Search

Supplemental Material, Repr_Sci_Supporting_Information for Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort by Marlieke A. de Wilde, Jacobien B. Eising, Marlise N. Gunning, Maria P. H. Koster, Annemieke M. V. Evelein, Geertje W. Dalmeijer, Cuno S. P. M. Uiterwaal, Marinus J. C. Eijkemans, Cornelis K. van der Ent, Folkert J. Meijboom, and Bart C. J. M. Fauser in Reproductive Sciences

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

In the fourth month of fetal development, there is a maximum of about 6-7 million follicles present in the ovaries. Thereafter, follicle numbers decline slowly. The progressive loss of quality and quantity of oocytes is called ovarian ageing. During the process of ovarian ageing, different phases can be discerned with about 10 year intervals: optimal fecundity, infertility, sterility and menopause. Consequently, if menopause occurs early in life, a woman’s fecundity has been compromised decades before. Therefore, accurate prediction of the rate of ovarian ageing and the associated fecundity is desirable. Estimation of ovarian reserve is possible by a wide array of endocrine, ultrasound and genetic tests currently available. This thesis discusses the value of genetic, vascular and other factors in the prediction of menopause and the clinical applicability of ovarian reserve tests is evaluated. The results of the various studies in this thesis underline the complexity of ovarian ageing and the difficulties that prediction of menopause entails. Based on its relationship with age and the antral follicle count, its cycle stability and longitudinal decline with age, anti-Mllerian Hormone (AMH) seems currently the best ovarian reserve test to predict age at menopause. Future longitudinal studies should confirm its accuracy and clinical applicability. The plausibility of vascular factors determining age at menopause is based primarily on indirect evidence. Since there is no consensus about the definition and mode of measurement of vascular ageing, future research should be interpreted cautiously. Diverse ovarian reserve tests are integrated in fertility work-up worldwide, although their capacity to predict pregnancy is poor. Moreover, current research involving ovarian reserve tests often ignores female age and past treatment outcomes as predictive factors of pregnancy. Identification of women with an adequate prognosis seems possible based on strict test cut-offs. Future research should focus on improving the accuracy of prediction models, possibly by incorporating AMH, familial age at menopause and cycle regularity into these models. Currently, there is no single ovarian reserve test able to predict age at menopause with enough certainty in individual women. Future research should focus on combining various ovarian reserve tests to improve the predictive accuracy.

Postponement of childbearing has led to increased rates of age-related female subfertility. Age-related decreases in ovarian follicle numbers and decay in oocyte quality influence the natural loss of fecundity and ultimately the start of menopause. The rate of ovarian ageing is highly variable among women, so it is relevant to be able to identify women who have severely decreased ovarian reserve for their age. Spontaneous Premature Ovarian Failure (POF) is the most extreme phenotype of ovarian failure at a young age. POF is characterized by spontaneous secondary amenorrhea before the age of 40. POF not only truncates the fertile lifespan, but also has major implications for long-term health (i.e. osteoporosis, cardiovascular health and cognition). The aetiology of the great majority of spontaneous POF cases remains unknown. Since family history has been shown to be the best predictor for early menopause and strong associations have been disclosed between the menopausal ages of mothers and daughters, sisters and twin pairs, idiopathic POF is most likely due to genetic factors. The aim of this thesis was to further elucidate the phenotype of premature ovarian failure and to explore the genetic mechanisms underlying this phenotype. Classically, ovarian dysfunction is categorized on the basis of cycle history and follicle-stimulating hormone (FSH). Our study indicated that anti-Mllerian hormone, a novel ovarian marker, may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses or with cycle disturbances but not fulfilling the POF diagnostic criteria. Early menopause is associated with a higher incidence of cardiovascular events later in life. Concurrent with the menopausal transition, there is a shift in lipid profile. POF provides a route to studying the effect of cessation of ovarian function on lipid profile independent of the effects of advanced chronological age. We found that loss of ovarian function at a very young age (POF) coincides with subtle changes in lipid profile (higher triglyceride levels, marginal lower HDL-cholesterol). Androgens are better markers for unfavourable lipid changes than oestrogen levels or duration of oestrogen deprivation. A genome wide association study was initiated to identify new genetic variants involved in POF. We did observe a possible association with a single nucleotide polymorphism in ADAMTS19, a biologically plausible candidate gene. This finding warrants a larger follow-up study to investigate its role in POF. Besides SNPs, the human genome contains multiple copy number variants (CNVs), small, sub-microscopic deletions and duplications. POF is associated with macroscopic deletions, in particular on the Xq arm. Using the intensities of high-density, genome-wide oligonucleotide arrays, it is now possible to obtain an increase in resolution of more than 100 times compared to conventional karyograms, and it is thus possible to detect CNVs. Sixty-three percent of the long arm CNVs (90% deletion) mapped to locus Xq21. Our findings are preliminary although the abundant overrepresentation of CNVs on Xq21 further substantiates the important role of this locus in the genetics of POF.