possible attenuation of results as a result of dietary changes over time. This analysis should be repeated in a population with a wider consumption range of whole-fat yogurt.

Vasomotor menopausal symptoms and cardiovascular disease risk in midlife: A longitudinal study.

OBJECTIVE: To ascertain the association between vasomotor menopausal symptoms (VSM), hot flushes and night sweats, and cardiovascular disease, coronary heart disease and cerebrovascular disease. STUDY DESIGN: The study sample comprised 8881 women (aged 45-50 years) with available hospital separation data from the 1946-51 cohort (1996-2016) of the ongoing Australian Longitudinal Study on Women's Health, a national prospective cohort study. MAIN OUTCOME MEASURES: First fatal or non-fatal cardiovascular disease, coronary heart disease, and cerebrovascular disease events were obtained through linkage with hospital admission data, the National Death Index, and Medicare Benefits Schedule. Hot flushes and night sweats were assessed via questionnaires at each main survey. Additionally, we calculated the duration of symptoms based on whether or not women reported vasomotor menopausal symptoms in each survey. RESULTS: There were 925 cardiovascular disease, 484 coronary heart disease and 154 cerebrovascular disease events. There was no consistent evidence of any association with vasomotor menopausal symptoms, hot flushes and night sweats. We did find marginally statistically significant associations between presence of night sweats and cardiovascular disease (Hazard Ratio = 1.18, 95 % Confidence Interval: 1.01-1.38), and between the duration of vasomotor menopausal symptoms [years] and coronary heart disease (Hazard Ratioper year = 1.03, 95 % Confidence Interval: 1.00-1.05). However, given the number of associations tested, these findings could very well have arisen by chance. CONCLUSION: In this large longitudinal study with 20 years of follow-up and clinical outcomes we did not find a convincing association between vasomotor menopausal symptoms, hot flushes, night sweats and cardiovascular disease, coronary heart disease and cerebrovascular disease.

The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown. OBJECTIVES: The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD. METHODS: In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables. RESULTS: We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: -0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: -0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (-205.6 pmol/L; 95% CI: -255.8, -155.3 pmol/L). No adverse events were reported. CONCLUSION: MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis.

CONTEXT: Anti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy. OBJECTIVE: To perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction. DATA SOURCES: A systematic literature search was performed using PubMed, Embase and Cochrane databases. STUDY SELECTION: Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion. DATA SELECTION: Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery. DATA SYNTHESIS: 2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age. CONCLUSION: AMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.

Fish consumption and risk of stroke, coronary heart disease, and cardiovascular mortality in a Dutch population with low fish intake.

BACKGROUND/OBJECTIVES: Fish consumption of at least 1 portion/week is related to lower cardiovascular disease (CVD) risk. It is uncertain whether a less frequent intake is also beneficial and whether the type of fish matters. We investigated associations of very low intakes of total, fatty, and lean fish, compared with no fish intake, with 18-year incidences of stroke, coronary heart disease (CHD), and CVD mortality. METHODS: Data were used from 34,033 participants, aged 20-70 years, of the EPIC-Netherlands cohort. Baseline (1993-1997) fish consumption was estimated using a food frequency questionnaire. We compared any fish consumption, <1 portion/week (<100 g) and ≥1 portion/week to non-fish consumption. RESULTS: During 18 follow-up years, 753 stroke events, 2134 CHD events, and 540 CVD deaths occurred. Among the fish consumers (~92%) median intakes of total, lean, and fatty fish were 57.9, 32.9, and 10.7 g/week, respectively. Any fish consumption compared with non-consumption was not associated with incidences of stroke, CHD, MI, and CVD mortality. Furthermore, consumption of <1 portion/week of total, fatty, or lean fish was not associated with any CVD outcome, as compared with non-consumption. Consumption of ≥1 portion/week of lean fish (HR: 0.70, 95% CI: 0.57-0.86) and of fatty fish (HR: 0.63, 95% CI: 0.39-1.02) were associated with lower incidence of ischaemic stroke. CONCLUSIONS: Baseline fish consumption of <1 portion/week, regardless of the type of fish, was unrelated to incidences of stroke, CHD, and CVD mortality in this Dutch cohort. Consumption of ≥1 portion/week of fatty or of lean fish reduced the incidence of ischaemic stroke.

Links between Atherosclerosis and Osteoporosis in Middle Aged and Elderly Men.

BACKGROUND: Although the incidences of osteoporosis and atherosclerosis increase with age, there is growing evidence that the coincidental occurrence of both diseases may be independent of age. In general, studies in men are scarce and results are inconsistent. OBJECTIVE: to investigate the relationship between atherosclerosis and bone mineral density, and the influence of insulin sensitivity and low grade inflammation on this relationship in 332 men without CVD. METHODS: Aortic Pulse wave velocity (PWV), augmentation index (AIX) and measurements of carotid intima media thickness (CIMT) were assessed. BMD measurements were performed with dual-X-ray absorptiometry (DEXA), subcutaneous fat by ultrasonography. Serum concentrations of lipids, hsCRP, glucose and insulin were measured. Insulin sensitivity was calculated by use of the quantitative insulin sensitivity (QUICKI). We used multivariate linear regression models to examine the association of hsCRP, insulin sensitivity, PWV, Aix, CIMT with BMD. RESULTS: A higher CIMT was significantly associated with higher BMD after multivariate adjustment (ß 99.7; p=0.02). Further adjustment for weight attenuated the estimates towards non-significant. No association was found between PWV or AIX and BMD. Lower insulin sensitivity was associated with higher BMD (ß -645.1; p<0.01). After adjustment for weight this association was no longer significant. A similar effect was seen for the association between hsCRP and BMD. CONCLUSION: In this population of healthy, non-obese, men without a history of cardiovascular disease the positively association between cardiovascular parameters and BMD was mainly explained by weight, suggesting that in this population weight plays a protective role in the development of osteoporosis.

Reproducibility and relative validity of a food frequency questionnaire to estimate intake of dietary phylloquinone and menaquinones.

BACKGROUND/OBJECTIVES: This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. SUBJECTS/METHODS: In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women. RESULTS: Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs=-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). CONCLUSIONS: The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.

Fluidity of the dietary fatty acid profile and risk of coronary heart disease and ischemic stroke: Results from the EPIC-Netherlands cohort study.

BACKGROUND AND AIMS: The fluidity of dietary fatty acids consumed has been suggested to inversely affect coronary heart disease (CHD) risk. Lipophilic index (LI) represents overall fluidity of the dietary fatty acid profile. Lipophilic load (LL) represents a combination of overall fluidity and absolute intake of dietary fatty acids. We investigated the relations of dietary LI and LL with risk of CHD and ischemic stroke (iStroke). METHODS AND RESULTS: We used data from the prospective EPIC-NL study, including 36,520 participants aged 20-70 years. LI and LL were calculated using dietary intake data estimated with a validated FFQ. Incident CHD (n = 2348) and iStroke (n = 479) cases were obtained through linkage to national registers during 15 years follow-up. LI and LL were not associated with CHD risk (HRshighest-versus-lowest-quartiles: 0.93 [95%CI: 0.83, 1.04], and 0.92 [95%CI: 0.79, 1.07], respectively), and neither with iStroke risk (HRs 1.15 (95%CI: 0.89, 1.48), and 0.98 (95%CI: 0.70, 1.38), respectively). Original fatty acid classes (SFA, MUFA and PUFA), and LI and LL stratified by these fatty acid classes, were overall not related to CHD and ischemic stroke either. CONCLUSIONS: In this Dutch population, neither the overall fluidity of the dietary fatty acid profile (LI), nor the combined fluidity and amount of fatty acids consumed (LL) were related to CHD or iStroke risk. Dietary LI and LL may have limited added value above original fatty acid classes and food sources in establishing the relation of fatty acid consumption with CVD.

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.

Trajectories of metabolic risk factors and biochemical markers prior to the onset of type 2 diabetes: the population-based longitudinal Doetinchem study.

BACKGROUND: Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15-20 years. METHODS: A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose ⩾11.1 mmol l-1) and 2130 controls were identified in a prospective cohort between 1987-2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations. RESULTS: Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15-20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5-8% over 15 years, whereas the increase among persons without type 2 diabetes was 0-2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women. CONCLUSIONS: Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15-20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

A pro-inflammatory diet is associated with increased risk of developing hypertension among middle-aged women.

BACKGROUND AND AIMS: A pro-inflammatory diet is thought to lead to hypertension through oxidative stress and vessel wall inflammation. We therefore investigated the association between the dietary inflammatory index (DII) and developing hypertension in a population-based cohort of middle-aged women. METHODS AND RESULTS: The Australian Longitudinal Study on Women's Health included 7169 Australian women, aged 52 years (SD 1 year) at baseline in 2001, who were followed up through 4 surveys until 2013. The DII, a literature-derived dietary index that has been validated against several inflammatory markers, was calculated based on data collected via a validated food-frequency questionnaire administered at baseline. Hypertension was defined as new onset of doctor-diagnosed hypertension, ascertained through self-report between 2001 and 2013. Generalised Estimating Equation analyses were used to investigate the association between the DII and incident hypertension. The analyses were adjusted for demographic and hypertension risk factors. During 12-years follow-up we identified 1680 incident cases of hypertension. A more pro-inflammatory diet was associated with higher risk of hypertension in dichotomised analyses with an ORfully adjusted of 1.24, 95% CI: 1.06-1.45. CONCLUSION: A pro-inflammatory diet might lead to a higher risk of developing hypertension. These results need to be replicated in other studies.

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.

Long-term effects of joint bleeding before starting prophylaxis in severe haemophilia.

INTRODUCTION: Early initiation of prophylaxis in severe haemophilia is critical for effective prevention of arthropathy. However, the optimum time for starting prophylaxis has not been established yet. AIM: This study assessed long-term effects of age at starting prophylaxis and joint bleeding before prophylaxis on haemophilic arthropathy. METHODS: In patients with severe haemophilia (FVIII/IX <0.01 IU mL-1 ), born between 1965 and 2000, haemophilic arthropathy was evaluated on X-rays. Patient groups were compared by multivariable regression analysis, adjusted for bleeding phenotype and lifetime intensity of prophylaxis. RESULTS: One hundred and twenty-four patients were evaluated at a median age of 22 years. When comparing patients according to age at starting prophylaxis, starting before age 6 years was significantly better than starting later (P < 0.01), but no additional benefit of starting before age 3 years was demonstrated. The number of joint bleeds before prophylaxis had a stronger association with arthropathy than age at starting prophylaxis. Starting prophylaxis before the onset of joint bleeding resulted in the best long-term outcome (P ≤ 0.02); starting after one joint bleed appeared to have acceptable long-term outcome. The difference between starting after 0-1 and 2-5 joint bleeds was notable, but statistical significance was not reached (P = 0.15). CONCLUSION: Future research with more patients on early prophylaxis will have to clarify whether starting prophylaxis before joint bleeding is superior.