Reference ranges of anti-Müllerian hormone and interaction with placental biomarkers in early pregnancy: the Generation R Study, a population-based prospective cohort study.

Objective: The primary objective of this study is to establish maternal reference values of anti-Müllerian hormone (AMH) in a fertile multi-ethnic urban pregnant population and to evaluate the effect of gestational age. The secondary objective of this study is to explore the association between AMH and placental biomarkers. Design: This study was embedded in the Generation R Study, an ongoing population-based prospective cohort study from early pregnancy onwards. Setting: City of Rotterdam, the Netherlands, out of hospital setting. Patients: In 5806 women, serum AMH levels were determined in early pregnancy (median 13.5 weeks; 95% range 10.5-17.2). Intervention(s): None. Main outcome measures: Maternal AMH levels in early pregnancy and its association with placental biomarkers, including human chorionic gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFLT), and placental growth factor (PLGF). Results: A nomogram of AMH in early pregnancy was developed. Serum AMH levels showed a decline with advancing gestational age. Higher AMH levels were associated with a higher level of the placental biomarkers hCG and sFLT in early pregnancy. This last association was predominantly mediated by hCG. AMH levels were negatively associated with PLGF levels. Conclusion: In this large study, we show that AMH levels in early pregnancy decrease with advancing gestational age. The association between AMH and the placental biomarkers hCG, sFLT, and PLGF suggests a better placental development with lower vascular resistance in mothers with higher AMH levels. Hence, AMH might be useful in predicting adverse pregnancy outcomes due to impaired placental development.

Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): A cross-sectional study.

OBJECTIVE: To compare vitamin D status in women with PCOS versus fertile women and subsequently evaluate the association between vitamin D status and metabolic disturbances in PCOS women. METHODS: We conducted a cross-sectional comparison study of 639 women with PCOS and 449 fertile women. Serum 25-hydroxyvitamin D (25(OH)D) was stratified into a severe deficient (< 25 nmol/l), insufficient (25-50 nmol/l), moderate (50-75 nmol/l) and adequate (> 75 nmol/l) status. The main outcome measures were the difference in vitamin D status between PCOS and fertile women, and the association between serum 25(OH)D and metabolic disturbances in PCOS women only. RESULTS: Serum 25(OH)D was significantly lower in PCOS women compared to fertile controls (mean 25(OH)D of 49.0 nmol/l versus 64.5 nmol/l). An adjusted significant difference was seen between serum 25(OH)D and homeostasis model assessment (HOMA-IR) (ß = 0.76; 95% CI: 0.63-0.91; p < 0.01), HDL-cholesterol (ß = 0.20; 95% CI: 0.05-0.60, p < 0.01) and apolipoprotein A1 (ß = 26.2; 95% CI: 7.5-45.0, p < 0.01) between the highest vitamin D group compared to the lowest vitamin D group. CONCLUSIONS: This study demonstrates that women with PCOS have a significantly lower serum 25(OH)D compared to fertile controls. A compromised vitamin D status in PCOS women is associated with a higher HOMA-IR and an unfavourable lipid profile. Large randomized controlled trials are necessary to explore the causality of this linkage.

The impact of self-reported ethnicity versus genetic ancestry on phenotypic characteristics of polycystic ovary syndrome (PCOS).

CONTEXT: It is well established that ethnicity is associated with the phenotype of polycystic ovary syndrome (PCOS). Self-reported ethnicity was shown to be an inaccurate proxy for ethnic origin in other disease traits, and it remains unclear how in PCOS patients self-reported ethnicity compares with a biological proxy such as genetic ancestry. OBJECTIVE: We compared the impact of self-reported ethnicity versus genetic ancestry on PCOS and tested which of these 2 classifications better predicts the variability in phenotypic characteristics of PCOS. PATIENTS: A total of 1499 PCOS patients from The Netherlands, comprising 11 self-reported ethnic groups of European, African, American, and Asian descent were genotyped with the Illumina 610K Quad BeadChip and merged with the data genotyped with the Illumina HumanHap650K available for the reference panel collected by the Human Genome Diversity Project (HGDP), in a collaboration with the Centre Etude Polymorphism Humain (CEPH), including 53 populations for ancestry reference. MAIN OUTCOME MEASURES: Algorithms for inferring genetic relationships among individuals, including multidimensional scaling and ADMIXTURE, were applied to recover genetic ancestry for each individual. Regression analysis was used to determine the best predictor for the variability in PCOS characteristics. RESULTS: The association between self-reported ethnicity and genetic ancestry was moderate. For amenorrhea, total follicle count, body mass index, SHBG, dehydroepiandrosterone sulfate, and insulin, mainly genetic ancestry clusters ended up in the final models (P values < .004), indicating that they explain a larger proportion of variability of these PCOS characteristics compared with self-reported ethnicity. Especially variability of insulin levels seems predominantly explained by genetic ancestry. CONCLUSIONS: Self-reported ancestry is not a perfect proxy for genetic ancestry in patients with PCOS, emphasizing that by using genetic ancestry data instead of self-reported ethnicity, PCOS-relevant misclassification can be avoided. Moreover, because genetic ancestry explained a larger proportion of phenotypic variability associated with PCOS than self-reported ethnicity, future studies should focus on genetic ancestry verification of PCOS patients for research questions and treatment as well as preventive strategies in these women.

Excess mortality in mothers of patients with polycystic ovary syndrome.

STUDY QUESTION: Do diabetic parents of patients with polycystic ovary syndrome (PCOS) encounter excess mortality compared with the mortality of men and women with type 2 diabetes, recruited without selection for PCOS? SUMMARY ANSWER: Type 2 diabetes among mothers of PCOS patients results in excess mortality compared with women with diabetes from the general population. WHAT IS KNOWN ALREADY: Insulin resistance is a prominent feature of PCOS. Because of the heritable nature of PCOS, parents of these patients are also prone to develop type 2 diabetes mellitus, which might influence their life expectancy. STUDY DESIGN, SIZE, DURATION: This reverse parent-offspring study included 946 mothers and 902 fathers of patients with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: The medical history of the parents was primarily obtained during the initial screening of each patient and updated via questionnaires. Mortality data of these parents were compared with the mortality rates of the general Dutch population and with mortality rates of a control population consisting of 1353 men and women diagnosed with type 2 diabetes mellitus. The standardized mortality ratio (SMR) was calculated as the ratio of the observed mortality of the parents to the expected mortality in the general Dutch population. The mortality of parents with type 2 diabetes mellitus relative to controls with diabetes but not related to anyone with PCOS was standardized for age, gender and calendar period using Poisson regression. MAIN RESULTS AND ROLE OF CHANCE: In total, 302 parents were deceased in 62 693 person-years. Mothers above age 60 had a significant excess mortality of 1.50 (95% CI 1.15-1.92) compared with the general Dutch population. Moreover, mothers with diabetes had two-times higher mortality risk compared with control women with diabetes (RR 2.0, 95% CI 1.19-3.41). No excess mortality among fathers of PCOS patients was observed. LIMITATIONS, REASON FOR CAUTION: Although recall bias for family history was previously demonstrated to be minimal for long-term chronic diseases, the prevalence of diabetes in the parents was based on their daughter's self-report and was not clinically confirmed. Also, no other additional clinical data regarding the parent population were available. Prospective long-term follow-up studies should be conducted to confirm this excess mortality. WIDER IMPLICATIONS OF THE FINDINGS: Our findings justify screening for type 2 diabetes mellitus among the mothers with a daughter suffering from PCOS to ensure that timely preventive and therapeutic measures according to the appropriate guidelines can be taken. STUDY FUNDING/COMPETING INTERESTS: No particular funding was received for this study. Y.V.L., M.E.R.-S., N.K., J.R.v.L., M.v.d.B., H.J.G.B. and E.J.G.S. do not have any conflict of interest. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono, and Wyeth. These companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review.

CONTEXT: Metabolic disturbances, in particular, insulin resistance (IR) and dyslipidemia, are common in women suffering from polycystic ovary syndrome (PCOS). Evidence is accumulating that vitamin D status may contribute to the development of metabolic disturbances in PCOS. OBJECTIVE: The aim of this study was to carry out a systematic review addressing the association between vitamin D status, vitamin D receptor polymorphisms, and/or polymorphisms related to vitamin D metabolism and metabolic disturbances in women with PCOS. DESIGN AND METHODS: A systematic search of electronic databases was carried out up to January 2013 for observational studies and clinical trials in women suffering from PCOS with outcome measures that were related to vitamin D status. We conducted univariate and multivariate regression analyses of the weighted means to gain insights into the association between vitamin D, BMI, and IR based on existing literature. RESULTS: We found 29 eligible trials with inconsistency in their results. One well-designed randomized controlled trial has been carried out until now. Univariate regression analyses of the weighted means revealed vitamin D to be a significant and independent predictor of IR in both PCOS and control women. The significance disappeared after adjustment for BMI in PCOS women. CONCLUSIONS: Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. The causal relationship between vitamin D status and metabolic disturbances in PCOS remains to be determined in well-designed placebo-controlled randomized clinical trials.

Genetic ancestry affects the phenotype of normogonadotropic anovulatory (WHOII) subfertility.

INTRODUCTION: Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. OBJECTIVE: Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio-geographic ancestry and predict the phenotype of individual patients. MATERIALS AND METHODS: A standardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. RESULTS: Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structure on a continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. CONCLUSION: Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility.