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Introduction : This Experts' opinion provides an updated scientific support to gynecologists, obstetricians, endocrinologists, nutritionists, neurologists and general practitioners on the use of Inositols in the therapy of Polycystic Ovary Syndrome (PCOS) and non-insulin dependent (type 2) diabetes mellitus (NIDDM). Areas covered : This paper summarizes the physiology of Myo-Inositol (MI) and D-Chiro-Inositol (DCI), two important molecules present in human organisms, and their therapeutic role, also for treating infertility. Some deep differences between the physiological functions of MI and DCI, as well as their safety and intestinal absorption are discussed. Updates include new evidence on the efficacy exerted in PCOS by the 40:1 MI/DCI ratio, and the innovative approach based on alpha-lactalbumin to overcome the decreased therapeutic efficacy of Inositols in some patients. Expert opinion : The evidence suggests that MI, alone or with DCI in the 40:1 ratio, offers a promising treatment for PCOS and NIDDM. However, additional studies need to evaluate some still unresolved issues, such as the best MI/DCI ratio for treating NIDDM, the potential cost-effectiveness of reduced gonadotropins administration in IVF due to MI treatment, or the benefit of MI supplementation in ovulation induction with clomiphene citrate in PCOS patients.

High carbohydrate intake and low-grade inflammation cooperate with insulin resistance and hyperandrogenism to constitute an interactive continuum acting on the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age characterised by oligo-anovulatory infertility and cardiometabolic disorders. The role of insulin in PCOS is pivotal both in regulating the activity of ovarian and liver enzymes, respectively involved in androgen production and in triggering low-grade inflammation usually reported to be associated with an insulin resistance, dyslipidaemia and cardiometabolic diseases. Although an acute hyperglycaemia induced by oral glucose loading may increase inflammation and oxidative stress by generating reactive oxygen species through different mechanisms, the postprandial glucose increment, commonly associated with the Western diet, represents the major contributor of chronic sustained hyperglycaemia and pro-inflammatory state. Together with hyperinsulinaemia, hyperandrogenism and low-grade inflammation, unhealthy diet should be viewed as a key component of the 'deadly quartet' of metabolic risk factors associated with PCOS pathophysiology. The identification of a tight diet-inflammation-health association makes the adoption of healthy nutritional approaches a primary preventive and therapeutic tool in women with PCOS, weakening insulin resistance and eventually promoting improvements of reproductive life and endocrine outcomes. The intriguing nutritional-endocrine connections operating in PCOS underline the role of expert nutritionists in the management of this syndrome. The aim of the present review is to provide an at-a-glance overview of the possible bi-directional mechanisms linking inflammation, androgen excess and carbohydrate intake in women with PCOS.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women and is characterized by two of the following three features: oligoovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism, or polycystic ovaries., Summary: It has been demonstrated that PCOS includes a complex number of systemic symptoms in addition to symptoms related to the reproductive apparatus. It has been associated with obesity, metabolic syndrome, type 2 diabetes and an increased risk of cardiovascular disease. Several clinical and basic studies have investigated the link between PCOS and the cardiovascular disease risk, which seems to be due to blunted lipid/glucose metabolism, hypertension, and systemic inflammatory and coagulation disorders. Therefore, the current manuscript aims to review the main findings on PCOS and obesity/obesity-related disease (glucose derangements and cardiovascular disease risk factors)., Key Message: Although there are no long-term data on the morbidity and mortality for cardiovascular disease in PCOS, it is advisable to perform a careful metabolic and cardiovascular assessment in women with PCOS in order to tailor the most suitable strategy to prevent cardiovascular disease., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Although oral contraceptives (OCs) are one the most widespread therapy in young polycystic ovary syndrome (PCOS) women and physical exercise represents a crucial first step in the treatment of overweight and obese PCOS, no studies were performed to compare the effects on cardiovascular risk (CVR) of OCs and physical exercise in PCOS., Objective: To compare the effects of OCs administration and physical exercise on the CVR, clinical, hormonal and metabolic parameters in PCOS women., Methods: One hundred and fifty PCOS women were enrolled and were randomized to OCs (3 mg drospirenone plus 30 μg ethinyloestradiol), structured exercise training programme (SETP) or polyvitamin tablets. The intervention phase study was of 6 months. Primary outcome was intima-media thickness (IMT) and flow-mediated dilation (FMD). Secondary outcomes were clinical, hormonal and metabolic changes., Results: A significant reduction of IMT and a significant increase of FMD were observed in the SETP group after treatment. Compared to baseline, in the SETP group, a significant improvement in anthropometric measures, insulin sensitivity indexes, lipid profile, cardiopulmonary function, inflammatory markers and frequency of menses was observed. Oral contraceptives use was associated with a significant decrease of hyperandrogenism and a significant improvement of frequency of menses. Further, OCs use had a neutral effect on CVR risk factors., Conclusion: OCs effectively treat hyperandrogenism and menstrual disturbances, while SETP is more effective in improving cardiometabolic profile and cardiopulmonary function in PCOS ., (© 2016 John Wiley & Sons Ltd.)

Competing Interests: GM declares that she has no conflict of interest; MC declares that he has no conflict of interest; SP declares that he has no conflict of interest; FO declares that he has no conflict of interest. Ethical approval All procedures performed in the study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Low 25(OH) vitamin D levels have been associated with several autoimmune diseases and recently with autoimmune thyroid disease (AITD). The aim of the study was to investigate the association of AITD with 25(OH) vitamin D levels in women with polycystic ovary syndrome (PCOS). Fifty women with PCOS were consecutively enrolled and underwent routine health checkups, which included measurements of 25(OH) vitamin D, anti-thyroid peroxidase (TPO-Ab), anti-thyreoglobulin (TG-Ab) antibodies, FT3, FT4, and TSH. Selecting 50 nmol/L as cut-off point, low 25(OH) vitamin D levels were detected in 23 of 50 patients (46 %). AITD was diagnosed when TPO-Ab levels exceeding 80 U/ml and/or TG-Ab levels exceeding 70 U/ml. AITD was detected in 12 of 50 patients (24 %). The levels of 25(OH) vitamin D were significantly lower in women with PCOS and AITD when compared with women with PCOS and without AITD (p = 0.02). In women with AITD no correlation was found between 25(OH) vitamin D and TG-Ab (r = 0.48; p = 0.16), TPO-Ab (r = 0.43; p = 0.21), TSH (r = 0.38; p = 0.27), FT3 (r = -0.40; p = 0.25) and FT4 levels (r = -0.54; p = 0.10). These findings suggest that low levels of 25(OH) vitamin D were significantly associated with AITD in women with PCOS.

Background: Polycystic ovary syndrome (PCOS) is a complex syndrome characterized by reproductive and metabolic implications. Lifestyle changes, such as diet and exercise, are considered first-line treatment for women affected by PCOS. Pharmacologic treatments target the hormonal and metabolic dysregulations associated to the disease such as insulin resistance, anovulation, hirsutism and menstrual irregularities., Objective: To focus on the role of inositol isoforms, as well as Mediterranean and ketogenic diets, as possible therapeutic strategies in PCOS women., Method: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases., Results: Accumulating evidence suggests that two inositol isoforms, myo- and D-chiro-, may play a pivotal role in re-addressing both hormonal and metabolic parameters toward homeostasis, counteracting the symptoms and signs typical of this syndrome. In addition, studies focused on Mediterranean and ketogenic diet provided positive results in patients affected by obesity and type 2 diabetes, so these dietetic regimens could represent a fascinating dietetic treatment for the management of PCOS., Conclusion: Both the isoforms of inositol are effective in improving ovarian function and metabolism in patients with PCOS. In spite of accumulating evidence, it is currently not possible to draw firm conclusion(s) about the efficacy of these interventions considering the severe bias due to different samples size, dose, and duration of intervention among the published studies on this topic. Furthermore, future longitudinal cohort studies along with prospective interventional trials may contribute to better clarify the role of Mediterranean and ketogenic diets in the treatment of PCOS.

The normal function of the female reproductive system is closely linked to energy homeostasis with the ultimate scope of fertility and human race perpetuation through the centuries. During a woman's lifetime there are normal events such as puberty, pregnancy and menopause which are related to alterations in energy homeostasis and gonadal steroids levels followed by increase of body fat and insulin resistance, important components of metabolic syndrome (MetS). Pathological conditions such as premature adrenarche, polycystic ovary syndrome and gestational diabetes also present with shifts in gonadal steroid levels and reduced insulin sensitivity. The aim of this review is to discuss these conditions, both normal and pathological, analyzing the changes or abnormalities in ovarian function that coexist with metabolic abnormalities which resemble MetS in relationship with environmental, genetic and epigenetic factors., (© 2015 European Society of Endocrinology.)

Adrenal incidentalomas (AIs) and polycystic ovary syndrome (PCOS) have often been associated with compensatory hyperinsulinemia and insulin resistance (IR). The link between these diseases and IR may be changes in hormone secretions that provoke IR and in turn promote the growth of adrenal gland masses and/or ovarian cysts through compensatory hyperinsulinemia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Alterations in lipid pattern and increased risk for obstetric/neonatal complications have been observed in patients with polycystic ovary syndrome (PCOS). Pregnancy leads to physiologic changes in lipoprotein metabolism, and alterations in lipid profile have been related with adverse pregnancy outcomes. Based on these considerations, the aim of the present prospective controlled clinical study was to test the hypothesis that the changes in the lipid profile in patients with PCOS during pregnancy are characteristic and potentially related to the increased risk of obstetric/neonatal complications. One hundred and fifty nonobese PCOS women and 150 age- and body mass index (BMI)-matched healthy controls were enrolled. Serum lipids, glucose, insulin, and androgens levels were serially assayed in all subjects before and throughout pregnancy. Serum low-density lipoprotein (LDL) and triglyceride (TG) concentrations were significantly (P<0.05) higher in PCOS group than in healthy controls at each assessment. Throughout pregnancy, serum LDL and TG levels increased significantly (P<0.05) in both groups, although the change from pre-pregnancy values was significantly (P<0.05) greater in PCOS patients than in healthy controls. A significant (P<0.05) relationship was observed between serum LDL and TG changes and changes in both insulin sensitivity indexes and androgen levels in PCOS patients alone. After adjusting for maternal age, pre-pregnancy BMI and lipid levels, body weight gain, and insulin-resistance markers, serum TG concentrations during pregnancy were directly and independently associated with obstetric complications in both groups, whereas serum LDL levels only in PCOS patients. We can conclude that nonobese PCOS patients had specific changes in lipid profile during pregnancy, and that the lipid pattern typical of PCOS may account for the more frequent adverse pregnancy outcomes. PCOS-related hormonal and metabolic features, such as insulin resistance and high androgen levels, may mediate this phenomenon., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Polycystic ovary syndrome (PCOS) and pregnancy are conditions characterized by an increased low-grade chronic inflammation state. A higher incidence of pregnancy complications has been detected in pregnant PCOS women., Objective: The objective of the study was to test the hypothesis that the low-grade chronic inflammation state typical of PCOS patients persists during gestation and is exacerbated by pregnancy and contributes to the increased risk of obstetric/neonatal complications., Design: This was a prospective controlled clinical study., Setting: The study was conducted at the Academic Department of Obstetrics and Gynecology of the "Pugliese-Ciaccio" Hospital of Catanzaro (Catanzaro, Italy)., Patients: One hundred fifty pregnant PCOS women and 150 age- and body mass index-matched healthy pregnant controls participated in the study., Interventions: INTERVENTIONS included serial clinical, biochemical, and ultrasonographic assessments before and throughout pregnancy., Main Outcome Measures: Serum levels of white blood cell count (WBC), C-reactive protein (CRP), and ferritin were measured., Results: Pregnant women with PCOS had higher WBC, CRP, and ferritin levels at study entry and at all gestational ages than controls. Changes in serum WBC and ferritin levels were significantly higher in PCOS than in controls starting from the 12th week of gestation whereas those in CRP from the 20th week of gestation. By multivariable Cox proportional hazard analysis, in the PCOS group, a significant association with the risk of adverse obstetric/neonatal outcomes was found for WBC [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.31-1.64; P = .010], CRP (HR 1.19, 95% CI 1.06-1.34; P = .019), and ferritin levels (HR 1.12, 95% CI 1.03-1.26; P = .011)., Conclusions: In PCOS patients, the low-grade chronic inflammation persists during gestation and is exacerbated by pregnancy, and it is associated with adverse pregnancy outcomes.

The management of oligo-amenorrhea in adolescent patients with polycystic ovary syndrome (PCOS) represents an important and difficult challenge. Metformin and/or oral contraceptives (OCs) are different strategies widely proposed in these patients. The objective of the current review was to provide an overview on the use of metformin and/or OCs for the management of oligo-amenorrhea in adolescents with PCOS underlining their potential risks and benefits in order to help the clinician to choose the best patients' tailored treatment.

Context: Bisphenol A, one of the highest-volume chemicals currently available, is known to act as endocrine disruptor and alters several metabolic functions, including inflammatory pathways. Elevated serum levels of bisphenol A have been found in women with polycystic ovary syndrome (PCOS) and a role of low-grade chronic inflammation has been recently reported in the pathogenesis of this syndrome. Increased spleen volume, a reliable and stable index of chronic inflammation, was strictly associated with the severity of hepatic steatosis (HS) in obese subjects, determining the so-called liver-spleen axis., Objective: To evaluate the contribution of increased serum bisphenol A levels to low-grade chronic inflammation, HS and hyperandrogenism in women with PCOS., Design, Setting and Participants: Forty lean and overweight/obese premenopausal women with PCOS and 20 healthy age-matched women were consecutively enrolled in a cross-sectional study from 2009 to 2011 at the Federico II University Hospital in Naples., Measurements: Bisphenol A, homoeostasis model assessment of insulin resistance (HoMA-IR), laboratory liver tests, testosterone, sex hormone-binding globulin, free androgen index (FAI), C-reactive protein, interleukin-6, and the ultrasound quantification of HS and spleen longitudinal diameter., Results: Independently of body weight, higher bisphenol A levels in PCOS women were associated with higher grades of insulin resistance, HS, FAI and inflammation, spleen size showing the best correlation. At multivariate analysis, spleen size and FAI were the best predictors of bisphenol A (β coefficients 0.379, P = 0.007 and 0.343, P = 0.014, respectively)., Conclusions: In premenopausal women with PCOS, we evidenced an association of serum bisphenol A levels with HS and markers of low-grade inflammation, in particular with spleen size, unravelling the presence of the liver-spleen axis in this syndrome., (© 2012 Blackwell Publishing Ltd.)

Objective: Foetal exposure to high testosterone concentrations seems to be involved in the development of mammalian brain and related to pervasive developmental disorders (PDDs). The aim of the current study was to test the hypothesis that children born from hyperandrogenic women with polycystic ovary syndrome (PCOS) are at higher risk of PDDs., Design: Longitudinal case-control study., Patients: Thirty pregnant PCOS patients with hyperandrogenaemia and other 45 pregnant healthy women were followed during pregnancy. All women had a healthy baby., Measurements: Clinical evaluations and biochemical assays of the mothers during pregnancy and after delivery were performed. The children's versions of the Autism-Spectrum Quotient (AQ-C), the Empathy Quotient (EQ-C) and Systemizing Quotient (SQ-C) tests were administered., Results: Total AQ-C and communication scores were significantly higher for children of PCOS patients. Stratifying our population according to sex, total AQ-C, communication and attention switching subscores were significantly higher only for daughters of PCOS patients. EQ-C and SQ-C scores resulted in significantly lower and higher scores, respectively, only in daughters of PCOS patients in comparison with those of healthy non-PCOS controls. AQ-C, EQ-C and SQ-C scores, irrespective of the studied group and/or subclassification by gender, were significantly influenced by amniotic testosterone levels., Conclusions: Daughters of mothers affected by hyperandrogenic PCOS seem to have a higher risk for PDDs probably due to an unbalanced prenatal exposure to high levels of testosterone., (© 2012 Blackwell Publishing Ltd.)

Objective: To test the hypothesis that the risk of persistent glucose impairment after gestational diabetes mellitus (GDM) is increased in patients with polycystic ovary syndrome (PCOS)., Research Design and Methods: The prospective case-control study included 42 pregnant patients with PCOS and GDM and 84 pregnant control patients with GDM but without clinical and biochemical hyperandrogenism, polycystic ovaries, and oligo-anovulation. The case and control subjects were matched one to two for age and BMI. The glycemic profiles were studied in all subjects 6 weeks, 12 weeks, and 18 months after delivery. The incidence and the relative risk (RR) were calculated for overall persistence of an abnormal glycemic pattern and for each specific alteration, i.e., impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus (DM)., Results: At 18 months after delivery, the incidences of IFG, IGT, and IFG-IGT were significantly (P < 0.05) higher in the cases than in the controls. At the 18-month follow-up, the RR for the composite outcome of glucose metabolism impairment in PCOS women was 3.45 (95% CI 1.82-6.58)., Conclusions: Patients with PCOS are at increased risk for a persistent impaired glucose metabolism after GDM.

The study aim was to evaluate our personal experience regarding the use and the reproductive effect of metformin administration in a large population of infertile patients with polycystic ovary syndrome (PCOS) undergoing gonadotropins ovarian stimulation for in vitro fertilization (IVF). Infertile patients with PCOS undergoing gonadotropins ovarian stimulation with (metformin group, n = 191) or without (control group, n = 187) metformin and IVF were evaluated. Treatment characteristics, patients' data and reproductive outcomes were evaluated. In all cases, metformin with an immediate-release formulation was administered, and in most of cases it was given as pre- and co-treatment (74.9%) and at a dosage of 1700 mg/day (59.7%). Stimulation length and gonadotropins doses were significantly (p < 0.05) higher in metformin group than in control group. The number of dominant follicles on day of ovarian maturation triggering and peak oestradiol levels were significantly (p < 0.05) lower in metformin group than in control group. Cycle cancellation rate under metformin resulted significantly influenced by interaction with body mass index (BMI), age and basal follicle-stimulating hormone (FSH) levels. Notwithstanding, metformin use in infertile PCOS patients who receive gonadotropins for IVF is not standardized, it seems to modulate the ovarian response to stimulation. This effect may benefit or harm on the basis of ovarian reserve and patients' characteristics.

Objective: To test whether metformin administration reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in infertile high-risk patients with polycystic ovary syndrome (PCOS) who have been treated with gonadotropins for IVF., Design: Parallel, randomized, double-blind, placebo-controlled clinical trial., Setting: Academic departments, general hospital, and IVF centers., Patient(s): One hundred twenty patients with PCOS at high risk for OHSS., Intervention(s): Gonadotropins ovarian stimulation for IVF and metformin (500 mg three times daily) or placebo tablets (three times daily)., Main Outcome Measure(s): The primary end point of the current clinical trial was the rate of OHSS. Anthropometric and reproductive data were evaluated., Result(s): The total OHSS and cancellation rates were significantly reduced in patients treated with metformin. The relative risk for OHSS was of 0.28 (95% confidence interval, 0.11-0.67). With metformin the stimulation length and the total amount of gonadotropins used were significantly increased, whereas the peak E(2) levels were significantly reduced., Conclusion(s): In patients with PCOS who are at high risk for OHSS and who have been stimulated with gonadotropins for IVF cycles, metformin reduces the risk of OHSS by modulating the ovarian response to the stimulation. REGISTRATION ID NUMBER FROM CLINICALTRIALS.GOV: NCT01233206., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Clomiphene citrate (CC) is the first-line therapy for the induction of ovulation in infertile women with polycystic ovary syndrome (PCOS), but ∼20% of patients are unresponsive. The aim of the current study was to test the hypothesis that a 6-week intervention that consisted of structured exercise training (SET) and hypocaloric diet increases the probability of ovulation after CC in overweight and obese CC-resistant PCOS patients., Methods: A cohort of 96 overweight and obese CC-resistant PCOS patients was enrolled consecutively in a three-arm randomized, parallel, controlled, assessor-blinded clinical trial. The three interventions were: SET plus hypocaloric diet for 6 weeks (Group A); 2 weeks of observation followed by one cycle of CC therapy (Group B); and SET plus hypocaloric diet for 6 weeks, with one cycle of CC after the first 2 weeks (Group C). The primary end-point was the ovulation rate. Other reproductive data, as well as anthropometric, hormonal and metabolic data, were also collected and considered as secondary end points., Results: After 6 weeks of SET plus hypocaloric diet, the ovulation rate was significantly (P =0.008) higher in Group C [12/32 (37.5%)] than in Groups A [4/32 (12.5%)] and B [3/32 (9.4%)] with relative risks of 3.9 [95% confidence interval (CI) 1.1-8.3; P = 0.035] and 4.0 (95% CI 1.2-12.8; P = 0.020) compared with Groups A and B, respectively. Compared with baseline, in Groups A and C, a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes was observed. In the same two groups, the insulin sensitivity index was significantly (P < 0.05) better than that in Group B., Conclusions: In overweight and obese CC-resistant PCOS patients, a 6-week intervention of SET and a hypocaloric diet was effective in increasing the probability of ovulation under CC treatment. The study was registered at Clinicaltrials.gov:NCT0100468.

Objective: To test the hypothesis that the risk of adverse obstetric or neonatal outcomes varies according to different phenotypes of polycystic ovary syndrome (PCOS), and to evaluate the clinical impact of the main features of PCOS., Design: Prospective controlled clinical study., Setting: Academic Departments of Obstetrics and Gynecology, and of Endocrinology, Italy., Patient(s): Ninety-seven pregnant women with PCOS and 73 healthy pregnant subjects were recruited as cases and controls, respectively., Intervention(s): Clinical, biochemical, and ultrasonographic evaluations., Main Outcome Measure(s): Obstetric and neonatal outcomes., Result(s): The relative risk (RR) for adverse obstetric or neonatal outcomes was increased (1.7, 95% confidence interval [CI] 1.12-2.96) in patients with PCOS and varied according to the PCOS phenotype (1.93, 95% CI 1.12-2.96; 2.23, 95% CI 1.21-3.15; 0.54, 95% CI 0.09-1.63, and 0.48, 95% CI 0.31-0.78 for full-blown, nonpolycystic ovaries [PCO], nonhyperandrogenic, and ovulatory phenotypes, respectively). The RRs were 1.57 (95% CI 0.85-2.52) and 0.48 (95% CI 0.31-0.78) for oligoanovulatory and ovulatory patients with PCOS, respectively. The risk for adverse obstetric or neonatal outcomes was affected significantly by ovarian dysfunction and biochemical hyperandrogenism, whereas no significant effect was detected for clinical hyperandrogenism and PCO., Conclusion(s): The increased risk for adverse obstetric and neonatal outcomes that was observed in patients with PCOS varies widely according to the different phenotypes and features of PCOS., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The cellular abundance of the phosphoprotein enriched in diabetes (PED/PEA-15), a 15 kDa protein related to insulin resistance (IR), is increased in women with polycystic ovary syndrome (PCOS)., Aim: To investigate whether metformin (MET) has additive effects on PED/PEA-15 protein levels., Material/subjects and Methods: This is an open label, prospective clinical study over 6 months. Ten hyperandrogenic obese PCOS women [age: 24.6+/-1.6 yr; body mass index (BMI): 30.7+/-1.2 kg/m(2)] were treated with MET (1250 mg/day). Ten age- and BMI-matched normo-androgenic women were used as controls. Outcome measures are: PED/PEA-15 protein levels, fasting plasma glucose and insulin (FPI), reciprocal index of homeostasis model assessment of insulin resistance (1/HOMA-IR); quantitative insulin sensitivity check index (QUICKI); wholebody insulin sensitivity index (ISI); SHBG; total testosterone; free androgen index (FAI)., Results: At baseline FPI and PED/PEA- 15 protein levels were higher, while 1/HOMA-IR, QUICKI, and ISI were lower (p<0.001) in MET group than in controls. After treatment, independently of body weight and hyperandrogenism, FPI, and PED/PEA-15 protein levels decreased (p=0.001 and 0.004, respectively), while, 1/HOMA-IR, QUICKI, and ISI increased (p<0.001). PED/PEA-15 protein levels correlated significantly with ISI either before (r=0.636; p=0.048), and after treatment (r=0.758; p=0.011)., Conclusions: PED/PEA-15 protein levels reduced after a short course of treatment with MET in a group hyperandrogenic obese PCOS women. This effect was independent of body weight and hyperandrogenism, and correlated with ISI, thus adding a further benefit to obese PCOS women.

Objective: The purpose of this study was to compare the effectiveness of laparoscopic ovarian diathermy (LOD) vs clomiphene citrate (CC) plus metformin in infertile patients with CC-resistant polycystic ovary syndrome (PCOS)., Study Design: Fifty primary infertile patients with CC-resistant PCOS were assigned randomly to receive LOD followed by a 6-month observation (group A) or 6-cycle course of CC plus metformin (group B). Reproductive and safety outcomes were analyzed., Results: No significant difference between 2 groups in pregnancy (15/92 women [16.3%] vs 14/107 women [13.1%]; P = .521) and live-birth (13/92 women [14.1%] vs 12/107 women [11.2%]; P = .536) rates per cycle was observed. With the use of a Cox regression analysis, patients under medical treatment, compared with patients who received surgical treatment, had a relative risk of pregnancy of 1.2 (95% confidence interval, 0.61-2.44; P = .582) and a relative risk of live-birth of 1.4 (95% confidence interval, 0.63-2.96; P = .425)., Conclusion: LOD and CC plus metformin seem to be 2 effective approaches to treat infertility in patients with CC-resistant PCOS., (Copyright 2010 Mosby, Inc. All rights reserved.)

Objective: To study the impedance to blood flow through the uterine artery in pregnant women with polycystic ovary syndrome (PCOS), and to evaluate its predictive value for adverse pregnancy and perinatal outcomes in this population., Design: Prospective case-control study., Setting: Academic Departments of Obstetrics and Gynaecology in Italy., Population: Seventy-three pregnant women with ovulatory PCOS (PCOS group) and 73 age- and body mass index-matched healthy pregnant controls (control group)., Methods: Serial Doppler velocimetry measurements of the uterine artery., Main Outcome Measures: Blood flow impedance indices and pregnancy/perinatal outcomes., Results: A significantly (P < 0.05) higher rate of subjects with abnormal velocimetry findings was observed in the PCOS group than in the control group. In the PCOS group, the pulsatility index (PI) at first (P = 0.042) and mid-second (P = 0.039) trimesters of pregnancy, and bilateral notch at first (P = 0.025) and mid-second (P = 0.007) trimesters of pregnancy, were the strongest independent predictors of adverse outcomes. Conversely, in the control group, PI at the first trimester of pregnancy was a predictor of adverse outcomes only when combined with bilateral notch (P = 0.042), whereas at mid-second trimester of pregnancy PI (P = 0.033) and bilateral notch (P = 0.048) were independent predictors of adverse outcomes., Conclusions: Uterine artery Doppler indices are more commonly altered in pregnant patients with PCOS than in controls, showing a high predictive value for abnormal pregnancy/perinatal outcomes.

Background: Several data have demonstrated the efficacy of metformin in inducing ovulation in patients with polycystic ovary syndrome (PCOS), however, the exact mechanism by which this drug acts remains unknown. The aim of the present study was to evaluate whether the efficacy of the drug in patients with PCOS is related to a systemic hormonal-metabolic improvement, or to a local action on the ovary., Methods: Twenty-four normal weight patients with PCOS, who were treated with metformin, were enrolled. Of these, 12 subjects were anovulatory (Group A1), whereas the other 12 were ovulatory but had failed to conceive (Group A2). A further 24 untreated subjects who were scheduled for laparoscopic surgery were enrolled as controls, 12 anovulatory patients with PCOS scheduled for laparoscopic myomectomy (Group B1) and a further 12 non-PCOS participants were scheduled for diagnostic laparoscopy (Group B2). Clinical assessments and biochemical evaluations in blood and antral follicular fluid were performed in each participant., Results: In 1/12 and 9/12 participants from Groups A1 and A2, respectively, the ovarian morphology was changed, and a significant (P < 0.05) reduction in the ovarian dimensions was observed only in Group A2. In both of these groups, and without difference between them, serum androgens and indices of insulin resistance improved significantly (P < 0.05) after metformin treatment. On the other hand, significant differences (P < 0.05) between the two groups were detected with respect to the same biochemical parameters in antral follicular fluid. In Groups A1 and A2, levels of androgens and indices of insulin resistance in the antral follicular fluid were significantly (P < 0.05) better than in Group B1, but worse than in Group B2., Conclusions: Irrespective of its systemic effects, the efficacy of metformin in the induction of ovulation is probably due to a direct action on the ovary, and the ovulatory response to the drug seems to be related to local sensitivity or resistance to the drug.

Objective: To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium., Research Design and Methods: A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 microg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated., Results: After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects., Conclusions: Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.

Objective: To evaluate the effect of pregestational metformin administration on abortion risk in polycystic ovary syndrome (PCOS) patients., Design: Systematic review and meta-analysis., Setting: Academic Department of Obstetrics and Gynecology in Italy., Patient(s): Women affected by PCOS receiving pregestational metformin., Intervention(s): Systematic review of randomized controlled trials (RCTs) published up to June 2008 and subsequent meta-analysis., Main Outcome Measure(s): Abortion rate., Result(s): Seventeen RCTs were included in the final analysis. Overall, no effect of the metformin administration was detected on the abortion risk. No statistically significant effect of metformin on the abortion risk was observed in any comparison when subgrouping the RCTs according to received treatment., Conclusion(s): Metformin has no effect on the abortion risk in PCOS patients when administered before pregnancy.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women and is characterized by chronic ovulatory dysfunction and hyperandrogenism. Clinical studies have shown that hyperandrogenism is linked with insulin resistance/metabolic syndrome in PCOS women. This review article summarizes the several potential mechanisms for the association of androgen excess with insulin resistance, including both direct and indirect actions of androgens on insulin target tissues. This review article also focuses on the beneficial effects of exercise training and diet on glucose metabolism and hyperandrogenism in PCOS women, pointing out that whether in conjunction with pharmacotherapy or as a stand-alone treatment, diet and exercise training represent a fundamental strategy in the treatment of PCOS women.

Objective: To evaluate ovulation and pregnancy predictors in infertile polycystic ovary syndrome (PCOS) patients who received clomiphene citrate (CC) and metformin as first-line ovulation inductors., Design: Prospective controlled study., Setting: Departments of Obstetrics and Gynecology, Universities Magna Graecia of Catanzaro and Federico II of Naples, Italy., Patient(s): Eighty infertile anovulatory PCOS patients allocated in two groups matched for body mass index (BMI) and age., Intervention(s): Metformin (1700 mg/day for 6 months) or CC (50 mg/day, increasing doses up to 250 mg/day)., Main Outcome Measure(s): Baseline clinical and biochemical parameters categorized according to interventions response., Result(s): The BMI was statistically significantly lower in patients who ovulated under both treatments. Insulin sensitivity indexes were statistically significantly worse in patients who ovulated under metformin and statistically significantly better in patients who ovulated under CC. Androgen levels and free androgen index (FAI) were statistically significantly lower in ovulatory patients than in anovulatory ones who received CC. Age, BMI, infertility duration, and insulin sensitivity indexes were statistically significantly different between patients who achieved and those who did not achieve a pregnancy under both treatments. Androgens levels and FAI were statistically significantly lower in patients who achieved a pregnancy under CC., Conclusion(s): Insulin-resistant PCOS patients with low BMI are more likely to respond to metformin whereas CC treatment is more effective in less hyperandrogenic and insulin-resistant PCOS patients with low BMI.

Background: We investigated whether several different inflammatory markers including C-reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO(2 max)) in women with polycystic ovary syndrome (PCOS)., Methods: In PCOS women (n = 124, 24.1 +/- 4.5 year-old) VO(2 max) was measured during symptom-limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter., Results: Pearson's analysis showed a significant correlation between VO(2 max) and logCRP (r = -0.437, P < 0.001), fibrinogen (r = -0.479, P < 0.001), and WBCs count (r = -0.438, P < 0.001). Multivariable logistic regression model showed that age (beta = -0.127, P = 0.005), AUC(INS )(beta = -0.335, P < 0.001), HDL-C (beta = 0.390, P < 0.001), physical activity score (beta = 0.238, P = 0.002), visceral fat (beta =-0.184), P = 0.023), FAI (beta = -0.291, P = 0.028); CRP (beta = -0.216, P = 0.011), fibrinogen (beta = -0.113, P = 0.008) and WBCs count (beta = -0.177, P < 0.001) were significantly associated with VO(2 max)., Conclusions: Acute-phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO(2 max)) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.

Background: To date, no systematic review or meta-analysis has been published of direct head-to-head studies comparing clomiphene citrate (CC) vs. metformin, or the combination of both drugs as first-line therapy in anovulatory polycystic ovary syndrome (PCOS) patients seeking pregnancy. The aim of the current paper was to define, if possible, the best evidence-based recommendations regarding the use of CC and/or metformin as the initial treatment of PCOS women with anovulatory infertility., Design: Systematic review and meta-analysis of the head-to-head randomized controlled trials (RCTs) available in the literature., Methods: A bibliographic search was performed using the following bibliographic databases: Medline, EMBASE, Biological Abstracts, Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews. Reference lists of included studies, other relevant review articles and textbooks were checked for additional citations of interest., Results: Four head-to-head RCTs were identified and qualified for inclusion in the analysis. No difference in fertility improvement was observed comparing CC with metformin (OR = 1.22, 95% CI 0.23-6.55, P = 0.815), whereas a significant (P < 0.0001) heterogeneity was observed. Homogeneous data showed no difference in fertility improvement between the combination treatment and CC monotherapy (OR = 0.99, 95% CI 0.70-1.40, P = 0.982), but a significant difference in comparison with metformin monotherapy (OR = 0.23, 95% CI 0.14-0.37, P < 0.0001)., Conclusions: In PCOS patients with anovulatory infertility and not previously treated, the administration of metformin plus CC is not better than monotherapy (metformin alone or CC alone), whereas to date no specific recommendation can be given regarding the use of CC or metformin as first-step drug.

Metformin is an insulin sensitizer widely used for the treatment of patients affected by type 2 diabetes mellitus. Because many women with polycystic ovary syndrome (PCOS) are insulin resistant, metformin was introduced in clinical practice to treat these patients also. Moreover, metformin's effect has other targets beside its insulin-sensitizing action. The present review was aimed at describing all evidence-based and potential uses of metformin in PCOS patients. In particular, we will analyze the uses of metformin not only for the treatment of all PCOS-related disturbances such as menstrual disorders, anovulatory infertility, increased abortion, or complicated pregnancy risk, hyperandrogenism, endometrial, metabolic and cardiovascular abnormalities, but also for the prevention of the syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous disease affecting about 5-10% of reproductive-age female population, which is predominantly characterized by chronic anovulation, hyperandrogenism and insulin resistance. PCOS women represent an intriguing biological model illustrating the relationship between hormonal pattern and cardiovascular risk profile, presenting a cluster of cardiovascular features, such as obesity, insulin resistance, hypertension, impaired cardiopulmonary functional capacity, autonomic dysfunction and low-grade chronic inflammation. Metabolic syndrome should be also considered in the clinical evaluation and management of PCOS. The treatment of PCOS and its complications should not be based solely on pharmacological therapies trying to improve hyperandrogenism, hyperinsulinemia and insulin resistance. Although mounting evidence recognizes the beneficial effects of lifestyle modifications, the clinical management of PCOS is not sufficiently focused on long-term maintenance of both exercise and dietary interventions and on further aspects of this syndrome (i.e. psychological status). Taking into consideration the patients' young age and the devastating effects of PCOS on hormonal and metabolic pattern, this complex and multifaceted disease requires a comprehensive approach in order to achieve concrete beneficial effects for PCOS patients. Multidisciplinary programs, including dietary and educational counseling, exercise training, stress management and psychosocial support, might represent the gold standard for adequate reduction of cardiovascular risk in young women with PCOS.

Purpose of Review: To review the current reproductive advances in insulin-sensitizing agents for treatment of polycystic ovary syndrome patients., Recent Findings: To date, among insulin-sensitizing drugs, only metformin should be used to improve reproductive function in well selected polycystic ovary syndrome patients. Preliminary data seem to show beneficial effects of thiazolidinediones in improving metabolic and hormonal patterns and in restoring regular menses., Summary: The use of insulin-sensitizing drugs offers a new perspective for the treatment of polycystic ovary syndrome-related reproductive disorders. However, further data are needed before we can draw definitive conclusions regarding their clinical role.

This study was intended to assess the effects of oral contraceptives given before treatment in infertile anovulatory patients with polycystic ovary syndrome who receive gonadotropins for controlled ovarian stimulation. Pretreatment with oral contraceptives increased the mono-ovulatory cycles, the duration of stimulation for noncanceled cycles, and the number of vials of gonadotropins used. It also reduced the number of dominant follicles and the peak E(2) levels for dominant follicles. No effect was observed in rates of cycle cancellation, pregnancy, abortion, live birth, multiple pregnancies, and ovarian hyperstimulation syndrome.

Objective: The aim of the present study was to determine if the favourable cardiopulmonary and metabolic benefits induced by exercise training (ET) programme are maintained after its cessation., Patients: Thirty-two young overweight polycystic ovary syndrome (PCOS) women matched for age and body mass index (BMI) with other 32 PCOS patients was enrolled. The first group [PCOS-T (trained)] underwent 24-week ET programme, whereas the second [PCOS-DT (detrained)] underwent 12-week ET programme followed by 12-week detraining period., Methods: At baseline, after 12- and 24-week follow-up, all PCOS women were studied for their hormonal (ovarian and adrenal androgens), metabolic (glucose and insulin) and lipid profile, and underwent cardiopulmonary exercise test., Results: After the initial 12-week ET programme, both PCOS-T and PCOS-DT groups, without differences between groups, showed a similar significant (P < 0.05) improvement in BMI, fasting insulin, areas under curve insulin (AUC(INS)), glucose and insulin AUC (AUC(GLU/INS)), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and maximal oxygen consumption at cardiopulmonary exercise test (VO2max). At 24-week follow-up, PCOS-T group showed a significant (P < 0.05) improvement in BMI, fasting insulin, AUC(INS), AUC(GLU/INS), LDL-C, HDL-C and VO2max, in comparison to baseline and 12-week follow-up. At same follow-up visit, the all parameters resulted significantly (P < 0.05) worsened in PCOS-DT group in comparison to 12-week follow-up and PCOS-T group. In PCOS-DT group, no parameter assessed at 24-week follow-up was significantly different in comparison with baseline., Conclusion: In young PCOS women, 12-week detraining resulted in a complete loss of the favourable adaptations obtained after ET.

Metformin is an insulin sensitizer currently used for treating type-2 diabetes mellitus and recently administered for inducing ovulatory menstrual cycles in oligo-amenorrhoeic patients with polycystic ovary syndrome (PCOS). The aim of the present review is to describe the efficacy of metformin as an ovulation inducer on the basis of the most important evidence-based medicine supported data, including meta-analyses and randomized controlled trials. Specifically, we reviewed the uses of metformin as first- and second-step treatment for PCOS related anovulatory infertility and as co-treatment in infertile PCOS patients who receive gonadotrophins. To date, there is evidence that metformin is effective for restoring normal menstrual cycles in anovulatory PCOS patients, and that it is more effective and cheaper than laparoscopic ovarian drilling as the second therapeutic step in PCOS patients previously defined as resistant to clomiphene citrate. Co-administration of metformin in PCOS patients treated with gonadotrophin improves the mono-ovulation rate and can prevent ovarian hyperstimulation syndrome in patients treated with gonadotrophins for IVF cycles.

Background: Lifestyle modifications are successfully employed to treat obese and overweight women with polycystic ovary syndrome (PCOS). The aims of the current pilot study were (i) to compare the efficacy on reproductive functions of a structured exercise training (SET) programme with a diet programme in obese PCOS patients and (ii) to study their clinical, hormonal and metabolic effects to elucidate potentially different mechanisms of action., Methods: Forty obese PCOS patients with anovulatory infertility underwent a SET programme (SET group, n = 20) and a hypocaloric hyperproteic diet (diet group, n = 20). Clinical, hormonal and metabolic data were assessed at baseline, and at 12- and 24-week follow-ups. Primary endpoint was cumulative pregnancy rate., Results: The two groups had similar demographic, anthropometric and biochemical parameters. After intervention, a significant improvement in menstrual cycles and fertility was noted in both groups, with no differences between groups. The frequency of menses and the ovulation rate were significantly (P < 0.05) higher in the SET group than in diet group but the increased cumulative pregnancy rate was not significant. Body weight, body mass index, waist circumference, insulin resistance indexes and serum levels of sex hormone-binding globulin, androstenedione and dehydroepiandrosterone sulphate changed significantly (P < 0.05) from baseline and were significantly different (P < 0.05) between the two groups., Conclusions: Both SET and diet interventions improve fertility in obese PCOS patients with anovulatory infertility. We hypothesize that in both interventions an improvement in insulin sensitivity is the pivotal factor involved in the restoration of ovarian function but potentially acting through different mechanisms.

Metformin, an insulin sensitizer widely used for the treatment of patients with type-2 diabetes mellitus (DM), was recently introduced in the clinical practice to treat women with polycystic ovary syndrome (PCOS). The aim of the current review was to evaluate the current role of metformin in the treatment of the PCOS-related disorders. The Authors analyze here the administration of metformin for treating the ovarian dysfunction due to PCOS, and show the evidences available in literature regarding its alternative uses.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-10% of reproductive aged women, about 1 out of 15 women worldwide. Traditionally it was considered as a reproductive disorder showing hyperandrogenism, chronic anovulation and infertility; it is now well accepted that PCOS represents a ''multifaceted'' syndrome with substantial metabolic and cardiovascular long term consequences. Several PCOS women present abdominal adiposity (visceral fat) with a level of peripheral insulin resistance (IR), similar to that present in women with type 2 diabetes, in association with an increased incidence of impaired glucose tolerance. Several cardiovascular risk factors are often related to metabolic alterations, such as dyslipidemia, hypertension, endothelial dysfunction, low grade chronic inflammation, that are present even at early age in PCOS women. Pathogenetic mechanisms of these impairments are not completely clarified yet, but IR appears to play a critical role, such as the key factor linking hypertension, glucose intolerance, obesity, lipid abnormalities and coronary artery disease. In conclusion, although increased incidence of metabolic abnormalities and metabolic disease like type 2 diabetes, and several cardiovascular abnormalities have been widely demonstrated in PCOS women, larger and multicenter trials of long term cardiovascular outcomes are required to better define the incidence of cardiovascular risk and cardiovascular disease in PCOS.

Background: Women with polycystic ovary syndrome (PCOS) have been reported to have subclinical cardiovascular disease (CVD) and increased abdominal fat. The aim of this study was to evaluate the relationship between visceral fat (VF) and early markers of CVD in PCOS women., Methods: Two hundred overweight PCOS women [(mean +/- SD) age 24.6 +/- 3.2 years, body mass index (BMI) 28.5 +/- 2.8 kg/m2] and 100 healthy age- and BMI-matched volunteer controls entered this cross-sectional study. In all subjects, the amount of VF was measured by ultrasonography. Anthropometric measurements [BMI and waist circumference (WC)], complete hormonal and metabolic pattern, carotid intima-media thickness (IMT), brachial arterial flow-mediated dilation (FMD) and inflammatory biomarkers [C-reactive protein (CRP), fibrinogen, white blood cells count and plasminogen activated inhibitor-1] were also obtained from all subjects. A stepwise linear regression model was used in PCOS patients to verify if IMT or FMD as dependent variables are affected by other independent variables., Results: VF amount was significantly (P < 0.001) higher in PCOS subjects than in healthy controls [31.4 +/- 7.3 versus 28.0 +/- 6.1 (mean+/-SD) mm, respectively] and directly related to insulin resistance: HOMA (r = 0.918, P < 0.001) and AUC(INS) (r = 0.879, P < 0.001), and to WC (r = 0.658; P < 0.001). In PCOS, the two linear regression analyses showed that IMT is positively affected by VF and CRP, whereas FMD is positively affected by IMT and negatively by VF and CRP., Conclusions: VF amount is associated with subclinical CVD in PCOS patients.

Objective: Heart rate recovery (HRR) is a measure derived from exercise test, defined as the fall in heart rate during the first minute after maximal exercise. Abnormal HRR is a measure of autonomic dysfunction associated with an increased mortality. This study was performed to evaluate the HRR in polycystic ovary syndrome (PCOS)., Design: Prospective controlled clinical study., Patients: Seventy-five PCOS women compared to 75 healthy women matched for age (21.7 +/- 2.1 years vs. 21.9 +/- 1.8 years, respectively) and body mass index (BMI) (29.0 +/- 2.6 kg/m(2) vs. 29.1 +/- 2.9 kg/m(2), respectively)., Measurements: Subjects were studied for their hormonal and metabolic profile, and underwent cardiopulmonary exercise test (CPX)., Results: PCOS women showed a significantly reduced HRR (12.9 +/- 1.8 vs. 20.4 +/- 3.1 beats/min, P < 0.001) compared to healthy controls, an impairment in maximal oxygen consumption (18.0 +/- 2.3 ml/kg/min vs. 29.3 +/- 3.9 ml/kg/min) and in oxygen consumption at anaerobic threshold (13.6 +/- 2.6 ml/kg/min vs. 24.2 +/- 3.0 ml/kg/min). In PCOS women, abnormal HRR was inversely correlated to BMI (r = -0.582, P < 0.001) and to the area under the curve for insulin (r = -0.596, P < 0.001)., Conclusions: Our data demonstrate an abnormal HRR after maximal CPX in young overweight PCOS patients, and that HRR should be investigated as a further potential marker of increased cardiovascular risk in PCOS.

Objective: To evaluate Ped/pea-15 (phosphoprotein enriched in diabetes) expression in polycystic ovary syndrome (PCOS) women., Design and Patients: Thirty PCOS women were studied and compared with other 30 age- and body mass index (BMI)-matched women, considered as the control group. Both patients and controls were divided according to BMI. All subjects underwent endocrine and metabolic investigation and Ped/pea-15 expression was evaluated by western blot analysis. Insulin resistance was assessed by HOMA model and insulin sensitivity index (ISI) composite., Results: Insulin resistance, evaluated by HOMA-R and ISI composite, was significantly higher in PCOS women and in obese controls than in normal weight controls. Ped/pea-15 expression (%) was higher in PCOS women than in controls (440.4 +/- 220.7 vs. 163.0 +/- 45.5; P < 0.001; range 145.5-987% and 97-281%, respectively), and was positively correlated with insulin, BMI, total testosterone, HOMA index, and family history (P < 0.001). In patients with PCOS univariate analysis of variance showed no effect of BMI variation (P = 0.13) on Ped/pea-15 expression levels. On multiple linear regression analysis, the major determinants of Ped/pea-15 overexpression were family history, insulin, and PCOS status independent of BMI., Conclusion: These preliminary data (1) highlight the overexpression of Ped/pea-15 in PCOS compared to normal controls, independent of obesity; (2) suggest that Ped/pea-15 overexpression might be an early component of the metabolic syndrome in PCOS; and (3) support the hypothesis that Ped/pea-15 represents a possible useful tool to assess the presence of a genetic condition associated with insulin resistance in PCOS.

Context: Clomiphene citrate (CC) and metformin are two effective drugs used to induce ovulation in patients with polycystic ovary syndrome (PCOS), even if it is still unclear which compound between them should be initially administered., Objective: The aim of the study was to compare in a clinical setting the efficacy of CC and metformin as first-line approaches for treating anovulation in infertile PCOS patients., Design: This study was a multicenter, nonrandomized, prospective, controlled study., Setting: The study was conducted at the Department of Obstetrics and Gynecology, Universities "Magna Graecia" of Catanzaro and "Federico II" of Naples, Italy., Patients: Patients included 80 infertile anovulatory patients with PCOS allocated in two body mass index- and age-matched groups (experimental and control groups)., Interventions: Six months of 1700 mg/d metformin treatment (experimental group) or CC was administered using a traditional incremental-dose protocol (control group). In both groups, patients who ovulated under treatment continued the therapy for a total of 6 months., Main Outcome Measures: Reproductive outcomes were measured., Results: Experimental and control groups were studied for a total of 204 and 169 cycles, respectively. No difference between the two groups was observed in ovulation (55.4 vs. 59.8%, respectively; P = 0.396), pregnancy (10.8 vs. 11.2%, respectively; P = 0.888), and abortion (19.5 vs. 26.3%, respectively; P = 0.530) rates. The cumulative pregnancy rate was not different between groups (62.9 vs. 48.6%, respectively; P = 0.225)., Conclusion: A 6-month course of 1700 mg/d metformin treatment and CC administered in an escalation protocol are two effective first-line approaches for improving fertility in anovulatory PCOS women.

Context: To date, the metabolic effects of the long-term metformin administration in anovulatory patients with polycystic ovary syndrome (PCOS) are known, whereas few data are available on the effects of its suspension., Objective: The objective of the study was to evaluate the effects of metformin suspension on insulin sensitivity in PCOS patients., Design: This was a prospective, randomized, placebo-controlled study., Setting: The study was conducted at the University "Magna Graecia" of Catanzaro, Italy., Patients: Patients included 30 normal-weight anovulatory PCOS women and 10 age- and body mass index-matched healthy controls., Intervention: PCOS patients were randomized to receive 1700 mg daily metformin (metformin group) or placebo tables (placebo group) for 12 months, whereas no treatment was administered in healthy women (control group)., Main Outcome Measures: Clinical, endocrine, and metabolic profile and clamp insulin sensitivity index were evaluated at study entry and after 6, 12, 18, and 24 months., Results: At baseline, the clamp insulin sensitivity index resulted significantly different (P < 0.05) in PCOS patients in comparison with healthy controls, without difference between metformin and placebo groups. During treatment, the clamp insulin sensitivity index was significantly improved (P < 0.05) in the metformin group in comparison with baseline and placebo group, without significant differences between the 6- and 12-month assessments. At 6 and 12 months after treatment suspension, in the metformin group, insulin sensitivity index significantly (P < 0.05) worsened in comparison with that observed at baseline and during treatment and with that observed in the placebo and control groups., Conclusion: In normal-weight anovulatory PCOS patients, long-term metformin administration exerts beneficial effects on peripheral insulin sensitivity. Furthermore, this effect disappears at treatment suspension.

Context: Increased abdominal fat has been linked to insulin resistance and increased cardiovascular risk. Because many patients with polycystic ovary syndrome (PCOS) present abdominal obesity, it may be the cause of insulin resistance in this disorder., Setting: Fat quantity and distribution were evaluated by dual x-ray absorptiometry at the Departments of Clinical Medicine at the University of Palermo and the University of Naples, Italy., Patients: A total of 110 patients with PCOS and 112 weight-matched controls were studied. Anthropometric data, blood glucose, serum insulin, and testosterone were evaluated. Total, trunk, and central abdominal fat quantity were measured by total-body dual x-ray absorptiometry., Results: Compared with weight-matched controls, patients with PCOS had similar quantity of total and trunk fat but higher quantity of central abdominal fat. This difference was not observed when comparing obese PCOS and obese controls but depended on differences between overweight and normoweight patients and controls. All obese subjects, independently of having PCOS or not, had increased central abdominal fat. The same parameter was increased in 71% of overweight PCOS, 50% of overweight controls, and 30% of normoweight PCOS patients. PCOS patients with increased central abdominal fat had significantly higher (P < 0.01) insulin levels and significantly reduced (P < 0.01) insulin sensitivity than controls with similar quantities of central abdominal fat. Overweight PCOS patients with normal abdominal fat had significantly higher (P < 0.05) insulin levels and significantly reduced (P < 0.05) insulin sensitivity than overweight controls with normal abdominal fat., Conclusions: Most obese subjects, independent of being affected by PCOS, have an abdominal form of obesity. However, abdominal fat excess may not be the only determinant of insulin resistance in PCOS.

Introduction: Polycystic ovary syndrome (PCOS) is a common disorder associated with a wide range of endocrine and metabolic abnormalities. Low-grade chronic inflammation is a related complication recently observed in PCOS. Increased white blood cell (WBC) count was previously reported in PCOS women., Objective: To evaluate the effects of six months metformin administration on WBC count in PCOS women., Patients and Methods: Fifty normal-weight PCOS women without additional metabolic or cardiovascular diseases were enrolled and treated with metformin (850 mg twice daily) for 6 months in a prospective baseline-controlled clinical study. At baseline and after treatment, WBC count and C-reactive protein (CRP) were evaluated in each patient. The whole hormonal profile, serum insulin and glucose levels (at fasting and during a 75 g 2-h oral glucose tolerance test), serum lipid profile were also assessed., Results: A significant difference was observed in WBC count (7050 +/- 552 vs 6080 +/- 577 cell/mm(3) +/- s.d., P<0.001) and CRP levels (1.8 +/- 0.9 vs 1.1 +/- 0.6 mg/l +/- s.d., P<0.001) after metformin treatment in comparison with baseline values. SHBG levels and the free androgen index also changed significantly (P<0.001). Finally, high-density lipoproteins and the area under curve for glucose/area under curve for insulin ratio also significantly increased (P<0.001), whereas low-density lipoproteins and area under curve for insulin were significantly reduced (P<0.001). No other change was found in any of the biochemical parameters evaluated., Conclusion: A six-month course of metformin reduces WBC count in PCOS women.

Objective: The aim of the present study was to investigate the potential alterations in electrocardiographic (ECG) pattern in patients with polycystic ovary syndrome (PCOS)., Patients: Fifty PCOS patients and 50 age- and body mass index-matched healthy women were studied., Methods: We assessed hormonal and metabolic pattern, and performed ECG analysis for evaluating PQ interval, QRS duration, minimum and maximum QT interval corrected for heart rate (QT(c)min and QT(c)max, respectively), corrected QT dispersion (QT(c)d), corrected J point/T-wave interval (JTend(c)), corrected JTmax interval (JTmax(c)), and corrected Tmax-end interval (Tmax-end(c))., Results: QT(c)min (399 +/- 21 vs. 396 +/- 25 ms, P = 0.51); QT(c) max (445 +/- 25 vs. 443 +/- 27 ms, P = 0.70); and QT(c)d (46 +/- 13 vs. 47 +/- 15 ms, P = 0.72); JTend(c) (337 +/- 14 vs. 336 +/- 16 ms(1/2), P = 0.74); and JTmax(c) (256 +/- 22 vs. 258 +/- 21 ms(1/2), P = 0.64); Tmax-end(c) (81 +/- 18 vs. 78 +/- 19 ms(1/2), P = 0.42) were not significantly different between PCOS and healthy women., Conclusion: Despite profound differences in hormonal and metabolic pattern, our data demonstrate no significant difference in ECG pattern in PCOS compared to healthy controls.