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.

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Background Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age.Methods Metabolomic profiling on fasting blood was carried out in 6055 individuals from the UK. Stepwise regression was performed to identify a panel of independent metabolites which could be used as a surrogate for age. We also investigated the association with birthweight overall and within identical discordant twins and with genome-wide methylation levels.Results We identified a panel of 22 metabolites which combined are strongly correlated with age (R2 = 59%) and with age-related clinical traits independently of age. One particular metabolite, C-glycosyl tryptophan (C-glyTrp), correlated strongly with age (beta = 0.03, SE = 0.001, P = 7.0 × 10−157) and lung function (FEV1 beta = −0.04, SE = 0.008, P = 1.8 × 10−8 adjusted for age and confounders) and was replicated in an independent population (n = 887). C-glyTrp was also associated with bone mineral density (beta = −0.01, SE = 0.002, P = 1.9 × 10−6) and birthweight (beta = −0.06, SE = 0.01, P = 2.5 × 10−9). The difference in C-glyTrp levels explained 9.4% of the variance in the difference in birthweight between monozygotic twins. An epigenome-wide association study in 172 individuals identified three CpG-sites, associated with levels of C-glyTrp (P < 2 × 10−6). We replicated one CpG site in the promoter of the WDR85 gene in an independent sample of 350 individuals (beta = −0.20, SE = 0.04, P = 2.9 × 10−8). WDR85 is a regulator of translation elongation factor 2, essential for protein synthesis in eukaryotes.Conclusions Our data illustrate how metabolomic profiling linked with epigenetic studies can identify some key molecular mechanisms potentially determined in early development that produce long-term physiological changes influencing human health and ageing.

T(4) is standard treatment for hypothyroidism. A recent study reported that combined T(4)/liothyronine (T(3)) treatment improved well-being and cognitive function compared with T(4) alone. We conducted a double-blind, randomized, controlled trial with a crossover design in 110 patients (101 completers) with primary hypothyroidism in which liothyronine 10 micro g was substituted for 50 micro g of the patients' usual T(4) dose. No significant (P < 0.05) difference between T(4) and combined T(4)/T(3) treatment was demonstrated on cognitive function, quality of life scores, Thyroid Symptom Questionnaire scores, subjective satisfaction with treatment, or eight of 10 visual analog scales assessing symptoms. For the General Health Questionnaire-28 and visual analog scales assessing anxiety and nausea, scores were significantly (P < 0.05) worse for combined treatment than for T(4) alone. Serum TSH was lower during T(4) treatment than during combined T(4)/T(3) treatment (mean +/- SEM, 1.5 +/- 0.2 vs. 3.1 +/- 0.2 mU/liter; P < 0.001), a potentially confounding factor; however, subgroup analysis of subjects with comparable serum TSH concentrations during each treatment showed no benefit from combined treatment compared with T(4) alone. We conclude that in the doses used in this study, combined T(4)/T(3) treatment does not improve well-being, cognitive function, or quality of life compared with T(4) alone.

Objectives Premature ejaculation (PE) is the most common ejaculatory dysfunction. We assessed the efficacy of sildenafil to increase the time to ejaculation, improve ejaculatory control, and decrease the postejaculatory erectile refractory time in men with PE. Design and Methods The main study was an 8-week, double-blind, placebo-controlled, parallel group study in men between 18 and 65 years of age with diagnosed PE. A substudy was also conducted using a subset of patients (two-way crossover, one center) before entry to the main study. The primary study measured intravaginal ejaculatory latency (IELT) and responses to the Index of Premature Ejaculation (IPE) questionnaire. The substudy measured vibrotactile stimulation ejaculatory latency time (VTS-ELT) and postejaculatory erectile refractory time. Differences between treatment groups were determined by ancova at the 5% level of significance. Results The change in IELT (1.6 ± 6.08 vs. 0.6 ± 2.07 minutes) and VTS-ELT (2.9 ± 0.4 vs. 2.4 ± 0.4 minutes) were higher after taking sildenafil, compared with placebo, but did not reach statistical significance. However, patients who took sildenafil (vs. placebo) reported significantly (P &lt; 0.05) increased ejaculatory control (1.8 ± 0.3 vs. 1.5 ± 0.3), increased ejaculatory confidence (2.2 ± 0.2 vs. 1.9 ± 0.2), and improved overall sexual satisfaction scores (3.1 ± 0.2 vs. 2.8 ± 02) on the IPE, and had a decreased postejaculatory erectile refractory time (3.2 ± 0.7 vs. 6.4 ± 0.7 minutes). The most common adverse events for sildenafil (vs. placebo) were headache (15% vs. 1%), flushing (15% vs. 0%), dyspepsia (5% vs. 1%), abnormal vision (5% vs. 0%), and rhinitis (5% vs. 0%). Conclusions Although IELT and VTS-ELT were not significantly improved, sildenafil increased confidence, the perception of ejaculatory control, and overall sexual satisfaction, and decreased the refractory time to achieve a second erection after ejaculation in men with PE.

Erectile dysfunction (ED) is a common problem in general medical practice affecting especially the elderly and those with cardiovascular disease and diabetes mellitus. A study was undertaken by questionnaire distributed to consecutive adult male attendees at 62 general medical practices. 1240 completed questionnaires were available for analysis. The mean age of participants was 56.4 y (range 18 ± 91 y). 488 men (39.4%) reported ED: 119 (9.6%)`occasionally', 110 (8.9%)`often', and 231 (18.6%)`all the time' (complete ED). Among 707 men aged 40±69 y 240 (33.9%) reported ED and 84 (11.9%) had complete ED. The prevalence of complete ED increased with age, rising from 2.0% in the 40 ± 49 y age group to 44.9% in the 70±79 y age group. Only 11.6% of men with ED had received treatment. Hypertension, ischaemic heart disease, peripheral vascular disease and diabetes mellitus were frequently associated with ED. 40% of diabetic men aged 60 y or older had ED all the time.

We have shown impaired QoL and increased prevalence of psychological morbidity in PCOS compared with population norms. The perception of inadequate information about the condition correlated with poorer QoL scores. Improved information delivery may lead to an improvement in QoL and needs to be tested with an intervention study.

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