Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.

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.This work was supported by the Medical Research Council [U106179472; MC_U106179472; U106179471; MC_U106179471] and the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981 to 23andMe). The UK Medical Research Council and Wellcome Trust (092731), together with the University of Bristol, provide core support for the ALSPAC study. AMH assays in ALSPAC were funded with a grant from the US National Institute of Health (R01 DK077659). DAL works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_12013/5).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms946

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

Contains fulltext : 109739.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown

Early initiation of gonadotropin-releasing hormone antagonist treatment results in a more stable endocrine milieu during the mid- and late-follicular phases: a randomized controlled trial comparing gonadotropin-releasing hormone antagonist initiation on cycle day 2 or 6

Objective: to compare the effect of initiating GnRH antagonist (GnRH-a) on cycle day (CD) 2 vs. CD 6 on LH, E2, and P levels in the mid and late follicular phases.Design: nested study within a multicenter randomized controlled trial.Setting: reproductive medicine center in an university hospital.Patient(s): one hundred sixty patients undergoing IVF/intracytoplasmic sperm injection (ICSI).Intervention(s): recombinant FSH (150–225 IU) was administered daily from CD 2 onward. The study group (CD 2) started GnRH-a cotreatment on CD 2, whereas the control group (CD 6) started on CD 6.Main Outcome Measure(s): the follicular phase endocrine profile.Result(s): the LH levels on CD 6 were lower in the CD 2 group (0.6 ± 0.4 vs. 1.9 ± 1.4 IU/L). The CD 2 group demonstrated both lower E2 levels on CD 6 (520.1 ± 429.6 pmol/L vs. 1,071.7 ± 654.2 pmol/L) and on the day of hCG administration (3,341.4 ± 1,535.3 pmol/L vs. 4,573.2 ± 2,445.4 pmol/L). The P levels did not differ on CD 6 or on the day of hCG administration.Conclusion(s): early initiation of GnRH-a cotreatment results in a more stable endocrine profile, with more physiological levels of E2 and LH during the follicular phase. The effect on clinical outcomes must be established in larger trial

Associations of Endogenous Estradiol and Testosterone Levels With Plaque Composition and Risk of Stroke in Subjects With Carotid Atherosclerosis

Sex steroids may play a role in plaque composition and in stroke incidence.status: publishe

Design of a frailty index among community living middle-aged and older people : the Rotterdam study

Item does not contain fulltextOBJECTIVES: To design a frailty index (FI) and evaluate three methods to handle missing data. Furthermore, we evaluated its construct (i.e., skewed distribution, correlation with age and sub-maximum score) and criterion validity (based on mortality risk). STUDY DESIGN: We included 11,539 participants (45+/- years) from a population-based cohort in the Netherlands. Frailty was measured with a FI, which we constructed based on the accumulation of 45 health-related variables, related to mood, cognition, functional status, diseases and conditions, biomarkers, and nutritional status. A total FI-score was calculated by averaging the scores of the deficits, resulting in a score between 0 and 1, with higher scores indicating increasing frailty. Mean imputation, single- and multiple imputation were applied. MAIN OUTCOME MEASURE: Mortality data were obtained by notification from the municipal administration. Median follow-up time was 9.5 years, during which 3902 (34%) participants died. RESULTS: The median FI for the full population was 0.16 (IQR=0.11-0.23). The distribution of the FI was slightly right-skewed, the absolute maximum score was 0.78 and there was a strong correlation with age (Pearson correlation=0.52;95%CI=0.51-0.54). The adjusted HR per unit increase in FI-score on mortality was 1.05 (95%CI=1.05-1.06). Multiple imputation seemed to provide more robust results than mean imputation. CONCLUSION: Based on our results we advise to the use of at least 30 deficits from different health domains to construct a FI if data are not imputed. Future research should use the continuous nature of the FI to monitor trajectories in frailty and find preventive strategies