The cardiovascular risk profile of middle age women previously diagnosed with premature ovarian insufficiency: A case-control study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 µm (500-615) versus 684 µm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02616510.

Endocrine and cardiometabolic cord blood characteristics of offspring born to mothers with and without polycystic ovary syndrome.

OBJECTIVE: To compare the endocrine and cardiometabolic cord blood characteristics of offspring of mothers with polycystic ovary syndrome (PCOS) with those of healthy controls. DESIGN: Cross-sectional case control study. SETTING: University medical centers. PATIENT(S): Offspring from mothers with PCOS (n = 61) and healthy controls (n = 82). INTERVENTION(S): Cord blood withdrawal from neonates. MAIN OUTCOME MEASURE(S): Cord blood estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone-binding globulin, free androgen index (FAI), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, c-reactive protein, adiponectin, and leptin. RESULT(S): Androstenedione and leptin concentrations were increased in the offspring of women with PCOS compared with the controls: androstenedione median 2.9 (interquartile range [IQR] 2.3-3.9) nmol/L vs. 2.2 [IQR 1.6-2.7] nmol/L; and leptin median 13.6 [IQR 8.3-22.9] µg/L vs. 9.8 [IQR 6.0-16.5] µg/L. After adjusting for maternal and pregnancy-related confounders (such as maternal age, gestational age, birth weight), androstenedione appeared associated with PCOS in both male (relative change 1.36 [1.04; 1.78]) and female offspring (relative change 1.40 [1.08; 1.82]). Similarly, in male offspring the leptin concentrations appeared associated with PCOS after correction for confounders (relative change 1.55 [1.12; 2.14]). After correction for multiple testing, these associations attenuated. CONCLUSION(S): Observed results suggest that androstenedione concentrations are increased in the cord blood of male and female offspring of women with PCOS, although this requires confirmation. This finding would support the hypothesis that a maternal hyperandrogenic environment during pregnancy in women with PCOS may predispose their offspring to fetal hyperandrogenism. The potential associations between fetal hyperandrogenism and long-term health effects remain to be elucidated. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

OBJECTIVE: To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. DESIGN: Cross-sectional comparison of serum biomarkers. SETTING: University Medical Center Utrecht. PATIENTS: Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30). MAIN OUTCOME MEASURE(S): Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). RESULTS: The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. CONCLUSION: In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.

Cardiovascular Risk in Women With Premature Ovarian Insufficiency Compared to Premenopausal Women at Middle Age.

CONTEXT: A young age at menopause has been associated with increased cardiovascular disease (CVD) risk. OBJECTIVE: To compare the cardiovascular risk profile between women with premature ovarian insufficiency (POI) and premenopausal controls of comparable age. DESIGN: Cross-sectional case control study. SETTING: Two university medical centers. PARTICIPANTS: Women above 45 years of age who were previously diagnosed with POI (n = 83) and premenopausal population controls of comparable age (n = 266). MAIN OUTCOME MEASURES: Blood pressure, body mass index, waist circumference, electrocardiogram, bilateral carotid intima media thickness, estradiol, T, androstenedione, dehydroepiandrosterone sulfate, SHBG, insulin, glucose, lipids, TSH, free T4, N-terminal pro-B-type natriuretic peptide, C-reactive protein, uric acid, creatinine, and homocysteine were measured. Potential associations between POI status and subclinical atherosclerosis were assessed. RESULTS: Women with POI exhibited an increased waist circumference (ß = 5.7; 95% confidence interval [CI], 1.6, 9.9), C-reactive protein (ß = 0.75; 95% CI, 0.43, 1.08), free T4 levels (ß = 1.5; 95% CI, 0.6, 2.4), and lower N-terminal pro-B-type natriuretic peptide (ß = -0.35; 95% CI, -0.62, -0.08), estradiol (ß = -1.98; 95% CI, -2.48, -1.48), T (ß = -0.21; 95% CI, -0.37, -0.06), and androstenedione (ß = -0.54; 95% CI, -0.71, -0.38) concentrations compared to controls, after adjusting for confounders. After adjustment, a trend toward increased hypertension (odds ratio = 2.1; 95% CI, 0.99; 4.56) and decreased kidney function was observed in women with POI (creatinine ß = 3.5; 95% CI, -0.05, 7.1; glomerular filtration rate ß = -3.5; 95% CI, -7.5, 0.46). Women with POI exhibited a lower mean carotid intima media thickness (ß = -0.17; 95% CI, -0.21, -0.13) and decreased odds of plaque presence compared to controls (odds ratio = 0.08; 95% CI, 0.03; 0.26). CONCLUSIONS: Women with POI exhibited an unfavorable cardiovascular risk profile, including higher abdominal fat, elevated chronic inflammatory factors, and a trend toward increased hypertension and impaired kidney function compared to controls. However, we observed no signs of increased subclinical atherosclerosis in women with POI. Additional studies are required to identify specific determinants of long-term CVD risk in women with POI.

Association of alcohol consumption with the onset of natural menopause: a systematic review and meta-analysis.

BACKGROUND: Early onset of menopause is associated with long-term health risks, including cardiovascular disease and premature death. Although alcohol intake has been suggested to affect the age at which natural menopause occurs, results from observational studies are not consistent. OBJECTIVE AND RATIONALE: In the view of the differing risks to the health of early menopause and the increasing trends in alcohol consumption in women, in this systematic review, we aimed to quantify the association between all levels of alcohol consumption and menopause onset. SEARCH METHODS: Six electronic databases (Medline, Embase, Cochrane, PubMed, Google Scholar and Web of Science) were systematically searched until 4 November 2015 to identify relevant studies assessing the association between alcohol consumption and onset of menopause. Two independent reviewers screened the titles and abstracts of all initially identified studies according to the selection criteria. Studies were sought if they (i) were observational cross-sectional, prospective and interventional studies, (ii) had reported on natural onset of menopause, (iii) had reported on alcohol consumption, (iv) had assessed the association between alcohol consumption and menopause onset, (v) were conducted in humans and (vi) were not conducted in patients with cancer. Data were extracted by two independent reviewers using a predesigned data-collection form. The primary exposure variable was the presence of active alcohol drinking at baseline compared with a reference group of non-drinkers. Pooled relative risks (RRs) were calculated. OUTCOMES: Of the 1193 references (all in English language) reviewed for eligibility, 22 articles based on 20 unique studies were included in the final analysis. A total of 41 339 and 63 868 non-overlapping women were included in the meta-analysis of cross-sectional and observational cohort studies, respectively. In cross-sectional studies, the pooled RR for earlier onset of menopause was 0.86 (95% confidence interval (CI): 0.78-0.96) between drinkers versus non-drinkers. Analysis of the levels of alcohol consumed showed that low and moderate alcohol consumption (more than one drink per week (RR = 0.60; 95% CI: 0.49-0.75) and three or fewer drinks per week (RR = 0.75; 95% CI: 0.60-0.94)) were associated with later menopause onset, compared to non-drinkers. In prospective studies, RR for earlier menopause onset was 0.95 (95% CI: 0.91-0.98) when comparing women who reported drinking alcohol versus women who did not. Analysis of the dose of alcohol consumed showed that low-to-moderate alcohol intake (0-8 g/day (RR = 0.95; 95% CI: 0.93-0.98), and 16 g/day (RR = 0.89, 95%CI: 0.86-0.92)) was associated with later menopause onset, compared to non-drinking. WIDER IMPLICATIONS: The findings of this review indicate that alcohol consumption, particularly low and moderate alcohol intake, might be associated with later onset of menopause although the magnitude of the association is low. Further studies are needed to corroborate these findings, clarify the level of alcohol intake at which menopause is delayed and identify the potential mechanisms behind this association.

Reproductive characteristics of women diagnosed with premature ovarian insufficiency.

In this retrospective cohort study (n = 479), the proportion of women with premature ovarian insufficiency (POI) who conceived was assessed, the reproductive characteristics of women with POI who had previously been pregnant or had never been pregnant compared, and the interval between last conception and the menopause in women with POI who had become pregnant assessed. Time to pregnancy and maternal age at first childbirth were compared between women with POI and population-based controls (n = 2304). Women with POI who had previously been pregnant (n = 249 [52%]) experienced menopause at a later age compared with controls (35.0 years: interquartile range [IQR] 32.0-37.5 versus 30.0 years [IQR 23.0-35.0]; P < 0.001). The median interval between last conception and menopause in the former group was 4.0 years (IQR 1.0-8.0). Time to pregnancy did not differ between women with POI and controls. Women with POI were younger at first childbirth compared with controls (27.3 years [IQR 23.4-30.5] versus 29.2 years [26.4-32.0]; P < 0.001). The reproductive capacity of young women with POI is comparable to women in the general population, up until a given age; thereafter a rapid loss of the potential to conceive occurs.

Menopause prediction and potential implications.

Reproductive ageing in women is characterized by a decline in both the quantity and quality of oocytes. Menopause is reached upon exhaustion of the resting primordial follicle pool, occurring on average at 51 years of age (range 40-60 years). The mean global age at natural menopause (ANM) appears robust, suggesting a distinct genetic control. Accordingly, a strong correlation in ANM is observed between mothers and daughters. Few specific genetic determinants of ANM have been identified. Substantial efforts have been made to predict ANM by using anti-Müllerian hormone (AMH) levels. AMH serum concentrations at reproductive age predict ANM, but precision is currently limited. Early ANM is associated with early preceding fertility loss, whereas late menopause is associated with reduced morbidity and mortality later in life. Menopause affects various women's health aspects, including bone density, breast, the cardiovascular system, mood/cognitive function and sexual well-being. If the current trend of increasing human life expectancy persists, women will soon spend half their life postmenopause. Unfortunately, increased longevity does not coincide with an equal increase in years spend in good health. Future research should focus on determinants of long term health effects of ANM, and efforts to improve women's postmenopausal health and quality of life.

Health in middle-aged and elderly women: A conceptual framework for healthy menopause.

Middle-aged and elderly women constitute a large and growing proportion of the population. The peri and postmenopausal period constitutes a challenging transition time for women's health, and menopausal health is a crucial aspect in healthy and successful aging. Currently, no framework for the concept of healthy menopause exists, despite its recognized importance. Therefore, we aimed to: (i) characterize healthy menopause; (ii) identify aspects that contribute to it; and (iii) explore potential approaches to measure it. We propose healthy menopause as a dynamic state, following the permanent loss of ovarian function, which is characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a woman's desired ability to adapt and capacity to self-manage. The concept of healthy menopause applies to all women from the moment they enter the menopausal transition, up until they reach early and late postmenopause and includes women with spontaneous, iatrogenic, and premature menopause. This conceptualization can be considered as a further step in the maintenance and improvement of health in menopausal women from different perspectives, foremost the woman's own perspective, followed by the clinical, public health, and societal perspectives, and can be seen as a further step in delineating lines for future research. Furthermore, it could facilitate the improvement of adequate preventive and treatment strategies, guide scientific efforts, and aid education and communication to health care practitioners and the general public, allowing women the achievement of their potential and the fulfillment of their fundamental role in society.

Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk?

OBJECTIVE: To study the cardiometabolic profile characteristics and compare the prevalence of cardiovascular (CV) risk factors between women with different polycystic ovary syndrome (PCOS) phenotypes. DESIGN: A cross-sectional multicenter study analyzing 2,288 well phenotyped women with PCOS. SETTING: Specialized reproductive outpatient clinic. PATIENT(S): Women of reproductive age (18-45 years) diagnosed with PCOS. INTERVENTION(S): Women suspected of oligo- or anovulation underwent a standardized screening consisting of a systematic medical and reproductive history taking, anthropometric measurements, and transvaginal ultrasonography followed by an extensive endocrinologic/metabolic evaluation. MAIN OUTCOME MEASURE(S): Differences in cardiometabolic profile characteristics and CV risk factor prevalence between women with different PCOS phenotypes, i.e., obesity/overweight, hypertension, insulin resistance, dyslipidemia, and metabolic syndrome. RESULT(S): Women with hyperandrogenic PCOS (n=1,219; 53.3% of total) presented with a worse cardiometabolic profile and a higher prevalence of CV risk factors, such as obesity and overweight, insulin resistance, and metabolic syndrome, compared with women with nonhyperandrogenic PCOS. In women with nonhyperandrogenic PCOS overweight/obesity (28.5%) and dyslipidemia (low-density lipoprotein cholesterol≥3.0 mmol/L; 52.2%) were highly prevalent. CONCLUSION(S): Women with hyperandrogenic PCOS have a worse cardiometabolic profile and higher prevalence of CV risk factors compared with women with nonhyperandrogenic PCOS. However, all women with PCOS should be screened for the presence of CV risk factors, since the frequently found derangements at a young age imply an elevated risk for the development of CV disease later in life.