From cardiovascular protection to cardiovascular risk: the metamorphosis of menopausal hormone therapy.

Over the last 70years, oestrogen therapy for the management of menopausal symptoms has undergone a metamorphosis from perceived cardiovascular protection to perceived cardiovascular risk. The former perception is based on the convincing evidence from the Nurses' Health Study cohorts and the epidemiological data surrounding early menopause. The latter, and later, perception is based on the disquieting results from two randomised controlled studies, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative study (WHI). The reality is probably more nuanced than the conclusions presented by any of these studies. When face to face with a patient, the clinician must negotiate the appropriate decision pathway around the interaction between cardiovascular risk, cardiovascular disease, menopause, and oestrogen +/-progestogen-containing hormone therapy.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Digenic Congenital Hypogonadotropic Hypogonadism Due to Heterozygous GNRH1 p.R31C and AMHR2 p.G445_L453del Variants.

A 28-year-old man with congenital hypogonadotropic hypogonadism (CHH) was found to be heterozygous for the GNRH1 p.R31C mutation, reported in the literature as pathogenic and dominant. The same mutation was found in his son at birth, but the testing of the infant at 64 days confirmed the hormonal changes associated with minipuberty. This led to further genetic sequencing of the patient and his son, which found a second variant, AMHR2 p.G445_L453del, in the heterozygous form, reported as pathogenic in the patient but not in his son. This suggests a digenic cause of the patient's CHH. Together, these mutations are postulated to contribute to CHH by the lack of anti-Müllerian hormone (AMH) signalling, leading to the impaired migration of gonadotrophin releasing hormone (GnRH) neurons, the lack of the AMH effect on GnRH secretion, and altered GnRH decapeptide with reduced binding to GnRH receptors. This led us to the conclusion that the observed GNRH1 mutation in the heterozygous state is not certain to be dominant or, at least, exhibits incomplete penetrance and variable expressivity. This report also emphasises the opportunity afforded by the time window of minipuberty in assessing the inherited genetic disorders of hypothalamic function.

Evaluation of 28-day estradiol and progesterone vaginal rings in a phase 1 clinical pharmacokinetic study.

OBJECTIVE: The aim of this work is to develop a combination of 17ß-estradiol (E2) and progesterone (P4) in a single-dose intravaginal ring (IVR) for the treatment of vasomotor symptoms (VMS) and genitourinary syndrome of menopause while providing endometrial protection. The objective of this study was to evaluate DARE-HRT1, a 28-day IVR that continuously delivers E2 and P4, in a phase 1 clinical trial to assess its pharmacokinetics. METHODS: This was an open-label, three-arm (group) study. Thirty-two (32) healthy postmenopausal women were recruited at two Australian sites. The average age was 57.2 years (47-69 y). The first arm received one ring for 28 days designed to release E2 at a rate of 80 µg/d and P4 at 4 mg/d (80/4 IVR); the second arm received a ring releasing E2 at 160 µg/d and P4 at 8 mg/d (160/8 IVR). The third arm received oral Estrofem (1 mg E2) and Prometrium (100 mg P4) both daily for 29 days. Blood samples were taken predose then intensively over the first day (day 1) and periodically thereafter over the remaining 27 days. After removal of the rings on the morning of day 29, intensive samples were collected. Similar procedures were conducted with women enrolled in the oral group. The plasma samples were analyzed for E2, estrone (E1), and P4 using validated bioanalytical methods. RESULTS: The baseline-adjusted steady-state plasma levels of E2 and P4 from 80/4 IVR were 20.4 ± 17.1 pg/mL and 1.32 ± 0.19 ng/mL (n = 10), respectively. The baseline-adjusted steady-state plasma levels of E2 and P4 from 160/8 IVR were 30.9 ± 8.7 pg/mL and 2.08 ± 0.50 ng/mL (n = 10), respectively. The baseline-adjusted average plasma concentrations of E2 and P4 at day 29 of the oral group were 35.4 ± 11.2 pg/mL and 0.79 ± 0.72 ng/mL (n = 11), respectively. The baseline-adjusted steady state of E1 from the 80/4 IVR and the 160/8 IVR were 22.1 ± 16.6 pg/mL (n = 10) and 25.2 ± 12.3 pg/mL (n = 10), respectively. The baseline-adjusted concentration of E1 in the oral arm was 209 ± 67.7 ng/mL (n = 11). The IVR were well tolerated, and no serious adverse events were reported. CONCLUSIONS: The 80/4 IVR and 160/8 IVR gave similar steady-state concentrations of E2 as seen with drug products approved by the US Food and Drug Administration for treatment of VMS and genitourinary symptoms of menopause. The E2 concentrations of this study support the potential of DARE-HRT1, a promising new option for hormone therapy for treatment of VMS and vaginal symptoms associated with menopause.

Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18-70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138. FINDINGS: Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 -39% [95% CI -46 to -31] vs placebo -26% [-33 to -18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events. INTERPRETATION: Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy. FUNDING: QUE Oncology.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

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.

Clinical audit of estradiol implant therapy: Long duration of action and implications in non-hysterectomised women.

We audited the files of 114 postmenopausal women who had been treated with subcutaneous Estrapel (50mg oestradiol implants). Of the 92 women who received more than one implant, the median number of days between implants was 223.5 (range 49-875), with an estimated median time to return to baseline of 311days (range 108-1228). Although oestradiol implants can provide an excellent non-oral treatment option, their prolonged action makes patient selection important, as the implants cannot easily be removed. In women with an intact uterus, the continuation of progestin therapy after cessation of implant therapy is imperative.

Polycystic ovary syndrome in type 2 diabetes: does it predict a more severe phenotype?

OBJECTIVE: To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS. DESIGN: Cross-sectional study. SETTING: Tertiary hospital. PATIENT(S): Female inpatients age 18-75 years with DM2. INTERVENTION(S): A face-to-face questionnaire was administered. MAIN OUTCOME MEASURE(S): Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy. RESULT(S): One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m2 vs. 36.8 kg/m2), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%). CONCLUSION(S): A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes.

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

Clustering of metabolic and cardiovascular risk factors in the polycystic ovary syndrome: a principal component analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent condition with heterogeneity of clinical features and cardiovascular risk factors that implies multiple aetiological factors and possible outcomes. OBJECTIVE: To reduce a set of correlated variables to a smaller number of uncorrelated and interpretable factors that may delineate subgroups within PCOS or suggest pathogenetic mechanisms. MATERIALS AND METHODS: We used principal component analysis (PCA) to examine the endocrine and cardiometabolic variables associated with PCOS defined by the National Institutes of Health (NIH) criteria. Data were retrieved from the database of a single clinical endocrinologist. We included women with PCOS (N = 378) who were not taking the oral contraceptive pill or other sex hormones, lipid lowering medication, metformin or other medication that could influence the variables of interest. PCA was performed retaining those factors with eigenvalues of at least 1.0. Varimax rotation was used to produce interpretable factors. RESULTS: We identified three principal components. In component 1, the dominant variables were homeostatic model assessment (HOMA) index, body mass index (BMI), high density lipoprotein (HDL) cholesterol and sex hormone binding globulin (SHBG); in component 2, systolic blood pressure, low density lipoprotein (LDL) cholesterol and triglycerides; in component 3, total testosterone and LH/FSH ratio. These components explained 37%, 13% and 11% of the variance in the PCOS cohort respectively. CONCLUSIONS: Multiple correlated variables from patients with PCOS can be reduced to three uncorrelated components characterised by insulin resistance, dyslipidaemia/hypertension or hyperandrogenaemia. Clustering of risk factors is consistent with different pathogenetic pathways within PCOS and/or differing cardiometabolic outcomes.

Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy.

CONTEXT: There is an association between nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS). Marine-derived omega-3 fatty acids have favorable effects on cardiovascular risk and could reduce liver fat in NAFLD. OBJECTIVE: The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors. DESIGN AND SETTING: We conducted a randomized, crossover study at a tertiary cardiovascular research center. SUBJECTS: Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m(2)) participated in the study. INTERVENTION: We compared 4g/d of omega-3 fatty acids with placebo over 8 wk. MAIN OUTCOME MEASURES: The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure. RESULTS: Omega-3 fatty acids significantly decreased liver fat content compared with placebo [10.2 (1.1) vs. 8.4 (0.9)%; P = 0.022]. There was also a reduction in triglycerides [1.19 (1.03-1.47) vs. 1.02 (0.93-1.18) mmol/liter; P = 0.002], systolic blood pressure [124.1 (12.1) vs. 122.3 (14.5) mm Hg; P = 0.018], and diastolic blood pressure [73.2 (8.4) vs. 69.7 (8.3) mm Hg; P = 0.005] with omega-3 fatty acids compared with placebo. Omega-3 fatty acids particularly decreased hepatic fat in women with hepatic steatosis, defined as liver fat percentage greater than 5% [18.2 (11.1) vs. 14.8 (9.3)%; P = 0.03]. CONCLUSIONS: Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. Whether this translates into a reduction in cardiometabolic events warrants further study.

Dissociation of endothelial function and arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS).

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk but it is not clear if this is independent of obesity and insulin resistance. This study therefore investigates endothelial function and arterial stiffness in nonobese, noninsulin resistant women with PCOS. DESIGN: This is cross-sectional case-control study. PATIENTS: A total of 19 young women with PCOS, with body mass index (BMI) <30 kg/m(2), and 19 healthy controls matched for age and BMI were included in the study. MEASUREMENTS: Endothelial function was assessed with flow mediated dilatation (FMD) of the brachial artery, while arterial stiffness was assessed with pulse wave velocity (PWV) and augmentation index (AI). RESULTS: There were no significant differences between PCOS and control subjects when assessing the following clinical and biochemical variables: blood pressure, homeostasis model assessment insulin-resistance index, lipids and oestradiol. Women with PCOS had higher free androgen index scores (5.14 ± 3.47 vs. 3.25 ± 1.42, P = 0.036). The PCOS subjects had significantly lower FMD of the brachial artery compared with the controls (6.5 ± 2.9%vs. 10.5 ± 4.0%, P < 0.01). There were no significant differences in markers of arterial stiffness (PWV 5.8 ± 1.1 vs. 6.0 ± 1.0, P = 0.58, AI 16.5 ± 10.2 vs. 20.3 ± 10.2, P = 0.25). CONCLUSIONS: Women with polycystic ovary syndrome who are young, nonobese, and have no biochemical evidence of insulin resistance, have abnormal vascular function, but normal arterial stiffness, when compared with age and weight matched control subjects. Whether this leads to a greater risk of cardiovascular disease requires further investigation.

Effects of the route of estrogen administration on insulinlike growth factor-I, IGF binding protein-3, and insulin resistance in healthy postmenopausal women: results from a randomized, controlled study.

OBJECTIVE: Oral estrogen therapy suppresses insulin like growth factor I (IGF-I) levels, whereas conventional dose transdermal estradiol (E2) does not. However, it has been proposed that if sufficiently high serum E2 levels are achieved, nonoral E2 will also suppress serum IGF-I. The aim of the study was to investigate the effects of intranasal E2 with norethisterone (E2/NET) versus oral E2/NET acetate on IGF-I, IGF binding protein 3, and insulin resistance in postmenopausal women. DESIGN: This was a randomized, multicenter, double-blind, double-dummy trial. Postmenopausal women were randomized to receive either daily intranasal E2/NET (175 microg/275 microg) as a spray and a placebo tablet (n = 41) or oral E2/NET acetate (1 mg/0.5 mg) plus placebo intranasal spray (n = 41) for 1 year. Fasting plasma concentrations of IGF-I, IGF binding protein 3, glucose and insulin, glucose and insulin at 120 minutes post-glucose challenge, and the homeostasis model assessment for insulin resistance were assessed at baseline and after 52 weeks of treatment. RESULTS: The two groups were well matched for all clinical and biochemical parameters at baseline. There were no significant between-group differences for fasting and 120-minute glucose, insulin, homeostasis model assessment for insulin resistance, and IGF binding protein 3. The mean IGF-I level at week 52 was significantly lower for women treated with oral versus intranasal therapy (116 +/- 21 [SD] versus 134 +/- 33 [SD], P = 0.005) and the mean difference in change over 52 weeks in IGF-I was significantly different between groups (-19, 95% CI:-37 to -1, P = 0.04). CONCLUSIONS: In healthy postmenopausal women, intranasal E2 at a dose that results in serum levels that exceed the proposed threshold for growth hormone and IGF-I effects, does not alter IGF-I levels. This suggests that the effect of exogenous estrogen on IGF-I is a function of the method of administration rather than being dose related.

Cardiometabolic risk in polycystic ovary syndrome: a comparison of different approaches to defining the metabolic syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and features in common with the metabolic syndrome (MetS)--factors shown to predict cardiovascular risk and type 2 diabetes. We investigated the prevalence and characteristics of the MetS in PCOS by three definitions-World Health Organization (WHO), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and International Diabetes Federation (IDF)--and compared that with the background population. METHODS: Cross-sectional study of 168 women with PCOS and 883 age-matched controls from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. RESULTS: Prevalence of the MetS in PCOS subjects was 33% by WHO, 37% by NCEP-ATP-III and 40% by IDF criteria, compared with 10% by NCEP-ATP-III and 13% by IDF in controls (P < 0.001). MetS by WHO criteria was not calculated in the AusDiab population. Age was an independent predictor of MetS in PCOS and controls. The prevalence of MetS was significantly higher among those with PCOS (P = 0.027) in obese women (BMI > 30 kg/m(2)), and higher but not significantly so in overweight (BMI 25-30 kg/m(2)) women (P = 0.052). Dehydroepiandrosterone sulphate was associated with a lower risk of the MetS--Odds ratio 0.86 (95% confidence interval, 0.77-0.97, P = 0.011). CONCLUSIONS: An approximate 4-fold increase in the prevalence of the MetS in women with PCOS compared with the general population, consistent with the proposed major role of insulin and obesity in the syndrome, implies greater risk of cardiometabolic disease in women with PCOS. However, this estimate is likely to vary according to PCOS definition, ethnicity and different aetiological pathways to PCOS.

Polymorphism in postinsulin receptor signaling pathway is not associated with polycystic ovary syndrome.

OBJECTIVE: To investigate polymorphisms in postinsulin receptor signaling. To investigate PIK3R1, SLC2A4, SLC2A4RG, and MEF2A to determine whether these genes are associated with susceptibility to polycystic ovary syndrome (PCOS) or key phenotypic features of insulin resistance in subjects with PCOS. DESIGN: Case-control study. SETTING: Participants with PCOS were recruited from a clinical practice database, and controls from the general community. PATIENT(S): One hundred seventy-three patients with PCOS conforming to the National Institutes of Health (NIH) diagnostic criteria, all of Caucasian descent; 107 normally ovulating women of white descent from the general community. INTERVENTION(S): Drawing of blood for DNA extraction. MAIN OUTCOME MEASURE(S): Frequency of PIK3R1, SLC2A4, SLC2A4RG, and MEF2A polymorphisms in case and control subjects. RESULT(S): No significant difference between the frequency of the polymorphisms in case and control women was identified. No single nucleotide polymorphism studied in any of these four genes was associated with the PCOS phenotype. CONCLUSION(S): Polymorphisms in the PIK3R1, SLC2A4, SLC2A4RG, and MEF2A genes are not associated with key PCOS phenotypes.

Prostate cancer following testosterone replacement in Klinefelter syndrome.

Klinefelter syndrome is a common cause of hypogonadism. Testosterone replacement therapy has beneficial effects on bone, muscle and psychosexual function. However, it may remove the relative protection from adenocarcinoma of prostate, which is otherwise rare in uncomplicated Klinefelter syndrome. We report the case of a 55-year-old man with Klinefelter syndrome who developed prostate cancer after only 7 years of androgen supplementation. Androgen deprivation therapy was complicated by the presence of testosterone implants. The patient was treated with androgen blockade followed by radiation therapy. We recommend that serum prostate specific antigen (PSA) and digital rectal examinations be carried out during, as well as before androgen replacement.

Metabolic syndrome and cardiometabolic risk in PCOS.

The cardiovascular risk associated with the polycystic ovary syndrome (PCOS) has recently attracted much interest. Women with PCOS are more likely to fulfill the diagnosis of the metabolic syndrome, a cluster of related cardiometabolic factors known to predict long-term risk of cardiovascular disease and type 2 diabetes. We review the literature pertaining to the link between the metabolic syndrome, cardiovascular disease, and PCOS. We focus on the influence of obesity and hyperandrogenemia, and on strategies for identifying cardiovascular risk in PCOS.

Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome.

OBJECTIVE: To investigate polymorphisms in androgen metabolism regulators that are implicated in the etiology of polycystic ovary syndrome (PCOS) in vitro; to investigate HSD17B6 and GATA6 to determine whether these genes are associated with susceptibility to PCOS or key phenotypic features of patients with PCOS. DESIGN: Case-control association study. SETTING: Participants with PCOS were recruited from a clinical-practice database, and controls, from the general community. PATIENT(S): One hundred seventy-three patients with PCOS and who were of Caucasian descent and conformed to the National Institutes of Health (NIH) diagnostic criteria; 107 normally ovulating women of Caucasian descent from the general community. INTERVENTION(S): Drawing of blood for DNA extraction. MAIN OUTCOME MEASURE(S): Frequency of HSD17B6 and GATA6 polymorphisms in cases and controls. Association of single-nucleotide polymorphisms from HSD17B6 in subjects with PCOS with key phenotypes of PCOS: androgen status, insulin resistance, and body mass index. RESULT(S): Allele distribution for the single-nucleotide polymorphism rs898611 in HSD17B6 was significantly different between PCOS and control subjects (P=.03). Presence of the polymorphic allele was associated with reduced fasting glucose-insulin ratio (P=.02) and increased homeostasis model assessment (P<.01) and body mass index (P<.001) as well as with reduced T (P=.03) in the PCOS group. No association was seen between GATA6 and any of the variables studied. CONCLUSION(S): These data suggest that polymorphisms in the HSD17B6 gene are associated with PCOS and key clinical phenotypes of the disorder.