Background:The role of metformin in the treatment of infertility in women with polycystic ovary syndrome (PCOS) is still controversial.Objective and Outcomes:We investigated whether metformin decreases the early miscarriage rate and improves the pregnancy rates (PR) and live-birth rates (LBR) in PCOS.Methods:This was a multicenter, randomized (1:1), double-blind, placebo-controlled study. Three hundred twenty women with PCOS and anovulatory infertility were randomized to metformin (n = 160, Diformin; obese women, 1000 mg two times daily; nonobese subjects, 500 mg + 1000 mg daily) or identical doses of placebo (n = 160). After 3 months' treatment, another appropriate infertility treatment was combined if necessary. If pregnancy occurred, metformin/placebo was continued up to the 12th week.Results:Miscarriage rates were low and similar in the two groups (metformin 15.2% vs. placebo 17.9%, P = 0.8). Intent-to-treat analysis showed that metformin significantly improved PR and LBR (vs. placebo) in the whole study population (PR: 53.6 vs. 40.4%, P = 0.006; LBR: 41.9 vs. 28.8%, P = 0.014) and PR in obese women (49.0 vs. 31.4%, P = 0.04), and there was a similar trend in nonobese (PR: 58.6 vs. 47.6%, P = 0.09; LBR: 46.7 vs. 34.5%, P = 0.09) and in obese women with regard to LBR (35.7 vs. 21.9%, P = 0.07). Cox regression analysis showed that metformin plus standard infertility treatment increased the chance of pregnancy 1.6 times (hazard rate 1.6, 95% confidence interval 1.13-2.27).Conclusion:Obese women especially seem to benefit from 3 months' pretreatment with metformin and its combination thereafter with routine ovulation induction in anovulatory infertility.

BACKGROUND Anti-Müllerian hormone (AMH) is secreted by ovarian granulosa cells and its serum levels reflect ovarian follicle reserve. The main objective of this study was to test the use of AMH assay in identifying women with primary amenorrhea (PA) and existing follicles and to study follicle phase dependent AMH secretion. METHODS Serum levels of AMH were measured in subjects with FSH-resistant ovaries (FSHRO, n= 12), primary ovarian insufficiency (POI) with PA (n= 11) or secondary amenorrhea (SA n= 20) of unknown etiology, and controls (n= 23), and in Turner syndrome (TS)[45,X (n= 18), mosaicism (n= 7), structural X chromosome abnormalities (SCA, n= 10)], and healthy controls (n= 34). RESULTS Serum levels of AMH in women with FSHRO were comparable with those in control women (2.76 ± 2.37 versus 3.77 ± 2.36 ng/ml) and significantly higher than in women with PA (0.05 ± 0.04 ng/ml; P < 0.001) or SA of unknown origin (0.12 ± 0.20 ng/ml; P < 0.001). TS girls/women with 45,X or SCA had low serum AMH levels (0.13 ± 0.09 and 0.27 ± 0.19 ng/ml) compared with their controls (3.34 ± 2.23 ng/ml) or subjects with mosaicism (2.33 ± 2.81 ng/ml). AMH expression was detected in granulosa cells of women with FSHRO but not in any of the 45,X fetal ovarian specimens. CONCLUSIONS A serum AMH assay could be used to identify patients with decreasing ovarian reserves and POI. Moreover, our results support the notion that AMH is secreted mainly by small non-selected follicles, since follicular granulosa cells were AMH-positive and serum AMH levels were normal/low normal in women with FSHRO, who lack follicle development beyond the small antral stage.

Objective: To establish the diagnostic accuracy of the transesophageal ventriculo-atrial (VA) interval in patients with paroxysmal supraventricular tachycardia (PSVT) and normal baseline electrocardiogram (ECG). Methods: The transesophageal VA interval during tachycardia was recorded in 318 patients (age 45 ± 17 years, 58% female) with PSVT and a normal surface ECG between attacks. Subsequently, all patients underwent an ablation procedure establishing the correct tachycardia diagnosis. Results: AV nodal reentrant tachycardia (AVNRT), AV reentrant tachycardia through a concealed accessory pathway (AVRT), and ectopic atrial tachycardia (EAT) were found in 213, 95, and 10 cases, respectively. Receiver operating characteristic curve analysis identified an optimal cutoff for a binary categorization of AVNRT versus AVRT/EAT at ≤80 ms (area under the curve 0.891). Owing to a biphasic distribution, AVNRT was very likely at VA intervals ≤90 ms with a sensitivity, specificity, and positive predictive value (PPV) of 87%, 91%, and 95%. In the range 91-160 ms the corresponding values for AVRT were 88%, 95%, and 88%(90%, 99%, and 98% in male patients). In the small group with VA intervals >160 ms (n = 29), the diagnosis was less clear (PPV of 67% for AVNRT). Conclusions: In patients with sudden onset regular tachycardia and a normal ECG during sinus rhythm, a transesophageal VA interval of ≤80 ms has the highest diagnostic accuracy to diagnose AVNRT versus AVRT/EAT. Overall, the biphasic distribution of VA intervals suggests considering AVNRT at 90 ms and below and AVRT between 91 and 160 ms (in particular in male patients) while the diagnosis is vague at VA intervals above 160 ms. Ann Noninvasive Electrocardiol 2011;16(4):327-335.

Eur J Clin Invest 2011 ABSTRACT: Background  Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrinopathy characterized by oligomenorrhea, amenorrhoea, clinical and/or biochemical hyperandrogenism and polycystic ovaries. Abdominal deposition of excess body fat and metabolic diseases like insulin resistance and compensatory hyperinsulinemia are commonly observed in PCOS subjects. It has been suggested that visfatin is an adipokine secreted from the abdominal fat influencing glucose metabolism and might therefore contribute to the metabolic disturbances in PCOS. Materials and methods  We measured circulating full-length visfatin levels with a specific enzyme immunoassay (AdipoGen Inc, Incheon, South-Korea) in 57 women with self-reported symptoms of PCOS (hirsutism and/or oligomenorrhea) and ultrasound confirmed polycystic ovaries, and in 57 controls from the Northern Finland 1966 Birth Cohort and explored its association with metabolic and inflammatory parameters. Results  Polycystic ovary syndrome cases had higher body mass index (BMI)(25·7 vs. 24·1 kg/m(2)) and waist circumference (83·2 vs. 78·8 cm) compared to controls, yet there was no difference in plasma visfatin levels between them. In contrast, visfatin significantly correlated with C-reactive protein (CRP) in the control group and with white blood cell count (WBC) in both groups. In linear regression analysis, adjusted for PCOS, smoking, socioeconomic status, BMI or waist circumference, serum lipids and markers of glucose metabolism and hormone status, only WBC remained significantly associated with plasma visfatin levels. Conclusion  Our results suggest that circulating visfatin levels correlate with WBC and CRP but are not associated with PCOS, obesity or metabolic markers, suggesting that visfatin may act as a proinflammatory cytokine.

Context:Postnatal pituitary-testicular activation in infant boys is well characterized. However, the ovarian response to pituitary activation in infancy is less well understood.Objective:The aim of the study was to compare postnatal developmental changes in the pituitary-ovarian axis in preterm and term infant girls.Participants and Design:Sixty-three infant girls, divided into three groups according to gestational age (GA)[i.e. full term (FT; n = 29; GA, 37-42 wk), near term (NT; n = 17; GA, 34-37 wk), and preterm (PT; n = 17; GA, 24-34 wk)] were examined monthly from 1 wk (D7) to 6 months (M1-M6) of age and reexamined at the corrected age of 14 months (cM14).Main Outcome Measures:We performed a longitudinal follow-up of urinary FSH and serum anti-Müllerian hormone (AMH) levels and the number of follicles in transabdominal ovarian ultrasonography.Results:The postnatal FSH surge was stronger and more prolonged in NT and PT girls than in FT girls (P ≤ 0.001). Increased folliculogenesis and a rise in AMH levels were observed in all three groups after the FSH surge. In NT and PT girls, follicular development was delayed in comparison with FT girls, and a decrease in high FSH levels around the 40th postmenstrual week was temporally associated with the appearance of antral follicles in ultrasonography and an increase in AMH levels.Conclusions:The postnatal FSH surge results in transient ovarian stimulation in term and preterm girls. A delay in ovarian folliculogenesis shown in ovarian ultrasonography and by low serum AMH levels may provide an explanation for the exaggerated FSH surge in NT and PT girls.

CONTEXT Women with polycystic ovary syndrome (PCOS) are known to suffer from hyperandrogenism and impaired glucose tolerance, as well as chronic inflammation, exposing them to an increased risk of cardiovascular diseases. However, the degree to which these hormonal and metabolic alterations persist after menopause (MP) is not well documented. OBJECTIVE Our objective was to explore whether adverse metabolic and hormonal alterations persist after MP in women with PCOS. DESIGN We conducted a cross-sectional university hospital-based study. PATIENTS AND INTERVENTIONS Twenty-one pre-MP (n = 10) and post-MP (n = 11) women diagnosed with PCOS were compared with 29 healthy controls (pre-MP, n = 11; post-MP, n = 18). Two-hour oral glucose tolerance tests were performed, and ovarian steroid secretion capacity was assessed (human chorionic gonadotropin tests). Areas under the curves (AUC) were calculated. RESULTS Both pre-MP and post-MP women with PCOS had increased insulin response in oral glucose tolerance tests (AUC(ins) pre-MP = 6733.7 vs. 3382.9; post-MP = 9732.1 vs. 3265.3) and were more insulin resistant than controls. Androgen secretion capacity was increased before and after MP in PCOS (AUC of androstenedione; pre-MP: 1218.4 vs. 853.2; post-MP: 1000.0 vs. 531.3). High-sensitivity C-reactive protein remained elevated after MP in PCOS (pre-MP: 1.3 vs. 0.7; post-MP: 1.4 vs. 0.9 mg/liter). Adjustment for body mass index did not alter the results except for glucose metabolism. CONCLUSIONS The results indicate that impaired glucose metabolism, enhanced ovarian androgen secretion, and chronic inflammation observed in pre-MP women with PCOS persist after menopausal transition emphasizing life-long health risks related to this syndrome.

To examine putative associations between zona pellucida (ZP) anomalies and sequence variations in genes expressing structural ZP glycoprotein components, sequence data of 31 volunteers participating in IVF treatments were obtained and analyzed together with morphologic data of the respective oocytes. Our results suggest that some of the most frequent zona anomalies may be at least partly explained by sequence variations in genes expressing the four human ZP proteins, especially those in ZP2 and ZP3.

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Of eight million oocytes formed in fetal ovaries, only 400 are ovulated and the rest are degraded via apoptosis. Studies in rodents suggest an important role for Bok and Bcl-X(L) in ovarian apoptosis, but their expression patterns and roles in human ovaries are not well known. Protein expression of Bok and Bcl-X(L) as well as the death pathway effectors TNF and caspase-3 were determined in an important collection of samples consisting of human fetal and adult ovaries. A penetrant expression of Bok, Bcl-X(L), TNF and full length and cleaved caspase-3 were characterized in fetal ovaries, with specific patterns in oocytes and pre-granulosa/granulosa cells. Bok and Bcl-X(L) were detected also in adult ovaries. Lentiviral shRNA delivery demonstrated that loss of Bok markedly reduces vulnerability to apoptosis and, conversely, loss of Bcl-X(L) increases apoptosis in human granulosa tumour cell line. The results suggest important roles for Bok and Bcl-X(L) in human ovarian development, follicle maturation and apoptosis.

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