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.
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.
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.
ClinicalTrials.gov Identifier: NCT02616510.
Reproductive disorders, such as polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI) and hypertensive pregnancy disorders (HPD) like pre-eclampsia (PE), are associated with an ...increased risk of cardiovascular disease (CVD). Detection of early signs of cardiovascular disease (CVD), as well as identification of risk factors among women of reproductive age which improve cardiovascular risk prediction, is a challenge and current models might underestimate long-term health risks. The aim of this study is to assess cardiovascular disease in patients with a history of a reproductive disorder by low-dose computed tomography (CT).
Women of 45 - 55 years, who experienced a reproductive disorder (PCOS, POI, HPD), are invited to participate in this multicenter, prospective, cohort study. Women will be recruited after regular cardiovascular screening, including assessment of classical cardiovascular risk factors. CT of the coronary arteries (both coronary artery calcium scoring (CACS), and contrast-enhanced coronary CT angiography (CCTA)) and carotid siphon calcium scoring (CSC) is planned in 300 women with HPD and 300 women with PCOS or POI. In addition, arterial stiffness (non-invasive pulse wave velocity (PWV)) measurement and cell-based biomarkers (inflammatory circulating cells) will be obtained.
Initial inclusion is focused on women of 45 - 55 years. However, the age range (40 - 45 years and/or ≥ 55 years) and group composition may be adjusted based on the findings of the interim analysis. Participants can potentially benefit from information obtained in this study concerning their current cardiovascular health and expected future risk of cardiovascular events. The results of this study will provide insights in the development of CVD in women with a history of reproductive disorders. Ultimately, this study may lead to improved cardiovascular prediction models and will provide an opportunity for timely adjustment of preventive strategies. Limitations of this study include the possibility of overdiagnosis and the average radiation dose of 3.5 mSv during coronary and carotid siphon CT, although the increased lifetime malignancy risk is negligible.
Netherlands Trial Register, NTR5531 . Date registered: October 21st, 2015.
What is the influence of ethnicity on the outcome of ovulation induction with clomifene citrate in women with polycystic ovary syndrome (PCOS)?
This was a retrospective cohort study. In total, 420 ...women diagnosed with PCOS who were of Northern European, Mediterranean, African, South-East Asian or South American descent, and who started ovulation induction treatment with clomifene citrate, were included. All women were treated with clomifene citrate according to a standardized treatment regimen. The minimal effective dose of clomifene citrate and prevalence of clomifene resistance (CRA) were assessed, and the chance of becoming ovulatory was predicted.
Differences were observed in body mass index (P = 0.008), waist circumference (P = 0.036) and serum LH, insulin and androgen concentrations (all P < 0.001) in women of different ethnicities with PCOS. Compared with women of Northern European descent, the minimal effective dose of clomifene citrate in women of other ethnic groups was not significantly different. The prevalence of CRA (P = 0.574) was similar in all ethnic groups A similar chance of ovulation (P = 0.504) was predicted for the different ethnic groups.
This is the first study aiming to link ethnicity to ovulation induction outcome in PCOS. Although women of different ethnicities who have PCOS exhibit a variation in phenotypic expression, there do not appear to be differences in the prevalence of clomifene-resistant anovulation or the minimal effective dose of clomifene citrate. Furthermore, a prediction model revealed no significant differences in the predicted chance of ovulation. A larger cohort is needed to validate these findings.
To determine a cutoff for the Elecsys AMH Plus immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) to identify polycystic ovarian morphology (PCOM), a polycystic ovary syndrome ...(PCOS) criterion.
The AMH Protein in Humans for polycystic ovaRian mOrphology DIagnostic TEsting (APHRODITE) study was a retrospective, multicenter, case-control study. The serum antimüllerian hormone (AMH) level was measured using the Elecsys AMH Plus immunoassay. The antral follicle count was determined using transvaginal ultrasound. An AMH cutoff was derived and validated in separate cohorts with cases of PCOS with full phenotype A (oligo/anovulation, hyperandrogenism, and PCOM) versus that with controls. Exploratory analyses of age and PCOS phenotype were performed.
Not applicable.
Polycystic ovary syndrome-positive (PCOS A–D per the Rotterdam criteria) and PCOS-negative women aged 25–45 years.
None.
A validated cutoff for AMH using the Elecsys AMH Plus assay for PCOM.
In the validation cohort (455 cases and 500 controls), an AMH cutoff of 3.2 ng/mL (23 pmol/L) resulted in a sensitivity of 88.6% (95% confidence interval CI 85.3–91.3) and specificity of 84.6% (95% CI 81.1–87.7) for PCOM diagnosis as well as an area under the receiver-operator characteristic curve of 93.6% (95% CI 92.2–95.1). In women aged 25–35 years, the sensitivity and specificity for the cutoff were 88.5% and 80.3%, respectively, versus 77.8% and 90.1%, respectively, in women aged 36–45 years. The results were consistent across PCOS phenotypes A–D.
The Elecsys AMH Plus immunoassay, with a cutoff of 3.2 ng/mL (23 pmol/L), is a robust method for identifying PCOM to aid in PCOS diagnosis.
Hormona antimülleriana para determinar la morfología del ovario poliquístico.
Determinar un punto de corte para el inmunoensayo Elecsys AMH Plus (Roche Diagnostics, Basel, Suiza) para identificar la morfología del ovario poliquístico (PCOM), un criterio de síndrome de ovario poliquístico (PCOS).
El estudio de la Proteína AMH en Humanos para Prueba Diagnóstica de la Morfología del Ovario Poliquístico fue un estudio retrospectivo, multicéntrico, caso-control. El nivel sérico de hormona antimülleriana (AMH) fue medido utilizando el inmunoensayo Elecsys AMH Plus. El conteo de folículos antrales fue determinado utilizando ecografía transvaginal. El punto de corte de AMH fue derivado y validado en cohortes separadas con casos de PCOS con fenotipo completo (oligo/ anovulación, hiperandrogenismo, y PCOM) versus controles. Se realizaron análisis exploratorios de edad y fenotipo PCOS.
No aplica.
Mujeres síndrome de ovario poliquístico-positivas (PCOS A-D por criterios de Rotterdam) y PCOS-negativas de 25-45 años.
Ninguna.
Un punto de corte validado para AMH utilizando el ensayo Elecsys AMH Plus para PCOM.
En la cohorte de validación (455 casos y 500 controles) un punto de corte de AMH de 3.2 ng/mL (23 pmol/L) resultó en una sensibilidad de 88.6% (intervalo de confianza 95% CI 85.3-91.3) y una especificidad de 84.6% ( CI 95% 81.1-87.7) para el diagnóstico de PCOM así como un área bajo la curva característica operador-receptor de 93.6% (CI 95% 92.2-95.1). En mujeres de 25-35 años, la sensibilidad y especificidad para el punto de corte fueron 88.5% y 80.3%, respectivamente, versus 77.8% y 90.1%, respectivamente, en mujeres de 36-45 años. Los resultados fueron consistentes en los fenotipos PCOS A-D.
El inmunoensayo Elecsys AMH Plus, con un punto de corte de 3.2 ng/mL (23 pmol/L), es un método robusto para identificar PCOM para ayudar en el diagnóstico de PCOS.
Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in ...up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.
It remains unclear whether endogenous sex hormones (ESH) are associated with risk of type 2 diabetes (T2D) in women. Data of 3,117 postmenopausal women participants of the Rotterdam Study were ...analyzed to examine whether ESH and sex hormone-binding globulin (SHBG) were associated with the risk of incident T2D. Additionally, we performed a systematic review and meta-analysis of studies assessing the prospective association of ESH and SHBG with T2D in women. During a median follow-up of 11.1 years, we identified 384 incident cases of T2D in the Rotterdam Study. No association was observed between total testosterone (TT) or bioavailable testosterone (BT) with T2D. SHBG was inversely associated with the risk of T2D, whereas total estradiol (TE) was associated with increased risk of T2D. Similarly, in the meta-analysis of 13 population-based prospective studies involving more than 1,912 incident T2D cases, low levels of SHBG and high levels of TE were associated with increased risk of T2D, whereas no associations were found for other hormones. The association of SHBG with T2D did not change by menopause status, whereas the associations of ESH and T2D were based only in postmenopausal women. SHBG and TE are independent risk factors for the development of T2D in women.
Abstract
Context
Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular ...disease (CVD).
Objective
To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women.
Design
The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years.
Setting
General community.
Participants
A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62).
Intervention
None.
Main Outcomes and Measures
Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone–binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD.
Results
Mean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (β 95% confidence interval (CI), 0.009 0.000 to 0.018). Highest quartile dehydroepiandrosterone β (95% CI), −0.008 (−0.015 to −0.001) and androstenedione β (95% CI), −0.010 (−0.017 to −0.003) levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD.
Conclusion
Postmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated.
Women with postmenopausal high androgen levels are not at elevated risk for CVD.
Abstract
Context
As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice.
Objective
Utilizing polygenic risk prediction, we aim to ...identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment.
Design, Patients, and Methods
Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS.
Results
The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: “morbid obesity”, “type 2 diabetes”, “hypercholesterolemia”, “disorders of lipid metabolism”, “hypertension”, and “sleep apnea” reaching phenome-wide significance.
Conclusions
Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome–phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.
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