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. We performed an international meta-analysis of genome-wide association studies combining over 10,000,000 genetic markers in more than 10,000 European women with polycystic ovary syndrome (PCOS) and 100,000 controls. We found three new risk variants associated with PCOS. Our data demonstrate that the genetic architecture does not differ based on the diagnostic criteria used for PCOS. We also demonstrate a genetic pathway shared with male pattern baldness, representing the first evidence for shared disease biology in men, and shared genetics with depression, previously postulated based only on observational studies.

Design: Valid data on acromegaly incidence, complications and mortality are scarce. The Danish Health Care System enables nationwide studies with complete follow-up and linkage among health-related databases to assess acromegaly incidence, prevalence, complications and mortality in a population-based cohort study. Method: All incident cases of acromegaly in Denmark (1991–2010) were identified from health registries and validated by chart review. We estimated the annual incidence rate of acromegaly per 10⁶ person-years (py) with 95% confidence intervals (95% CIs). For every patient, 10 persons were sampled from the general population as a comparison cohort. Cox regression and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used. Results: Mean age at diagnosis (48.7 years (CI: 95%: 47.2–50.1)) and annual incidence rate (3.8 cases/10⁶ persons (95% CI: 3.6–4.1)) among the 405 cases remained stable. The prevalence in 2010 was 85 cases/10⁶ persons. The patients were at increased risk of diabetes mellitus (HR: 4.0 (95% CI: 2.7–5.8)), heart failure (HR: 2.5 (95% CI: 1.4–4.5)), venous thromboembolism (HR: 2.3 (95% CI: 1.1–5.0)), sleep apnoea (HR: 11.7 (95% CI: 7.0–19.4)) and arthropathy (HR: 2.1 (95% CI: 1.6–2.6)). The complication risk was also increased before the diagnosis of acromegaly. Overall mortality risk was elevated (HR: 1.3 (95% CI: 1.0–1.7)) but uninfluenced by treatment modality. Conclusion: (i) The incidence rate and age at diagnosis of acromegaly have been stable over decades, and the prevalence is higher than previously reported. (ii) The risk of complications is very high even before the diagnosis. (iii) Mortality risk remains elevated but uninfluenced by mode of treatment.

The aims of the study were to clarify the impact of storage time and centrifugation strategy on brain-derived neurotrophic factor (BDNF) levels in human serum and plasma samples. In addition, we analyzed associations between BDNF levels, cardiorespiratory fitness and waist circumference. Seventeen healthy males (25.2 (4.1) years) were included in the study. Blood samples were drawn after an overnight fast and treated to different protocols, varying in time before centrifugation and centrifugation strategy. BDNF was analyzed in serum, normal plasma (NP) and platelet-poor plasma (PPP). Also, waist circumference and cardiorespiratory fitness were measured. A large increase was observed in serum BDNF levels during the first hour of clotting. BDNF in NP correlated with PPP, whereas no correlations were found between BDNF in serum and plasma. Though not statistical significant, correlations between fitness and BDNF in serum changed from positive at 30 min. to negative when clotting time was ≥60 min. In conclusion, BDNF levels in serum were affected by clotting time, whereas BDNF levels in plasma were influenced by centrifugation strategy. Importantly, BDNF in serum and plasma appears to reflect two different pools of BDNF. The biological relevance of the velocity of BDNF release during clotting and its dependence upon fitness must be investigated further.

Objective Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited. Design National Patient Register–based study. Methods Patients with PCOS [PCOS Denmark and embedded cohort, PCOS Odense University Hospital (OUH)] and a control population with no previous diagnosis of T2D. PCOS OUH (N = 1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N = 18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N = 54,680). Main outcome T2D events according to diagnosis codes and filled medicine prescriptions. Results The median (quartiles) follow-up was 11.1 (6.9 to 16.0) years. The hazard ratio (HR) with 95% confidence interval (CI) for development of T2D in PCOS Denmark was HR = 4.0 (95% CI, 3.7 to 4.3; P < 0.001), and the total event rate of T2D was 8.0 per 1000 person years in PCOS Denmark vs 2.0 per 1000 person years in controls (P < 0.001). The median age at diagnosis of T2D was 31 (26 to 37) years in PCOS Denmark vs 35 (27 to 44) years in controls (P < 0.001). In multiple regression analyses, body mass index, glycated hemoglobin, fasting blood glucose, 2-hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D. Conclusion The event rate of T2D was higher in PCOS compared with controls, and T2D was diagnosed at a younger age.