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Concept: Polycystic ovary syndrome

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Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.183.

Concepts: Luteinizing hormone, Autism, Pervasive developmental disorder, Metformin, Asperger syndrome, Autism spectrum, PDD-NOS, Polycystic ovary syndrome

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Human pre-ovulatory follicular fluid (FF) contains a higher concentration of melatonin than serum. The aim of this study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcomes of an in-vitro maturation (IVM) IVF-embryo transfer programme for patients with polycystic ovarian syndrome (PCOS). Melatonin concentrations in the culture media of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes after using IVM media with or without melatonin were analysed. In the culture media of GC or COC, melatonin concentrations gradually increased. When human chorionic gonadotrophin priming protocols were used, implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control group (P<0.05). Pregnancy rates were also higher, although not significantly. The findings suggest that the addition of melatonin to IVM media may improve the cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes. It is speculated that follicular melatonin may be released from luteinizing GC during late folliculogenesis and that melatonin supplementation may be used to improve the clinical outcomes of IVM IVF-embryo transfer. Melatonin is primarily produced by the pineal gland and regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. Interestingly, human pre-ovulatory follicular fluid contains a higher concentration of melatonin than serum. However, in contrast to animal studies, the direct role of melatonin on oocyte maturation in the human system has not yet been investigated. So, the aim of the study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcome of an in-vitro maturation (IVM) IVF-embryo transfer programme for PCOS patients. The melatonin concentrations in culture medium of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes of IVM IVF-embryo transfer using IVM medium alone or supplemented with melatonin were analysed. In the culture media of GC or COC, the melatonin concentration gradually increased. With human chorionic gonadotrophin priming, the pregnancy and implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control (P<0.05). Our findings suggest that follicular melatonin is released from luteinizing GC during late folliculogenesis and plays a positive role in oocyte maturation. Therefore, addition of melatonin into IVM medium may improve cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes.

Concepts: Luteinizing hormone, Pineal gland, Human chorionic gonadotropin, Circadian rhythm, Ovulation, Polycystic ovary syndrome, Folliculogenesis, Melatonin

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BACKGROUND: The Bone Morphogenetic Proteins (BMPs) are growth factors involved in the folliculogenesis. Alteration in their expression may compromise the reproductive process in disease such as the polycystic ovary syndrome (PCOS). The present study investigated the expression and role of granulosa cell BMP from normal cycling and PCOS women. METHODS AND RESULTS: This prospective study was performed in granulosa cells obtained from 14 patients undergoing IVF : (i) 6 women with normal ovulatory cycles and tubal or male infertility and (ii) 8 women with PCOS. BMP-2, BMP-4, BMP-5, BMP-6, BMP-7 and BMP-8A, and their receptors BMPR-IA, BMPR-IB and BMPR-II were identified by RT-PCR in granulosa cells from normally cycling and PCOS women. BMP-4, 6 and 7 expression were confirmed by immunohistochemistry, Quantitative transcript analysis showed the predominant expression of BMP-6. In granulosa cells from PCOS women, an over-expression of BMP-6 (p<0.01) and BMPR-IA mRNA (p<0.05) were observed. Granulosa cell culture experiments demonstrated that basal estradiol (E2) production was 3-fold higher but FSH-induced E2 increment 2-fold lower in PCOS compared to controls. In PCOS, BMP-6 and 7 exerted a stimulatory effect on basal E2 production while BMP-4 and 6 inhibited FSH-induced E2 production. FSH receptor and aromatase expression were not different between both groups. CONCLUSION: The BMP system is expressed in human granulosa cells from normal cycling and PCOS women. The BMP may be involved in reproductive abnormalities found in PCOS.

Concepts: Protein, Signal transduction, Menstrual cycle, Polycystic ovary syndrome, Folliculogenesis, Anovulation, Granulosa cells, Bone morphogenetic protein

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CONTEXT: Prevalence of Cushing’s syndrome (CS) in patients presenting with hirsutism is not well-known. OBJECTIVE: Screening of CS in patients with hirsutism. SETTING: Referral hospital PATIENTS AND OTHER PARTICIPANTS: This study was carried out on 105 patients who admitted to Endocrinology Department with the complaint of hirsutism. INTERVENTION: All the patients were evaluated with low dose dexamethasone suppression test (LDDST) for CS. MAIN OUTCOME MEASURE: Response to LDDST in patients presenting with hirsutism RESULTS: All the patients had suppressed cortisol levels following low dose dexamethasone administration excluding CS. The etiology of hirsutism were polycystic ovary syndrome in 79%, idiopathic hirsutism in 13%, idiopathic hyperandrogenemia in 6% and non-classical congenital hyperplasia in 2% of the patients. CONCLUSION: Routine screening for CS in patients with a referral diagnosis of hirsutism is not required. For the time being, diagnostic tests for CS in hirsute patients should be limited to patients who have accompanying clinical stigmata of hypercortisolism.

Concepts: Obesity, Glucocorticoid, Cortisol, Spironolactone, Polycystic ovary syndrome, Cushing's syndrome, Hirsutism, Dexamethasone suppression test

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OBJECTIVE: Although extensive evidence indicates the hyperinsulinemia directly contributes to reproductive dysfunction in polycystic ovarian syndrome (PCOS), influence of insulin resistance (IR) on assisted reproductive technology outcomes is poorly understood. In this study we aimed to evaluate the effects of IR on in vitro maturation - in vitro fertilization-embryo transfer (IVM-IVF-ET) in patients with PCOS. DESIGN: Prospective observational study. PATIENTS: Women with PCOS (n = 115) commencing IVM. MEASURMENTS: IR (n = 51) and non-IR (n = 64) women with PCOS ready to commence an IVM cycle were recruited. IR was diagnosed using the glucose tolerance test (GTT) and homeostasis model assessment (HOMA) index. Patients with an abnormal GTT and/or HOMA index > 2.4 were considered IR. Patients underwent 115 cycles of unstimulated hCG-primed IVM. RESULTS: Maturation, fertilization, cleavage rates, the number of good-quality embryo, and blastocyst formation rates were not significantly different between groups. However, implantation (11.6% vs 28.7%, P = 0.001, respectively), clinical pregnancy (23.5% vs 53.1%, P = 0.002, respectively), and ongoing pregnancy rates (21.6% vs 46.9%. P = 0.006, respectively) were significantly decreased in the IR group. The negative effect of IR on pregnancy outcomes remained after controlling for age, body mass index (BMI) and lipid profiles (OR 4.928, 95% CI 1.735-13.991, P = 0.003). CONCLUSIONS: Pregnancy rate after IVM is impaired in IR patients with PCOS. Oocyte development and embryo quality are not affected, suggesting that the effects of hyperinsulinemia on endometrial function and implantation process underlie the decreased pregnancy rate. © 2012 Blackwell Publishing Ltd.

Concepts: Pregnancy, Embryo, Glucose tolerance test, In vitro fertilisation, Menstrual cycle, Implantation, Polycystic ovary syndrome, Blastocyst

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STUDY OBJECTIVE: To evaluate the differences in adipokines, namely adiponectin, leptin, and ghrelin, in obese adolescent girls with or without polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: 38 adolescent girls (age 15-20 years). Group I: 17 Obese adolescent girls with PCOS (BMI ≥ 30 kg/m(2)); Group II: Control group of 21 obese adolescent girls (BMI ≥ 30 kg/m(2)). MAIN OUTCOME MEASURES: Adiponectin, leptin, and ghrelin measurements. RESULTS: LH, LH/FSH, and cortisol levels were significantly higher in the obese PCOS girls compared to the obese controls (6.94 ± 3.28 vs 4.44 ± 1.79; 1.50 ± 0.72 vs 0.90 ± 0.36; 16.02 ± 4.28 vs 12.46 ± 5.29; P < .05, respectively). Adiponectin, leptin, and ghrelin levels were similar between the obese PCOS girls and the obese controls (11.13 ± 6.00 vs 15.26 ± 12.66; 23.66 ± 11.54 vs 23.11 ± 11.17; 665.69 ± 402.12 vs 650.22 ± 467.73, respectively). Adiponectin negatively correlated with BMI (r = -0.32; P = .04) and positively correlated with fasting glucose (r = 0.40; P = .01). Leptin positively correlated with BMI (r = 0.534; P = .001), estradiol (r = 0.354; P = .02), and TSH (r = 0.374; P = .02). No significant correlation was found between ghrelin and the test parameters. CONCLUSION: Among obese adolescents with PCOS, adiponectin, and leptin levels do not seem to be determined by the existence of PCOS, while ghrelin presents no significant correlation.

Concepts: Obesity, Luteinizing hormone, Adipose tissue, Metformin, Menstrual cycle, Polycystic ovary syndrome

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Context: In the general population, about 30% of asymptomatic women have polycystic ovary-like abnormalities (PCO-L), i.e. polycystic ovarian morphology (PCOM) at ultrasound and/or increased anti-Müllerian hormone (AMH) serum level. PCOM has also been reported in 30-50% of women with functional hypothalamic amenorrhea (FHA). Objective: The aim of this study was to verify whether both PCOM and excessive AMH level indicate PCO-L in FHA and to elucidate its significance. Design: We conducted a retrospective analysis using a database and comparison with a control population. Setting: Subjects received ambulatory care in an academic hospital. Patients: Fifty-eight patients with FHA were compared to 217 control women with nonendocrine infertility and body mass index of less than 25 kg/m(2). Interventions: There were no interventions. Main Outcome Measures: We measured serum testosterone, androstenedione, FSH, LH, AMH, and ovarian area values. The antral follicle count (AFC) was used as a binary variable (i.e. negative or positive) because of the evolution of its sensitivity over the time of this study. The ability of these variables (except AFC) to detect PCO-L in both populations was tested by cluster analysis. Results: One cluster (cluster 2) suggesting PCO-L was detected in the control population (n = 52; 24%), whereas two such clusters were observed in the FHA population (n = 22 and n = 6; 38 and 10%; clusters 2 and 3, respectively). Cluster 2 in FHA had similar features of PCO-L as cluster 2 in controls, with higher prevalence of positive AFC (70%) and PCOM (70%), higher values of ovarian area and higher serum AMH (P < 0.0001 for all), and testosterone levels (P < 0.01) than in cluster 1. Cluster 3 in FHA was peculiar, with frankly elevated AMH levels. In the whole population (controls + FHA), PCO-L was significantly associated with lower FSH values (P < 0.0001). Conclusion: PCO-L in FHA is a frequent and usually incidental finding of unclear significance, as in controls. The association of PCO-L with hypothalamic amenorrhea should not lead to a mistaken diagnosis of PCOS.

Concepts: Estrogen, Endocrinology, Luteinizing hormone, Body mass index, Testosterone, Anorexia nervosa, Puberty, Polycystic ovary syndrome

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Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)?

Concepts: Estrogen, Luteinizing hormone, Syndromes, Menstrual cycle, Gynecology, Polycystic ovary syndrome

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Abstract The October 2010 ESHRE/ASRM polycystic ovary syndrome (PCOS) workshop concluded: (1) all combined oral contraceptives (COC) appear to have equal efficacy for PCOS, (2) addition of antiandrogens (spironolactone) to COCs has little treatment benefit and (3) metformin does not improve the live-birth rate and should only be used with impaired glucose tolerance. We compared these guidelines to current practice in the United States IMS claims-database. Time-series analyses were conducted by calendar-year in women with PCOS to evaluate prescribing preferences for COCs, concomitant use of spironolactone, and utilization of metformin. Trends were analyzed with linear regression. Our cohort included 1.6 million women taking COCs, 46 780 with a PCOS claim. Drospirenone utilization increased by 1.52% (SE:0.48%, p = 0.007) per-year more in women with PCOS (4.16%, SE:0.45%, p < 0.001) than in women without PCOS (2.64%, SE:0.17%, p < 0.001)). Concomitant use of drospirenone and spironolactone was common (14.26%) and increased by 0.75% (SE:0.15%, p = 0.002) per-year. Although plasma glucose tests were unavailable, women with PCOS were more likely to take metformin than have a diabetes claim (45.8% versus 15.2%, p < 0.001), indicating some women likely receive metformin solely for PCOS. Our data suggests further attention is needed to medication management of PCOS to bridge the gap between guidelines and practice.

Concepts: Combined oral contraceptive pill, Endocrinology, Glucose tolerance test, Metformin, Menstrual cycle, Spironolactone, Polycystic ovary syndrome, Hirsutism