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PubMed2006

A twenty-first century research agenda for polycystic ovary syndrome.

Notwithstanding the significant progress made in our understanding of polycystic ovary syndrome (PCOS), the field remains ripe for further discovery and more intensive translational research. Immediate priorities include developing evidence-based criteria for diagnosing PCOS and for assessing the response to the various treatments available. The basis for the identification of PCOS remains mainly expert opinion, and the lack of universally accepted evidence-based criteria limits the generalizability of research studies on PCOS. Additional important areas requiring intensive investigation include the natural history and etiology and the long-term sequelae and prevention of the disorder. Overall, this disorder is a prototype for the benefits of translational science and a transdisciplinary approach to understanding the pathophysiology and therapy for anovulatory infertility.

Evidence-Based Medicine↗

PubMed2006

Role of lifestyle modification in the management of polycystic ovary syndrome.

Overweight and obesity are common findings in polycystic ovary syndrome (PCOS). Obesity-particularly central obesity-is strongly indicated as a cause of insulin resistance, a central feature of PCOS. The prevalence of obesity is reaching epidemic proportions in many developed countries, and this increase is of particular concern in adolescent women. Obesity worsens both the metabolic and endocrine profiles in PCOS and may decrease the response to treatment. In the short term, weight reduction improves both metabolic and endocrine aspects of PCOS as well as clinical markers such as ovulation. However, extreme non-surgical efforts to lose weight are rarely successful and are associated with high rates of weight regain. Lifestyle modification with modest weight loss goals of 5-10% appear to be equally effective in restoring fertility and may be more compatible with long-term success; however, further research is needed.

Adolescent↗

PubMed2004

The pathogenesis of infertility and early pregnancy loss in polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) frequently present with reproductive dysfunction. Ovarian function might be disturbed, with resultant abnormal folliculogenesis and steroidogenesis and, although it is difficult to define the exact pathogenesis of anovulation, many possible mechanisms have been postulated. Folliculogenesis in anovulatory women with PCOS is characterized by failure of dominance and the ovary has multiple small follicles, which are arrested but capable of steroidogenesis. Abnormalities in gonadotrophin and insulin secretion and disordered paracrine function have been identified. Women with PCOS have an increased prevalence of miscarriage, both after spontaneous and induced ovulation. Hypersecretion of LH, hyperandrogenaemia and hyperinsulinaemia have all been investigated as possible causes of PCOS. It is likely that these factors are interlinked and together might result in disordered ovarian and endometrial function. Multiple other possible abnormalities have been postulated as contributory factors in the reproductive failure. These include decreased plasminogen activator inhibitor activity, endothelial dysfunction and obesity. Ideally, therapy should target the underlying disorders but at present data are inadequate and further investigations are essential before therapeutic recommendations are truly based on an understanding of the pathophysiology.

Abortion, Spontaneous↗

PubMed2005

Uterine arterial blood flow and the substances of ovarian renin-angiotensin system in women with polycystic ovaries undergoing in vitro fertilization.

OBJECTIVE: To find whether plasma and follicular prorenin concentrations have any effect on the uterine arterial blood flow in women with polycystic ovarian syndrome (PCOS) compared to those with normal menstrual cycles (NMC). STUDY DESIGN: Controlled prospective clinical study involved 55 women undergoing in vitro fertilization: 24 with PCOS and 31 with NMC. In both groups transvaginal colour Doppler assessment of uterine arterial blood flow was analysed on day 22 of the cycle, on the day of human chorionic gonadotrophin (HCG) administration and 36 h after HCG. Plasma and follicular (in the dominant follicle containing mature oocyte, and in the pooled follicles) prorenin and active renin, and serum estradiol and androstenedione concentrations were measured at these time-points. The Student's t-test and Pearson correlation were used for the statistical analysis. RESULTS: The resistance index (RI) in the NMC group decreased from 0.84+/-0.05 on the day of HCG to 0.78+/-0.08 36 h after HCG (P < 0.05); in the PCOS group the RI did not decrease. Follicular prorenin concentrations in the dominant follicle and in the pooled follicles were lower in the PCOS than in the NMC group (20,210+/-10,831 microU/l, 16,753+/-8634 microU/l versus 42,637+/-35,400 microU/l, 33,067+/-26,200 microU/l; P < 0.05). CONCLUSIONS: Plasma prorenin concentrations do not affect vascular impedance to the uterine artery, but follicular prorenin do by newly formed low resistant vessels in the follicles.

Arteries↗

PubMed2007

Agreement among insulin sensitivity indexes on the diagnosis of insulin resistance in polycystic ovary syndrome and ovulatory women.

OBJECTIVE: The objective was to compare agreement on the diagnosis of insulin resistance (IR) among insulin sensitivity indexes in both ovulatory women and those with polycystic ovary syndrome (PCOS). STUDY DESIGN: In an observational study, the 75-g oral glucose tolerance test was performed in 105 women with PCOS and 51 ovulatory women. The insulin sensitivity indexes used were insulin quantitative sensitivity check index (QUICKI), 1/homeostasis model assessment-insulin resistance (1/HOMA-IR), area under curve for insulin (AUC-I), and the Matsuda insulin sensitivity index (COMP). For the IR diagnosis we used cut-off values described in recent publications (insulin >12 microIU/ml, 1/HOMA-IR <0.47, QUICKI < or =0.333, AUC-I > or =7000 microIU/ml 120 min, and COMP <4.75. RESULTS: Excellent agreement was assessed among insulin, QUICKI, and 1/HOMA-IR. However, the rate of IR detected by these indexes in the PCOS group (44.8-51.4%) was lower than expected. New cut-offs were then determined based on COMP results. Using these values, 1/HOMA-IR and QUICKI showed excellent agreement (kappa=0.83) with COMP. CONCLUSION: The observed agreements among insulin, QUICKI and 1/HOMA-IR were higher than 93%. Therefore, clinicians may choose any of those obtaining similar results. For clinicians who prefer COMP, but are looking for a simpler test to detect IR in PCOS women, the use of QUICKI and 1/HOMA-IR with the new cut-offs seems reasonable.

Adult↗

PubMed2004

Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary (PCOS) patients. DESIGN: Controlled clinical study. SETTING: PCOS patients in a clinical research environment. PATIENT(S): Twenty nonobese PCOS patients were enrolled after informed consent. INTERVENTION(S): All patients underwent hormonal evaluations and a pulsatility study (sampling every 10 minutes for 4 hours) before and at the sixth month of therapy (metformin, 500 mg, p.o. b.i.d.). Ultrasound examinations and Ferriman-Gallwey scoring were also performed. MAIN OUTCOME MEASURE(S): Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17-hydroxy-progesterone (17-OHP), and testosterone (T), glucose, insulin, and C-peptide concentrations. RESULT(S): After 6 months of metformin administration, the plasma LH, 17-OHP, A, and T levels and LH/FSH ratio were significantly reduced. Insulin sensitivity, expressed as the glucose-to-insulin ratio, was significantly improved under glucose load after 6 months of treatment. Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women. The ovarian volume and Ferriman-Gallwey scores also were significantly reduced. CONCLUSION(S): Metformin administration improves reproductive axis functioning in hyperandrogenic nonobese PCOS patients. By acting on the ovary and restoring normal ovarian activity, metformin positively modulates the reproductive axis (namely GnRH-LH episodic release).

17-alpha-Hydroxyprogesterone↗

PubMed2004

Serum resistin levels in women with polycystic ovary syndrome.

OBJECTIVE: To measure serum resistin levels in women with polycystic ovary syndrome (PCOS) and assess possible correlations of resistin to the hormonal and metabolic parameters of the syndrome. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): Ninety selected women were classified as follows: group I: 35 anovulatory women with PCOS (body mass index [BMI] >25 kg/m(2)); group II: 35 anovulatory women with PCOS (BMI <25 kg/m(2)); group III: 20 ovulating women (controls) without hyperandrogenemia (BMI <25 kg/m(2)); women of group III were volunteers. INTERVENTION(S): Blood samples were collected between the 3rd and the 6th day of the menstrual cycle of the ovulating women, and between the 3rd and the 6th day of a spontaneous bleeding of the anovulatory women, at 9 a.m., after an overnight fast. MAIN OUTCOME MEASURE(S): Serum levels of FSH, LH, PRL, 17alpha-hydroxyprogesterone, sex hormone-binding globulin, androgens, insulin, resistin, and glucose. RESULT(S): Resistin levels were found to be significantly increased in group I compared with those of group II and those of group III. No significant difference in resistin levels was found between groups II and III, despite significant differences in insulin levels and the glucose-to-insulin ratio. Multiple regression analysis showed that resistin levels do not correlate with any parameter independent of BMI. CONCLUSION(S): Based on the above findings, we presume that resistin is unlikely to be a major determining factor of PCOS-associated insulin resistance and is not actively involved in the pathogenesis of the syndrome.

Adult↗

PubMed2004

Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: Women with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. PATIENT(S): Twenty-four insulin-resistant women with PCOS. INTERVENTION(S): Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily. MAIN OUTCOME MEASURE(S): Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated. RESULT(S): A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone-binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month. CONCLUSION(S): Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS.

Adolescent↗

PubMed2004

A common interleukin-6 gene promoter polymorphism influences the clinical characteristics of women with polycystic ovary syndrome.

OBJECTIVE: To investigate the association of a common polymorphism of the interleukin-6 gene (IL6) promoter with the occurence and the clinical characteristics of polycystic ovary syndrome (PCOS). DESIGN: Prospective, case-control study. SETTING: Academic research institution. PATIENT(S): Sixty-two patients with PCOS and 94 healthy controls. INTERVENTION(S): Peripheral venous puncture, ultrasonography, oral glucose tolerance test (OGTT), questionnaire. MAIN OUTCOME MEASURE(S): Genotype analysis with respect to the common -174 G/C polymorphism of the IL6 gene promoter, analysis of testosterone (T), androstendione, and sex hormone binding globulin serum levels, and evaluation of the OGTT. RESULT(S): Allele frequencies among women with PCOS and controls were 62.9% and 64.4%, respectively, for the wild-type G allele, and 37.1% and 35.6%, respectively, for the mutant C allele. We ascertained a significant association between presence of at least one mutant C allele and the clinical characteristics of affected women: these women were more likely to present with a body mass index >27 kg/m(2), elevated total T serum levels, and a pathological OGTT result. CONCLUSION(S): A common polymorphism of the IL6 promoter, although not associated with the presence of PCOS, is associated with the clinical characteristics of women affected by this condition.

Adult↗

PubMed2004

Comparison of follicular vascularization in normal versus polycystic ovaries during in vitro fertilization as measured using 3-dimensional power Doppler ultrasonography.

OBJECTIVE: The growth of the follicles induced by gonadotropins during IVF treatment is accompanied by physiologic angiogenesis, which is essential for the maturation of the oocytes. We describe the IVF-induced changes in the vascularization and compare normal with polycystic ovaries (PCOs). DESIGN: Prospective study. SETTING: Assisted reproductive unit at a university hospital. PATIENT(S): Sixty women who underwent IVF cycles. INTERVENTION(S): The ovarian vascularization was measured after pituitary down-regulation, FSH stimulation, and hCG-injection using three-dimensional power Doppler ultrasonography. MAIN OUTCOME MEASURE(S): The total ovarian vascularization was divided by the number of follicles. RESULT(S): After pituitary suppression, the ovarian vascularization/follicle was lower in polycystic ovary (PCO) patients. During ovarian stimulation, follicles in PCOs required a lesser amount of FSH to acquire the same level of vascularization than the follicles in normal ovaries. In addition, hCG induced an increase in the follicular vascularization in both normal and PCOs. The follicle count correlated with the total vascularized volume in the ovaries throughout the IVF cycle. CONCLUSION(S): Follicles in PCOs seem to be less vascularized than the follicles in normal ovaries after GnRH treatment but not after gonadotropin stimulation. It is possible that restricted blood supply to the follicles in PCO might be associated with the follicular arrest that is observed. We could confirm that follicles in PCO are more sensitive to gonadotropin stimulation than follicles in normal ovaries.

Adult↗

PubMed2004

Serum leptin levels correlate with obesity parameters but not with hyperinsulinism in women with polycystic ovary syndrome.

OBJECTIVE: To examine serum leptin concentrations in obese and lean patients with polycystic ovary syndrome (PCOS) to assess whether the changes in leptin levels are due to obesity or hormonal alterations. DESIGN: Controlled clinical study. SETTING: Academic research environment. PATIENT(S): Obese and lean women with PCOS. INTERVENTION(S): Blood samples were collected before and after food consumption. MAIN OUTCOME MEASURE(S): Serum leptin and insulin levels. RESULT(S): Serum leptin concentrations were significantly correlated with body mass index (r = 0.649) and also with HOMA (r = 0.535). However, after controlling for body mass index in a partial correlation analysis, no significant correlation was found between serum leptin levels and HOMA or hyperinsulinemia. While lean patients with PCOS had a significant correlation between leptin concentrations and obesity parameters, they did not show any significant correlation with insulin resistance parameters. CONCLUSION(S): Although leptin concentrations in women with PCOS correlate with insulin resistance/hyperinsulinemia, this is related only to obesity.

Adult↗

PubMed2005

N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of N-acetyl-cysteine (NAC), a mucolytic drug with insulin sensitizing properties, as an adjuvant therapy in subjects with polycystic ovary syndrome (PCOS) resistant to clomiphene citrate (CC). DESIGN: Placebo-controlled, double-blind randomized trial. SETTING: University-based hospital and private infertility practice. PATIENT(S): One hundred fifty women diagnosed with CC-resistant PCOS, aged 18-39 years undergoing therapy for infertility were included. INTERVENTION(S): The patients were assigned randomly to receive either NAC 1.2 g/d (group I) or placebo (group II) with CC 100 mg/d for 5 days starting at day 3 of the cycle. MAIN OUTCOME MEASURE(S): Ovulation rate and pregnancy rate (PR). RESULT(S): Combination of CC and NAC significantly increased both ovulation rate and PR in women with CC-resistant PCOS (49.3% vs. 1.3% and 21.3% vs. 0%, respectively). No cases of ovarian hyperstimulation syndrome (OHSS) were reported in the NAC group; two cases of miscarriage (12.5%) were reported. CONCLUSION(S): The NAC as an adjuvant to CC was more effective than placebo for CC-resistant patients with PCOS. It is safe and well tolerated.

Acetylcysteine↗

PubMed2005

Obstetric outcome of patients with polycystic ovary syndrome treated by in vitro maturation and in vitro fertilization-embryo transfer.

OBJECTIVE: To assess the obstetric outcome of pregnancies resulting from in vitro maturation (IVM) and IVF-ET of immature oocytes retrieved from women with polycystic ovary syndrome (PCOS). DESIGN: Prospective observational study. SETTING: University fertility clinic. PATIENT(S): One hundred thirty-nine women undergoing 203 IVM treatment cycles. INTERVENTION(S): Immature oocyte recovery from unstimulated ovaries. In vitro oocyte maturation and fertilization. Fresh ET and assessment of obstetric outcomes in the pregnant women. MAIN OUTCOME MEASURE(S): Pregnancy and obstetric outcome. RESULT(S): Forty-one pregnancies were obtained in 187 ETs, resulting in a pregnancy rate of 21.9%. Except for three patients lost to follow-up in these pregnancies, the abortion and live birth rates were 36.8% (14 of 38) and 63.2% (24 of 38), respectively. The mean (+/-SD) gestational age and birth weight at delivery for singletons were 38.4 +/- 2.0 weeks (range, 33-41.6 weeks) and 3,252 +/- 516 g (1,750-4,100 g), respectively. For twins these were 36.7 +/- 1.9 weeks (34.6-39 weeks) and 2,361 +/- 304 g (1,900-2,990 g), respectively. Pregnancy complications occurred in five patients (13.2%); these included preterm labor (n = 3) and placenta previa (n = 2). Two patients (5.3%) had a major congenital anomaly diagnosed by ultrasonography. CONCLUSION(S): The abortion rate, gestational age and birth weight at delivery, and obstetric complications of pregnancies conceived by IVM-ET in women with PCOS were comparable with those of other women with PCOS being treated by conventional IVF-ET. In vitro maturation followed by IVF-ET seems to be a useful treatment option for women with PCOS, thus avoiding the risk of ovarian hyperstimulation syndrome.

Adult↗

PubMed2005

Subcutaneous administration of pulsatile gonadotropin-releasing hormone decreases serum follicle-stimulating hormone and luteinizing hormone levels in women with polycystic ovary syndrome: a preliminary study.

OBJECTIVE: The main objectives of this study were to investigate whether [1] subcutaneous (SC) administration of pulsatile gonadotropin-releasing hormone (GnRH) decreases the increased levels of luteinizing hormone (LH) observed in women with polycystic ovary syndrome (PCOS); and [2] GnRH administration modifies the pattern of LH secretion observed in these patients. DESIGN: Serum follicle-stimulating hormone (FSH) and LH levels and LH pulse amplitude and pulse interval were determined in 13 patients with PCOS during the first 3 days of the cycle following the administration of 10 mg of medroxyprogesterone acetate during 5 days. SETTING: Infertility clinic. PATIENT(S): Thirteen women with PCOS. INTERVENTION(S): Determination of FSH and LH serum levels after SC administration of pulsatile GnRH. MAIN OUTCOME MEASURE(S): The FSH and LH levels in serum. RESULT(S): Mean FSH and LH levels in serum decreased following the administration of subcutaneous pulsatile GnRH in all treated women compared with baseline values. The LH pulse amplitude and pulse interval decreased in all patients following the administration of pulsatile GnRH. CONCLUSION(S): The SC administration of pulsatile GnRH in women with PCOS significantly decreases FSH and LH levels in serum. A decrease in the secretion of gonadotropins, without reaching the intense suppression observed with GnRH analogues, could be of great utility in in vitro fertilization (IVF) treatments.

Adult↗

PubMed2005

The M235T polymorphism of the angiotensinogen gene in women with polycystic ovary syndrome.

To explore the relationship between variation in AGT M235T gene and the development of the polycystic ovary syndrome (PCOS) and its sequelae, in the present study we evaluated AGT polymorphism M235T in women with PCOS and in a control group. Moreover, to detect any relationship between AGT M235T variation and intermediate and quantitative traits relevant to the pathogenesis of cardiovascular disease and PCOS, we looked for genotype-dependent differences within the subjects with PCOS.

Aged↗

PubMed2006

Polymorphisms of the peroxisome proliferator-activated receptor-gamma and its coactivator-1alpha genes in Chinese women with polycystic ovary syndrome.

The polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and its coactivator-1 (Gly482Ser) genes were investigated among 201 Chinese Han women with polycystic ovary syndrome (PCOS) and among 147 regularly cycling women as control subjects. We did not find statistically significant differences with peroxisome proliferator-activated receptor-gamma2 Pro12Ala and peroxisome proliferator-activated receptor-gamma-1alpha Gly482Ser polymorphism distributions between Chinese women with PCOS and controls, or with body mass index and reproductive hormones among various genotypic groups of PCOS, suggesting that these genetic mutants did not have an effect on the susceptibility to PCOS.

China↗

PubMed2006

Family size in women with polycystic ovary syndrome.

Given that polycystic ovary syndrome (PCOS) is associated with oligo-ovulatory infertility and is an inherited trait, we hypothesized that the families of patients with PCOS are smaller than those of matched controls. However, our study of 106 white patients with PCOS, ages 18-45, and 53 healthy eumenorrheic nonhirsute white controls did not indicate a difference in family size between the groups; these results have important implications for the design of prospective studies of the heritability and genetics of PCOS.

Adolescent↗

PubMed2006

A microsatellite polymorphism (tttta)n in the promoter of the CYP11a gene in Chinese women with polycystic ovary syndrome.

A (tttta)n microsatellite polymorphism in the promoter of CYP11a gene was investigated in 201 Chinese Han women with polycystic ovary syndrome (PCOS) and 147 control women. The 6/6 genotype was defined with significant difference of CYP11a polymorphism between women with PCOS and control women, and associated with greater BMI in PCOS patients, suggesting a certain role of the six-repeat allele variant in the pathogenesis of Chinese women with PCOS.

Adult↗