Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome

BACKGROUND: The aim of this study was to investigate serum and adipocyte mRNA expression of resistin in lean and obese women with polycystic ovary syndrome (PCOS) before and 3 months after laparoscopic ovarian electrocauterization (LOE). METHODS: Adipose tissue obtained from 12 women with PCOS (six obese and six lean, body mass index > 27 kg m(-1) as threshold point) before and after LOE was analysed. Gene expression of resistin was measured by semi-quantitative RT-PCR. Ten lean, age-matched healthy women served as controls. RESULTS: Both lean and obese women with PCOS had significantly higher fasting and 2 h insulin and homeostasis model insulin resistance index (HOMA(IR)) values and lower fasting glucose-to-insulin ratios (G(0)/I(0)) than did the controls. The serum levels of glucose and insulin and HOMA(IR) were significantly decreased, and the G(0)/I(0) ratio was significantly increased 3 months after LOE. No difference was found in serum resistin levels between controls and either obese or lean women with PCOS before LOE, nor between PCOS patients before and after LOE. However, resistin mRNA expression levels in both lean and obese women with PCOS before LOE were significantly higher than that in controls and were decreased significantly after LOE back to control levels. CONCLUSION: Local resistin activity may be actively involved in the pathogenesis of PCOS. LOE reduces insulin resistance and down-regulates resistin mRNA expression in lean and obese women with PCOS.     

Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery

BACKGROUND: Increased Ser(312) phosphorylation of insulin receptor substrate (IRS)-1 is one possible molecular mechanism of insulin resistance in polycystic ovary syndrome (PCOS). We investigated whether laparoscopic ovarian electrocautery (LOE) improved insulin sensitivity in women with PCOS and examined the underlying molecular mechanism of LOE. METHODS: Adipose tissue and blood samples from 12 women with PCOS before, and 3 months after, LOE were analysed. RESULTS: Before LOE, women with PCOS were found to have significantly higher 2 h glucose, fasting and 2 h insulin levels, homeostasis model insulin resistance index and lower fasting glucose-to-insulin ratio (G(0)/I(0)) than healthy, lean, age-matched controls. Serum levels of glucose and insulin were significantly decreased, and G(0)/I(0) ratio was significantly increased 3 months after LOE. Levels of activated extracellular signal-regulated kinase 1/2 in PCOS women were higher than in controls, but were significantly decreased after LOE. Levels of insulin receptor, glucose transporter-4 and phosphatidylinositol 3-kinase were lower in PCOS patients before LOE than in controls and increased after LOE. Levels of Ser(312)-phosphorylated IRS-1 in PCOS women before LOE were higher than in controls and decreased significantly after LOE, whereas IRS-1 tyrosine phosphorylation in PCOS women before LOE was lower than in controls and increased significantly after LOE. CONCLUSION: Over the short observation period of this study, our results demonstrated that LOE effectively ameliorated insulin resistance in women with PCOS via decreased IRS-1 Ser(312) phosphorylation.     

Resumption of ovarian function during lactational amenorrhoea in breastfeeding women with polycystic ovarian syndrome: metabolic aspects

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common endocrine-metabolic disorder in women, a high percentage of whom exhibit peripheral insulin resistance. After delivery, in normal women, lactation imposes a metabolic adaptation, the impact of which on the insulin resistance of PCOS patients is not known. The aim of this study was to evaluate the effect of lactation on insulin resistance, glucose and insulin metabolism, and sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP)-1 concentrations in fully breast-feeding normal and PCOS women during the postpartum period (lactational amenorrhoea) and also after weaning. METHODS: Twelve lactating PCOS (LPCOS) women and six normal lactating (NL) women of similar age and body mass index (BMI) were selected for the study. At the 4th and the 8th week postpartum (pp), and 8 weeks after weaning, a 2 h, 75 g oral glucose tolerance test (oGGT) was performed, followed by an insulin tolerance test 2 days later. For the oGGT, glucose and insulin were measured in each sample and SHBG and IGFBP-1 were determined in the fasting sample. RESULTS: During lactation, fasting insulin levels were similar in both groups. In LPCOS women 2 h insulin concentrations were significantly higher, and SHBG and IGFBP-1 concentrations were significantly lower, than those observed in NL women. In both groups, insulin sensitivity evaluated by the insulin tolerance test was not modified. After weaning, in LPCOS women, SHBG and IGFBP-1 concentrations remained lower and insulin concentrations remained higher than those observed in NL women ( P < 0.05 ). CONCLUSIONS: In PCOS women, insulin resistance is not modified during lactation. Lactation has a transitory beneficial effect on insulin levels and biological markers of insulin resistance.     

Insulin sensitivity, insulin secretion, and metabolic and hormonal parameters in healthy women and women with polycystic ovarian syndrome

To study the contributions of body mass, body fat distribution and family history of type 2 diabetes mellitus to hyperinsulinaemia, insulin secretion and resistance in polycystic ovarian syndrome (PCOS), 17 lean (LC) and 17 obese (OC) healthy control subjects, and 15 lean (LPCOS) and 28 obese (OPCOS) women with PCOS were investigated. Waist:hip ratio (WHR), serum concentrations of sex steroids, glucose and insulin during a 75 g oral glucose tolerance test (OGTT), and insulin and C-peptide early phase secretion, and insulin sensitivity index using a euglycaemic hyperinsulinaemic clamp were assessed. The PCOS subjects had a higher mean WHR than the controls. A trend towards hyperinsulinaemia and impairment of insulin sensitivity (including the rates of both glucose oxidation and non-oxidation) was observed in LPCOS subjects, but only in OPCOS subjects were these changes significant. Early phase insulin secretion but not the early phase C-peptide secretion was increased in PCOS subjects compared to controls, suggesting that peripheral hyperinsulinaemia in PCOS women was mainly due to the observed lowered hepatic insulin extraction and insulin resistance in skeletal muscle. Moreover, the presence of a family history of type 2 diabetes did not affect early phase insulin or C-peptide secretion in the PCOS group. These results confirm and strengthen earlier contentions, that insulin resistance is a characteristic defect in PCOS and is worsened particularly by abdominal obesity.     

A pilot study of the long-term effects of acipimox in polycystic ovarian syndrome

BACKGROUND: To evaluate the effects of long-term acipimox administration on glucose-induced insulin secretion and peripheral insulin sensitivity in polycystic ovarian syndrome (PCOS), 20 PCOS subjects (eight lean and 12 obese) and 14 body mass index-matched controls (seven lean and seven obese) were investigated. METHODS: Fasting blood samples were collected for basal hormone and lipoprotein assays, after which patients underwent an oral glucose tolerance test (OGTT). The following day a euglycaemic-hyperinsulinaemic clamp was performed. After 4-6 weeks of treatment with acipimox at a dose of 250 mg given orally three times a day, the patients repeated the study protocol. RESULTS: No significant differences were found in the glucose, insulin or C-peptide responses to OGTT before and after anti-lipolytic drug administration in any group, nor was there any effect on insulin sensitivity. Concerning the lipid profile, acipimox administration led to a significant decrease of cholesterol and low-density lipoprotein levels in obese PCOS patients as well as in obese and lean controls. Lower triglycerides were found after the drug administration in both obese groups. Post-treatment free fatty acid levels were not significantly different when compared with basal values. CONCLUSIONS: Acipimox does not appear to be an effective insulin-lowering drug in PCOS, even if it can be used in obese women with PCOS as an additional therapeutic agent to ameliorate the atherogenic lipid profile of the syndrome.     

Serum and follicular resistin levels in women with polycystic ovarian syndrome during IVF-stimulated cycles

BACKGROUND: Resistin is a hormone linking obesity and insulin resistance. The aim of this study was to compare resistin levels in serum or follicular fluid from women with polycystic ovarian syndrome (PCOS) and controls, both of whom were undergoing IVF. METHODS: We compared serum and follicular resistin levels in 21 PCOS women and in 18 healthy, normal ovulation, age- and body mass index (BMI)-matched non-PCOS women undergoing IVF. Correlations between serum or follicular fluid resistin levels and reproductive outcome were evaluated. RESULTS: There was no significant difference in either serum or follicular resistin levels between the control group and the PCOS group as a whole or those with insulin resistance [homeostasis model assessment of insulin resistance index applied to oral glucose tolerance test (HOMA(OGTT)) <4.7]. However, resistin levels in follicular fluid were unexpectedly significantly lower than serum levels (P<0.0001) in both the PCOS and control groups. No significant correlation was found between resistin levels and BMI, estradiol, LH, or fasting or 2 h glucose or insulin levels or between follicular resistin levels and fertilization rate, implantation rate, clinical pregnancy rate, or early miscarriage rate in PCOS. CONCLUSION: Resistin is unlikely to be a major determining factor in the growth and maturation of oocytes during IVF-stimulated cycles in PCOS.     

Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS

BACKGROUND Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. However, PCOS has a strong resemblance to the metabolic syndrome, including preponderance of visceral fat deposition. The aim of this study is to compare fat distribution between lean women with PCOS and controls matched for body composition but with regular menstrual cycles and proven fertility. METHODS In this prospective cross-sectional study in a fertility outpatient clinic, 10 Caucasian women with PCOS and 10 controls, all with a BMI between 19 and 25 kg/m(2), were included. Fasting glucose, insulin and C-peptide concentrations, homeostasis model assessment (HOMA), hormonal levels and bioelectrical impedance analysis (BIA) variables were assessed and fat content and ovarian volume determinations were obtained with magnetic resonance imaging (MRI). Multiple axial cross-sections were calculated. RESULTS The age of the PCOS and control groups were [mean (SD)] 28.2 years (2.6) versus 33.7 years (2.3) P < 0.0001, respectively, and both groups were matched for BMI: 21.6 kg/m(2) (1.1) versus 21.8 kg/m(2) (2.1) (ns), fasting glucose, insulin, C-peptide, HOMA-insulin resistance (IR) levels and BIA parameters. PCOS cases had higher ovarian volumes and less visceral fat compared with controls. CONCLUSIONS Lean women with PCOS have higher MRI-determined ovarian volumes and less visceral fat content when compared with control women.     

Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study

BACKGROUND: We conducted a cross-sectional case-control study to evaluate the possible involvement of adiponectin and resistin in the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Seventy-six PCOS patients and 40 non-hyperandrogenic women matched for BMI and degree of obesity were included. Serum adiponectin and resistin levels, anthropometrical and hormonal variables, the 45 T-->G and 276 G-->T polymorphisms in the adiponectin gene, and the -420 C-->G variant in the resistin gene, were analysed. RESULTS: Serum adiponectin concentrations were reduced in PCOS patients compared with controls (P = 0.038) irrespective of the degree of obesity, whereas serum resistin levels were increased in overweight and obese women compared with lean subjects (P = 0.016), irrespective of their PCOS or controls status. The adiponectin and resistin polymorphisms were not associated with PCOS and did not influence serum levels of adiponectin, resistin and other clinical and hormonal variables. In a multiple regression model, the waist-to-hip ratio, free testosterone levels and age, but not insulin resistance, were the major determinants of hypoadiponectinaemia. CONCLUSIONS: PCOS patients present with hypoadiponectinaemia, in relation with abdominal adiposity and hyperandrogenism. Our present results suggest that hyperandrogenism and abdominal obesity, by reducing the serum levels of the insulin sensitizer adipokine adiponectin, might contribute to the insulin resistance of PCOS.     

Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea

Hyperinsulinaemic insulin resistance is commonly associated with hyperandrogenaemia, and menstrual dysfunction. The aim of this study was to examine the effects of the insulin sensitizing drug, metformin, on ovarian function, follicular growth, and ovulation rate in obese women with oligomenorrhoea. Twenty obese subjects with oligomenorrhoea [polycystic ovarian syndrome; (PCOS)] were observed longitudinally for 3 weeks prior to and for 8 weeks during treatment with metformin (850 mg twice per day). Fifteen patients completed the study. The frequency of ovulation was significantly higher during treatment than before treatment (P = 0.003). A significant decline in both testosterone and luteinizing hormone concentrations was recorded within 1 week of commencing treatment. Patients with elevated pretreatment testosterone concentrations showed the most marked increase in ovulation rate (P < 0.005), and significant reductions in circulating testosterone from 1.02 to 0.54 ng/ml (P < 0.005) after only 1 week of treatment. However, the sub-group with raised fasting insulin showed less marked changes, and the sub-group with normal testosterone concentrations showed no effect of treatment. Metformin had a rapid effect upon the abnormal ovarian function in hyperandrogenic women with PCOS, correcting the disordered ovarian steroid metabolism and ovulation rate; however, there appeared to be no effect in cases where the circulating androgen concentration was normal.     

Effect of feeding on growth hormone response to growth hormone-releasing hormone in polycystic ovarian syndrome: relation with body weight and hyperinsulinism

The plasma growth hormone (GH) response to direct stimulation with growth hormone-releasing hormone (GHRH) before and after a standard meal was investigated in 14 polycystic ovarian syndrome (PCOS) subjects. Data were compared with those obtained from 14 healthy normovulatory matched patients. All women underwent an oral glucose tolerance test (OGTT) (75 g) and basal plasma hormone concentrations were evaluated. On a different day all subjects had a GHRH test (50 microg GHRH) both before and after lunch randomly. In obese PCOS subjects the GH response to GHRH was blunted after a meal, while in obese control patients there was an enhanced response of GH to GHRH after a meal. Normal control subjects showed an inhibition of the GH response after feeding and lean PCOS subjects showed a trend toward an augmented GHRH related secretion after a meal significantly higher than normal controls (P < 0.05) but not significantly higher than the pre-prandial response. In conclusion, the data indicate in PCOS a derangement of GH secretion related to food ingestion; in particular obese PCOS patients did not exhibit any change of GH response after a meal compared with the paradoxical response observed in obese controls. Several other factors beyond body mass index and hyperinsulinism could be involved in these pathophysiological events.     

Insulin sensitivity in non-obese women with polycystic ovary syndrome during treatment with oral contraceptives containing low-androgenic progestin.

BACKGROUND: Combined oral contraceptives (COC) effectively suppress hyperandrogenism in women with polycystic ovary syndrome (PCOS), though deterioration of insulin sensitivity during treatment is assumed. The study aim was to investigate insulin action and androgen production during treatment with COC containing low-androgenic progestin. METHODS: A total of 13 PCOS women and nine controls was enrolled into the study. Only non-obese women with a body mass index (BMI) 相似文献   

Serum levels of insulin-like growth factor-1, IGF binding protein-1 and insulin and the response to human menopausal gonadotrophins in women with polycystic ovary syndrome

In order to determine which factors influence the large variationsin sensitivity to gonadotrophins witnessed in women with polycysticovary syndrome (PCOS), a prospective study was conducted ofthe correlation between basal clinical and endocrinologicalfeatures and gonadotrophin requirements of 20 women with clomiphene-resistantPCOS undergoing ovulation induction. Baseline evaluation ofserum concentrations of luteinizing hormone (LH), follicle stimulatinghormone (FSH), testosterone, fasting insulin, insulin-like growthfactor-1 (IGF-1), IGF binding protein-1 (IGFBP-1) and sex hormone-bindingglobulin (SHBG) were performed before administering gonadotrophin-releasinghormone agonist (GnRHa). Two weeks later, human menopausal gonadotrophin(HMG) was given in a standard individualized protocol accordingto ovarian response, until human chorionic gonadotrophin (HCG)was given. Serum concentrations of insulin, IGF-1, and IGFBP-1were unaffected by GnRHa. The BMI correlated positively withinsulin and inversely with IGFBP-1 serum concentrations andinsulin and IGFBP-1 were inversely correlated. The amount ofHMG required correlated positively with BMI and insulin concentrationsand inversely with IGFBP-1 in the whole group and these correlationswere maintained in the sub-group of lean women. No correlationwas observed between HMG requirements and IGF-1 or other hormones.Womenwith hyperinsulinaemia and low IGFBP-1 concentrations requiredsignificantly more HMG. Multiple regression analysis revealedthat insulin concentration is the most significant determinantof HMG requirement even when dissociated from BMI. We concludedthat requirement of HMG in PCOS is not merely determined byobesity but by a cardinal role of insulin concentrations which,when high, induce, hypothetically, a hyperandrogenic intrafollicularmilieu.     

Obstetric outcome in women with polycystic ovarian syndrome

Women with polycystic ovarian syndrome (PCOS) often have insulin resistance and hyperinsulinaemia and may therefore be at an increased risk for gestational diabetes mellitus (GDM). Hyperinsulinaemia may also be associated with pre-eclampsia. Information concerning outcome of pregnancies in PCOS women is scanty and somewhat controversial. Therefore, 99 pregnancies were retrospectively evaluated in women with PCOS and the findings were compared with an unselected control population. The average body mass index (BMI) in PCOS patients was greater than that in controls (25.6 versus 23.0) (P < 0.0001), and PCOS patients were more often nulliparous than controls (76 versus 42%) (P < 0.001). The multiple pregnancy rate was 9.1% in PCOS patients and 1.1% in controls [odds ratio (OR) 9.0; 95% confidence interval (CI) 3.5-23.3]. GDM developed in 20% of the PCOS patients and in 8.9% of the controls (P < 0.001). After logistic regression analysis, BMI >25 seemed to be the greatest predictor for GDM (adjusted OR 5.1; CI 3.2-8.3), while PCOS remained as another independent predictor (adjusted OR 1.9; CI 1.0-3.5). In contrast, PCOS was not a significant predictor for pre-eclampsia, which was merely associated with nulliparity. Premature delivery (16.1% in PCOS and 6.5% in controls) was explained to a large extent by multiple pregnancies and marginally by nulliparity and PCOS. In singleton pregnancies, there was no difference in birth weights, Apgar scores or perinatal morbidity of infants. In conclusion, PCOS slightly increases the risk for GDM, but does not have an important effect on the rate of premature delivery and pre-eclampsia.     

Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome

The induction of ovulation by clomiphene could be the result of interaction of the drug at various levels: hypothalamus, pituitary and ovary. It was demonstrated that administration of clomiphene to women with polycystic ovarian syndrome (PCOS) is accompanied by a reduction in plasma concentrations of insulin-like growth factor-I (IGF-I). IGF-I seems to have an overall negative effect on normal folliculogenesis and ovulation. The aim of the present study was to evaluate the effect of clomiphene on plasma concentrations of IGF-I and IGF binding protein (IGFBP)-1 and on insulin resistance associated with PCOS. Fifteen patients diagnosed with PCOS were recruited. Clinical diagnosis was based on chronic oligomenorrhoea or amenorrhoea and hyperandrogenaemia. Clomiphene citrate was administered at a dose of 100mg/day to all women from day 5 to day 9 of the spontaneous or medroxyprogesterone acetate (MAP)-induced menstrual cycle. Blood sampling and a 2 h oral glucose loading test (75 g) were performed the day before and after the course of clomiphene. Ovulation was confirmed in 13/15 PCOS patients. Plasma concentrations of IGF-I decreased by 31.5% (434 +/- 84 versus 297 +/- 71 ng/ml; P: < 0.05) after 5 days of clomiphene therapy, whereas plasma concentrations of IGFBP-1 increased by approximately 28.1% (26.3 +/- 4 versus 36.6 +/- 7 ng/ml; P: < 0.05). This gave a 56.5% reduction in the IGF-I:IGFBP-1 ratio (21.9 versus 9.53). No significant changes in basal plasma concentrations of fasting insulin or area under the insulin curve were observed in response to oral loading. The present results show that clomiphene does not cause changes in insulin resistance associated with PCOS but reduces plasma concentrations of IGF-I and increases those of IGFBP-1, with a consequent marked reduction in the IGF-I:IGFBP-1 ratio.     

Proinsulin serum concentrations in women with polycystic ovary syndrome: a marker of beta-cell dysfunction?

BACKGROUND: The aim of this study was to establish the effect of polycystic ovary syndrome (PCOS) adjusted for adiposity on proinsulin concentrations. METHODS: Ninety-one women with PCOS and 72 normal cycling (NC) women were recruited. A 2 h, 75 g oral glucose tolerance test was performed. Glucose and insulin were measured in each sample. Proinsulin and C-peptide were determined at 0 and 30 min and the fasting proinsulin/insulin ratio (PI/I) was calculated. Insulin sensitivity was estimated by insulin sensitivity index (ISI) composite, and beta-cell function was estimated by insulinogenic index. RESULTS: Insulin, proinsulin and C-peptide concentrations were higher in women with PCOS than in NC women (P < 0.05). PI/I and insulinogenic index were similar in both groups. Proinsulin concentrations increased with body mass index (P < 0.05) only in women with PCOS; therefore, proinsulin concentrations were higher in obese PCOS patients compared with obese control women (P < 0.05). Moreover, a positive association between proinsulin concentrations and waist diameter adjusted for C-peptide (P < 0.05) and a negative association between proinsulin concentrations and ISI composite values were observed in PCOS patients (P < 0.05). CONCLUSIONS: Data suggest that in PCOS patients an elevated proinsulin concentration could reflect insulin resistance more than beta-cell dysfunction. However, the elevated concentration of proinsulin in these patients could also result from impaired beta-cell function resulting from intra-abdominal obesity independently of insulin resistance.     

Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions on these parameters

BACKGROUND: The aim of this study was to quantify the three-dimensional (3D) ultrasound characteristics of ovaries in Caucasian women with polycystic ovarian syndrome (PCOS) and to examine if these values differed between different phenotypic forms. METHODS: 3D pelvic ultrasound was performed in 40 women with PCOS and in 40 controls. Total ovarian volume, stromal volume and echogenicity and antral follicle count (AFC) were measured and ovarian blood flow was quantified using both 3D power Doppler and two-dimensional pulsed-wave Doppler. RESULTS: Women with PCOS had a higher AFC (median 16.3 versus 5.5 per ovary, P < 0.001) and ovarian volume (12.56 versus 5.66 ml, P < 0.001). Stromal volume (10.79 versus 4.69 ml, P < 0.001) and stromal vascularization (VI: 3.85 versus 2.79%, P < 0.001; VFI: 1.27 versus 0.85, P < 0.001) were also increased in women with PCOS. There were no significant differences in stromal echogenicity or pulsed-wave Doppler indices between women with PCOS and the controls. Among the women with PCOS, ovarian vascularity was significantly higher in 30 women who were hirsute compared with normoandrogenic women (FI: 33.94 versus 29.30, P < 0.05) and in 14 women with PCOS who were of normal weight compared with obese women (VI: 4.51 versus 3.25%, P < 0.05; VFI: 1.56 versus 1.22, P < 0.05). CONCLUSIONS: Based on 3D ultrasound, women with PCOS have an increased stromal volume and vascularity. Stromal vascularity is significantly higher in women with PCOS who are hirsute and of normal weight.     

Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial

BACKGROUND: This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome (PCOS) patients with normal glucose tolerance. METHODS AND RESULTS: Thirty-two patients were randomized to metformin (n = 16) and placebo (n = 16) groups. Hormonal assessment, a 75 g oral glucose tolerance test (OGTT) and a frequently sampled i.v. glucose tolerance test (FSIGTT) were performed before and after oral administration of metformin (850 mg twice daily) or placebo for 6 weeks. Recombinant FSH treatment was undertaken, thereafter, in women who did not ovulate on metformin (n = 10) or placebo (n = 15). There was no significant change in all insulin sensitivity indices in both groups. The only change noted was a decline in mean serum free testosterone concentration in the metformin group (P = 0.049). One patient on placebo and six patients on metformin ovulated spontaneously (P < 0.05). All parameters of ovarian response were comparable between the two groups during rFSH treatment. Combining the 6 week placebo or metformin-only period with a single rFSH treatment cycle, the overall ovulation rates were 75 and 94% in the placebo and metformin groups respectively (P > 0.05). The respective figures for pregnancy were 6.3 and 31.3% (P > 0.05). CONCLUSIONS: Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during rFSH treatment.     

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and/or activin serum concentrations. METHODS: The study group included 24 obese and 20 non-obese (body mass index vertical line and <27 kg/m2 respectively) clomiphene-failure PCOS patients. The control group included 16 obese and 46 non-obese patients with normal ovulatory cycles. Blood samples were obtained from the patients on day 3-5 of a progesterone-induced or spontaneous cycle and were assayed for LH, FSH, testosterone, 17-hydroxy-progesterone, androstenedione, follistatin, activin A, fasting glucose and insulin. RESULTS: Follistatin concentrations were comparable between obese and non-obese PCOS patients (mean +/- SE; 1171 +/- 103 and 1045 +/- 159 pg/ml respectively) and significantly higher than their respective controls (628 +/- 61 and 592 +/- 49 pg/ml, P < 0.0001 and P < 0.02 respectively). Activin A concentrations were comparable between the four groups (590 +/- 35, 513 +/- 74, 661 +/- 87 and 595 +/- 43 pg/ml in obese and non-obese PCOS and controls respectively). Stepwise regression analyses for relationships between follistatin or activin A levels and all other variables indicated that follistatin was significantly and independently positively affected by PCOS (P < 0.0001), age (P < 0.02), androstenedione (P < 0.03) and weight (P < 0.05). Activin A was significantly and independently negatively affected by PCOS (P < 0.003) and FSH (P < 0.03), and positively affected by weight (P < 0.009) and androstenedione (P < 0.02). CONCLUSIONS: Serum follistatin is increased in PCOS patients, regardless of obesity. PCOS is the most significant variable that relates to high follistatin and low activin A serum concentration. A high follistatin/activin ratio could well contribute to the pathophysiology of PCOS.     

Decreased serum paraoxonase 1 (PON1) activity: an additional risk factor for atherosclerotic heart disease in patients with PCOS?

BACKGROUND: Patients with polycystic ovary syndrome (PCOS) may have an increased risk for the development of hypertension and atherosclerotic heart disease (AHD), the pathophysiological mechanisms of which are not clear. Paraoxonase1 (PON1) is a high-density lipoprotein-associated enzyme that prevents oxidative modification of low-density lipoprotein. The aim of this study was to measure the serum levels of PON1 activity in patients with PCOS and to compare with those of regularly cycling controls. METHODS: Serum lipid parameters, malondialdehyde (MDA) levels and PON1 activity, were measured in PCOS patients (n = 23) and regularly cycling, age-, body mass index- and smoking status-matched controls (n = 23). All patients had normal glucose tolerance test as assessed by a 75 g oral glucose tolerance test. None of the patients had clinically evident hypertension or AHD. RESULTS: Apart from the mean serum PON1 activity, all parameters in the lipid profile including serum MDA levels were comparable between the two groups. There were no significant differences in respect to fasting glucose (4.64 +/- 0.5 versus 4.43 +/- 0.83 mmol/l) and fasting glucose insulin ratio (11.06 +/- 8.26 versus 11.49 +/- 4.90) among the two groups (P > 0.05). However, HOMA insulin resistance index was significantly higher in patients with PCOS compared with the controls (2.06 +/- 0.86 versus 1.51 +/- 0.49; P = 0.01). Also, mean serum PON1 activity was significantly lower in the PCOS group compared with the controls (151.2 +/- 90.8 versus 217.7 +/- 101.6, respectively; P = 0.027). CONCLUSIONS: Reduced serum PON1 activity might contribute to the increased susceptibility for the development of AHD in women with PCOS.     

The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome

BACKGROUND: Oxidative stress and hyperhomocysteinaemia are risk factors for cardiovascular diseases. The aim of this study was to assess the effects of rosiglitazone and metformin on cardiovascular disease risk factors such as insulin resistance, oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome (PCOS). METHODS: Fifty lean patients (BMI <25 kg/m2) with PCOS and 35 healthy subjects were included this study. Serum homocysteine, sex steroids, fasting insulin, fasting glucose and lipid levels were measured. Total antioxidant status (TAS; combines concentrations of individual antioxidants) and malonyldialdehyde concentration (MDA) were determined. Insulin resistance was evaluated by using the homeostasis model insulin resistance index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Area under the curve insulin (AUCI) and the insulin sensitivity index (ISI). Patients were divided into two groups. One group was treated with metformin (n = 25) and the other received rosiglitazone (n = 25) for 12 weeks. All measurements were repeated at the end of 12 weeks. RESULTS: Compared with healthy women, those with PCOS had significantly elevated serum MDA, homocysteine, HOMA-IR, AUCI and lipoprotein a levels, and significantly decreased serum TAS, QUICKI and ISI. Serum free testosterone levels showed a significant positive correlation with MDA, AUCI and HOMA-IR, and a negative correlation with TAS, ISI and QUICKI in PCOS patients. HOMA-IR and AUCI significantly decreased, while QUICKI and ISI significantly increased after treatment in both groups. Serum TAS level increased and serum MDA level decreased after the rosiglitazone treatment, but these parameters did not change after the metformin treatment. Serum homocysteine and lipid levels did not change in either group, while serum androgen levels and LH/FSH ratio significantly decreased after the treatment period in only the rosiglitazone-treated group. CONCLUSION: Elevated insulin resistance, oxidative stress and plasma homocysteine levels and changes in serum lipid profile (risk factors for cardiovascular disease) were observed in lean PCOS patients. Rosiglitazone seemed to decrease elevated oxidative stress when compared with metformin treatment in lean PCOS patients.