Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

BACKGROUND Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. OBJECTIVE: To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. DESIGN: A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. SUBJECTS: Twenty-nine women with PCOS [aged 27.52 +/- 5.77 years; body mass index (BMI) 35.43 +/- 5.31 kg/m(2)] and 18 controls (aged 32.06 +/- 5.64 years; BMI 36.39 +/- 6.47 kg/m(2)). MEASUREMENTS: Serum AGE levels (U/ml), hormonal and metabolic profile. RESULTS: PCOS and controls did not differ in BMI (P = 0.58), waist-to-hip ratio (WHR) (P = 0.44), fasting insulin concentration (P = 0.45) and glucose-to-insulin ratio (GIR) (P = 0.34). PCOS women exhibited statistically higher AGE (P < 0.001) and testosterone levels (P < 0.001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9.08 +/- 1.84, post-orlistat 8.56 +/- 1.95, P = 0.001; controls: baseline 5.02 +/- 0.62, post-orlistat 4.91 +/- 0.69, P = 0.03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0.001; controls: P < 0.001), WHR (PCOS: P = 0.002; controls: P = 0.04), fasting insulin (PCOS: P < 0.001; controls: P = 0.008), and testosterone concentrations in PCOS (P < 0.001). SHBG concentration (PCOS: P = 0.004; controls: P = 0.008) and GIR (PCOS: P < 0.001; controls: P = 0.03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. CONCLUSIONS: Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes.     

Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors and are considered to be at increased risk for atherosclerosis. Elevated concentrations of advanced glycation end-products (AGE), which exert their effects through interaction with specific receptors (RAGE), have been implicated in the cellular and tissue damage during atherosclerotic processes. DESIGN/PATIENTS: We investigated serum AGE levels in 29 young women with PCOS as well as the expression of their receptor, RAGE, in circulating monocytes and compared them levels with 22 healthy control women. MEASUREMENTS/RESULTS: Women with PCOS had higher levels of serum AGE proteins compared to healthy individuals (9.81 +/- 0.16 vs. 5.11 +/- 0.16, P < 0.0001), and increased RAGE expression was observed in monocytes of PCOS women compared to controls (30.91 +/- 10.11 vs. 7.97 +/- 2.61, P < 0.02). A positive correlation was observed between AGE proteins and testosterone (T) levels (r = 0.73, P < 0.0001). The correlation between AGE proteins and T levels remained high (partial correlation coefficient = 0.61, P = 0.0001) after controlling for body mass index (BMI), insulin levels and the area under the curve for glucose (AUCGLU) during an oral glucose tolerance test (OGTT). A positive correlation was also observed between AGE proteins and the free androgen index (FAI) (r = 0.58, P < 0.0001), waist-to-hip ratio (WHR) (r = 0.31, P < 0.02), insulin (r = 0.46, P < 0.001), homeostasis model assessment (HOMA) (r = 0.47, P < 0.0001), AUCGLU (r = 0.52, P < 0.002) and RAGE (r = 0.59, P < 0.01). A negative correlation was observed between AGE proteins and glucose/insulin ratio (GLU/INS) (r = -0.35, P < 0.01), and the quantitative insulin sensitivity check index (QUICKI) (r =-0.50, P < 0.01). In multiple regression analysis T was the only independent predictor of AGE levels (P < 0.0001, b = 0.044) between BMI, insulin, SHBG and AUCGLU (adjusted R2 = 0.59, F = 44.41, P < 0.0001). CONCLUSION: These data clearly demonstrate, for the first time, that PCOS women without overt hyperglycaemia have increased AGE levels and elevated RAGE expression when compared with controls.     

Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 +/- 5.47 years; body mass index, 25.85 +/- 6.73 kg/m(2)) and 21 with PCOS (mean age, 25.29 +/- 5.06 years; body mass index, 30.40 +/- 7.51 kg/m(2)) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.     

Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome

Some actions of insulin are mediated by putative inositolphosphoglycan mediators, and a deficiency in D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Furthermore, similar effects of DCI and metformin, an insulin-sensitizing drug, have been demonstrated in PCOS women. To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS, we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4-8 wk of metformin or placebo. After treatment, the mean (+/-SE) area under the curve (AUC) during the oral glucose tolerance test of insulin (AUC(insulin)) decreased significantly more in the metformin group, compared with the placebo group [-3574 +/- 962 vs. +1367 +/- 1021 micro IU/min.ml (-26 +/- 7 vs. +10 +/- 7 nmol/min.liter), P = 0.003], but the AUC of DCI-IPG (AUC(DCI-IPG)) decreased similarly in both groups (-1452 +/- 968 vs. -2207 +/- 1021%/min, P = 0.60). However, the ratio of AUC(DCI-IPG)/AUC(insulin) increased by 160% after metformin and decreased by 29% after placebo (P = 0.002 between groups). Moreover, metformin seemed to improve the positive correlation between AUC(DCI-IPG) and AUC(insulin) but not placebo (r = 0.32, P = 0.68 at baseline; r = 0.52, P = 0.12 after metformin; and r = -0.39, P = 0.30 after placebo). We conclude that in obese women with PCOS, metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators, as evidenced by increased bioactive DCI-IPG released per unit of insulin.     

Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment

CONTEXT: Insulin resistance plays a significant role in the pathogenesis of the polycystic ovary syndrome (PCOS) and represents a link to the unfavorable cardiovascular risk profile frequently found in affected patients. The endogenous nitric oxide synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is associated with atherosclerosis and represents an independent marker for cardiovascular morbidity and mortality. OBJECTIVE: We investigated ADMA levels among other cardiovascular, metabolic, and hormonal parameters in women with PCOS and the effects of metformin treatment on these parameters. DESIGN: A cross-sectional study and clinical trial were performed. PATIENTS AND PARTICIPANTS: Women with PCOS (n = 83) compared with a control group of healthy women (n = 39) were studied. INTERVENTIONS: In a subgroup of patients with PCOS (n = 21), the effect of metformin was assessed after 6 months of treatment. MAIN OUTCOME MEASURES: ADMA, intima media thickness (IMT), metabolic and hormonal parameters, and markers of inflammation were investigated. RESULTS: ADMA levels were significantly higher in the PCOS group compared with controls (0.57 +/- 0.15 vs. 0.50 +/- 0.11; P = 0.024). Androgens, C-reactive protein, fasting C-peptide, area under the curve (AUC) insulin, AUC glucose, homeostatic assessment of insulin resistance, fasting insulin, glycosylated hemoglobin, cholesterol, low-density lipoprotein cholesterol, triglycerides, and IMT were significantly higher in women with PCOS compared with controls. In PCOS patients ADMA was found to be positively correlated with body mass index (BMI), waist to hip ratio, parameters of insulin sensitivity, hyperandrogenemia (free testosterone, free androgen index), and IMT. Treatment with metformin ameliorated hyperandrogenemia and decreased ADMA levels (0.53 +/- 0.06 vs. 0.46 +/- 0.09, P = 0.013). Decrease in ADMA levels subsequent to metformin treatment did not correlate with change in BMI or metabolic parameters. CONCLUSIONS: ADMA amd parameters of insulin sensitivity are elevated in women with PCOS and the degree of insulin resistance confers the greatest influence on ADMA level. Metformin treatment led to improvement of hormonal and metabolic parameters and decreased ADMA levels possibly independent of BMI and metabolic changes.     

Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study

CONTEXT: Recent data indicate that women affected by the polycystic ovary syndrome (PCOS) are at greater risk for cardiovascular disease and that metformin may improve the metabolic alterations in these patients. OBJECTIVE: The objective of this study was to evaluate the effects of 6 months of metformin administration on endothelial structure and function in women with PCOS. DESIGN: This was a prospective, baseline-controlled, clinical study. SETTING: The study was performed at University Federico II (Naples, Italy). PATIENTS: Thirty young normal-weight women with PCOS without additional metabolic or cardiovascular diseases were studied. INTERVENTIONS: Metformin (850 mg daily) was administered for 6 months. MEAN OUTCOME MEASURES: The main outcome measures were complete hormonal profile, including total testosterone, SHBG, dehydroepiandrosterone sulfate, prolactin, and gonadotropin levels; serum insulin and glucose levels during a 75-g 2-h oral glucose tolerance test; plasma endothelin-1 concentrations (picomoles per liter +/- sd); serum lipid profile; brachial artery baseline diameter (millimeters +/- sd), diameter after reactive hyperemia (millimeters +/- sd), and flow-mediated dilation (percentage +/- sd); and the intima media thickness (millimeters +/- sd) on both common carotid arteries. RESULTS: After treatment, SHBG levels and the free androgen index changed significantly (P < 0.001). High-density lipoproteins and the area under curve for glucose/area under curve for insulin ratio also significantly (P < 0.001) increased, whereas low-density lipoproteins and plasma endothelin-1 levels were significantly (P < 0.001) reduced. No other change was found in any of the biochemical parameters evaluated. A significant difference was observed in brachial artery baseline diameter (3.24 +/- 0.30 vs. 3.0 +/- 0.30), flow-mediated dilation (14.30 +/- 1.90 vs. 15.70 +/- 1.50) (P < 0.01, each), diameter after reactive hyperemia (3.70 +/- 0.30 vs. 3.55 +/- 0.10) (P < 0.05), and intima media thickness (0.53 +/- 0.09 vs. 0.40 +/- 0.07) (P < 0.001) after metformin treatment in comparison with baseline values. CONCLUSIONS: A 6-month course of metformin improves endothelial structure and function in young, normal-weight women with PCOS.     

Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome

The objective of the present study was to investigate whether metformin affected plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an open study conducted by the Department of Obstetrics and Gynecology at the University of Siena, Italy. Seventeen women with PCOS participated in the study and were administered metformin at a dose of 500 mg three times a day. Treatment was continued for 30-32 days, after which the pretreatment evaluation was repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I, IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led to a significant reduction in areas under the insulin curves (9310 +/- 1509 vs. 6520 +/-1108 mU/mL x min; P < 0.05) and was associated with a decrease in plasma free testosterone levels (12.7 +/- 1.7 vs. 10.3 +/- 2 pg/mL; P < 0.05) and an increase in plasma sex hormone-binding globulin concentrations (62 +/- 8 vs. 94 +/- 13 nmol/L; P < 0.05). A nonsignificant increase in plasma IGF-I levels was observed after metformin (276 +/-48 vs. 291 +/- 71 mcg/L), with a significant increase in plasma IGFBP-I levels (0.56 +/- 0.2 vs. 0.98 +/- 0.38 mcg/L; P < 0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 +/- 117 vs. 296.9 +/- 82; P < 0.05) at the end of therapy than before treatment. In conclusion, it seems to be appropriate to intervene with an insulin-sensitizing agent such as metformin in an attempt to break the pathogenetic link between hyperinsulinemia and hormonal perturbations in PCOS.     

Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome

The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS). Twenty-one Caucasian women with PCOS [mean (+/-SEM) age 27 +/- 0.9 yr and body mass index 36.7 +/- 3.3 kg/m(2)] participated in this prospective, randomized, open-labeled study. All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months. Weight, blood pressure, and fasting blood samples were taken at screening, randomization, and on completion. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA)-IR method [HOMA-IR = (insulin x glucose)/22.5]. The results are expressed as mean +/- SEM. When compared with baseline, treatment with both orlistat [93.5 +/- 11.5 ng/dl (3.24 +/- 0.4 nmol/liter) vs. 114.5 +/- 11.5 ng/dl (3.97 +/- 0.4 nmol/liter), P = 0.039] and metformin [97.2 +/- 11.5 ng/dl (3.37 +/- 0.4 nmol/liter) vs. 120.0 +/- 8.7 ng/dl (4.16 +/- 0.3 nmol/liter), P = 0.048] produced a significant reduction in total testosterone. Treatment with orlistat produced a 4.69% reduction in weight (99.0 +/- 6.0 vs. 94.6 +/- 6.1 kg, P = 0.002), and this reduction was more significant than the reduction produced by metformin (4.69 vs. 1.02%, P = 0.006). There was no significant reduction seen after either treatment group for fasting insulin, HOMA-IR, SHBG, or any of the lipid parameters studied. In this study, orlistat produced a significant reduction in weight and total testosterone. The reduction in total testosterone was similar to that seen after treatment with metformin. Therefore, orlistat may prove to be a useful adjunct in the treatment of PCOS.     

Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance

Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17alpha, the rate-limiting enzyme in androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tolerance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fifteen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/m(2).min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion. After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose tolerance. Total and free T decreased [1.5 +/- 0.2 vs. 1.0 +/- 0.1 nmol/liter (P = 0.022) and 41.3 +/- 8.3 vs. 22.2 +/- 2.1 pmol/liter (P = 0.028), respectively]. Insulin-stimulated glucose disposal increased (21.5 +/- 2.2 vs. 25.0 +/- 2.2 micromol/kg.min; P = 0.041). Fasting insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimulated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment [2.8 +/- 0.4 vs. 1.7 +/- 0.3 nmol/liter (P = 0.014), 7.0 +/- 0.6 vs. 5.3 +/- 0.5 nmol/liter (P = 0.011), and 30.4 +/- 3.7 vs. 25.7 +/- 4.2 nmol/liter (P = 0.054)]. Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008). In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, placebo-controlled studies will determine whether insulin-sensitizing therapy corrects not only ovarian hyperandrogenism but also functional adrenal hyperandrogenism in adolescents with PCOS.     

Time course of specific AGEs during optimised glycaemic control in type 2 diabetes

BACKGROUND: Several advanced glycation endproducts (AGEs) are formed in the hyperglycaemic state. Although serum AGEs correlate with average glycaemic control in patients with type 2 diabetes and predict the development of complications, it is not known how serum AGEs change during optimisation of diabetes therapy. METHODS: We evaluated the change in serum levels of total AGE and the AGEs CML (Nepsilon-carboxymethyllysine) and MGHI (methylglyoxal-derived hydroimidazolone), as well as markers of endothelial function in 28 subjects with type 2 diabetes, who were poorly controlled on oral agents,before and after the institution of insulin therapy. RESULTS: Mean subject age (+/- SEM) was 58 +/- 2 years,body mass index 27.7 +/- 0.8 kg/m2, and known duration of diabetes was 8.1 +/- 0.9 years. With insulin treatment fasting blood glucose levels dropped from 12.1 +/- 0.9 mmol/l to 6.9 +/- 0.3 and 8.1 +/- 0.4 mmol/l after three and six months, respectively (both p<0.001), while HbA1c decreased from 10.0 +/- 0.3 to 7.8 +/- 0.2% (p<0.001). Endothelial function improved as indicated by a small but significant decrease in soluble intercellular cell adhesion molecule (sICAM-1) (152 +/- 10 to 143 +/- 8 ng/ml, p<0.02)and sE-selectin (111 +/- 16 to 102 +/-12 ng/ml, p<0.02)levels. In contrast, we observed only a tendency towards a decrease in CML levels (110 +/-22 to 86 +/- 13 microg/mg protein, p=ns), but a small increase of MGHI (from 0.23 +/- 0.02 to 0.29 +/- 0.04 U/mg protein, p<0.02). At baseline, 16 patients were on metformin, which is known to reduce methylglyoxal levels and reduce generation of reactive oxygen species. They had similar levels of CML and MGHI to the 12 non-metformin users, although their HbA1c was lower (9.4 +/- 0.3 vs 10.7 +/- 0.6 %). During insulin, patients receiving concomitant metformin therapy showed a similar course of CML and MGHI to those not taking metformin. CONCLUSION: Although insulin therapy improved HbA1c and markers of endothelial function, the levels of serum AGEs did not follow the same time course. This suggests that these specific AGEs are influenced by other factors in addition to overall glycaemia, such as oxidative stress.     

An observational study of reduction of insulin resistance and prevention of development of type 2 diabetes mellitus in women with polycystic ovary syndrome treated with metformin and diet

Our first specific aim in an observational study of 431 nondiabetic women with polycystic ovary syndrome (PCOS), aged >or=20 years and with >or=11 months follow-up on metformin diet, was to prospectively assess relationships between pretreatment glucose and insulin resistance (IR) and the development of type 2 diabetes mellitus (T2DM) or gestational diabetes (GD). Our second specific aim was to determine whether development of T2DM and GD was independently associated with lesser reduction of IR on metformin diet when compared with women who remained free of T2DM and GD. Women with body mass index <25 kg/m(2) and those with body mass index >or=25 kg/m(2) were, respectively, instructed in a 2000- or 1500-cal/d, high-protein (26% of calories), low-carbohydrate (44%) diet, with 30% of calories as fat and a polyunsaturate-saturate ratio of 2:1. Three groups of women with PCOS were categorized: (a) 17 with no previous GD, who developed T2DM on metformin diet (mean +/- SD follow-up, 49 +/- 33 months), (b) 401 with no previous GD and free of T2DM on metformin diet (follow-up, 38 +/- 25 months), and (c) 13 with either previous GD or GD on metformin diet (follow-up, 38 +/- 25 months). On metformin diet, women who developed T2DM vs those who remained free of T2DM had higher pretreatment glucose (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.03-1.16; P = .003) and homeostasis model assessment of insulin resistance (HOMA-IR) (OR, 1.22; 95% CI, 1.04-1.42; P = .01), and less reduction of HOMA-IR (OR, 0.82; 95% CI, 0.72-0.92; P = .0008). On metformin diet, women either with previous GD or who developed GD vs those who remained free of T2DM had less reduction of HOMA-IR (OR, 0.88; 95% CI, 0.78-0.99; P = .03). By repeated-measures analysis, on metformin diet, women who did not develop T2DM had reduction in HOMA-IR (P < .0001), with the slope of this curve different (P = .002) from the unchanged IR exhibited by women who developed T2DM and different (P = .017) from an increased IR slope (P = .049) in women who had GD. In women with PCOS, pretreatment glucose and IR, and lesser reduction in IR on metformin diet were associated with T2DM and GD.     

Circulating ghrelin concentrations in the polycystic ovary syndrome

Ghrelin is a novel gastric peptide which has orexigenic and adipogenic properties. Circulating ghrelin concentrations are influenced by nutritional status and, probably, regulate food intake and body weight. Obesity is a common feature in women with polycystic ovary syndrome (PCOS). To investigate the relationship of circulating ghrelin concentrations to the hormonal and metabolic features of PCOS women, plasma ghrelin and several hormone concentrations were evaluated in thirty-three women with PCOS and in thirty-two healthy women matched for age and body mass index (BMI). Plasma ghrelin concentrations were similar between the PCOS (179 +/- 27, pmol/l +/- SEM) and the control (181 +/- 24, pmol/l +/- SEM) groups. In both groups, there was a significant (P < 0.001) inverse correlation between fasting ghrelin concentrations and BMI (PCOS: r = -0.45; Controls: r = -0.59). Multivariate regression analysis did not demonstrate any correlation (P = NS) between fasting ghrelin concentrations and the other hormone levels in the PCOS patients. In conclusion, our data demonstrate that in women with PCOS plasma ghrelin concentrations are not different from those of weight matched controls and are inversely correlated with BMI. There is no relationship between circulating ghrelin and the abnormal hormonal pattern of the PCOS syndrome.     

Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study

We compared the efficacy of spironolactone (50 mg/d) with metformin (1000 mg/d) after random allocation in 82 adolescent and young women with polycystic ovary syndrome (PCOS) on body mass index (BMI), waist-to-hip ratio, blood pressure, menstrual cyclicity, hirsutism, hormonal levels, glycemia, and insulin sensitivity at baseline and at the 3rd and 6th months of treatment. Sixty-nine women who completed the follow-up had a mean age of 22.6 +/- 5.0 yr and mean BMI of 26.8 +/- 4.0 kg/m2. The number of menstrual cycles in the spironolactone and metformin groups increased from 6.6 +/- 2.1 and 5.7 +/- 2.3 at baseline to 9.0 +/- 1.9 and 7.4 +/- 2.6 at 3rd month and to 10.2 +/- 1.9 and 9.1 +/- 2.0/ year at the 6th month (P = 0.0037), respectively. The hirsutism score decreased from 12.9 +/- 3.2 and 12.5 +/- 4.9 at baseline to 10.1 +/- 3.1 and 11.4 +/- 4.1 at the 3rd month and to 8.7 +/- 1.9 and 10.0 +/- 3.3 at the 6th month, respectively. Both groups showed improvement in glucose tolerance and insulin sensitivity, although the metformin effect was significant in the latter. Serum LH/FSH and testosterone decreased in both groups. BMI, waist-to-hip ratio, and blood pressure did not change with either drug. We conclude that both drugs are effective in the management of PCOS. Spironolactone appears better than metformin in the treatment of hirsutism, menstrual cycle frequency, and hormonal derangements and is associated with fewer adverse events.     

Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome

Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP), has recently been linked to obesity, insulin resistance syndromes such as polycystic ovary syndrome (PCOS), and an increased risk of cardiovascular disease. Because the insulin sensitizer metformin has been shown to improve metabolic disturbances in PCOS, it was of particular interest to examine serum CRP levels during metformin therapy. Twenty nonobese women [body mass index (BMI) /==" BORDER="0"> 27 kg/m(2)) with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months) or ethinyl estradiol (35 micro g)-cyproterone acetate (2 mg) oral contraceptive pills. The serum concentrations of CRP were significantly higher in obese than in nonobese subjects at baseline [4.08 +/- 0.53 (SE) vs. 1.31 +/- 0.28 mg/liter; P < 0.001] and correlated to BMI and to a lesser extent waist-hip ratio, suggesting that the elevated CRP levels may be related to obesity and not only to PCOS itself. During metformin treatment, serum CRP levels decreased significantly from 3.08 +/- 0.7 mg/liter to 1.52 +/- 0.26 mg/liter at 6 months in the whole study population (P = 0.006) and especially in obese subjects. In contrast, the treatment with ethinyl estradiol-cyproterone acetate increased serum CRP levels from 2.91 +/- 0.68 mg/liter to 4.58 +/- 0.84 mg/liter (P < 0.001). Whether this effect is related to estrogen action in the liver or whether it reflects increased inflammation process and possible risks for cardiovascular disease remains unclear. The decrease of serum CRP levels during metformin therapy is in accordance with the known beneficial metabolic effects of this drug and suggests that CRP or other inflammation parameters could be used as markers of treatment efficiency in women with PCOS.     

Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study

Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.     

Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome

Twenty-nine patients with polycystic ovary syndrome (PCOS) and 30 normal women had lipoprotein lipid and androgen profiles compared after a 12-h fast. Both PCOS and normal women were evaluated in the proliferative phase of the cycle. PCOS patients had higher serum LH to FSH ratios [2.0 +/- 1.3 (+/- SEM) vs. 0.6 +/- 0.1), higher testosterone (T; 66 +/- 5 vs. 33 +/- 2 ng/ml), higher free T (1.1 +/- 1 vs. 0.4 +/- 0.02 ng/dl), and higher dehydroepiandrosterone sulfate (291 +/- 28 vs. 140 +/- 12 micrograms/dl) levels, and lower T-estrogen-binding globulin-binding capacity (1.5 +/- 0.2 vs. 2.2 +/- 0.1 micrograms/dl) than normal women (all P less than 0.05). The PCOS patients had higher mean serum triglycerides [122 +/- 11 (+/- SEM) 63 +/- 3 mg/dl] and very low density lipoprotein cholesterol levels (24 +/- 2 vs. 13 +/- 1 mg/dl), but lower high density lipoprotein cholesterol levels (43 +/- 2 vs. 58 +/- 2 mg/dl; P less than 0.05). While PCOS patients were heavier and more sedentary and their diets were higher in saturated fat and lower in fiber (P less than 0.01, respectively), the differences in lipoprotein lipid concentrations could not be attributed to body weight. T-estrogen-binding globulin-binding capacity correlated with high density lipoprotein cholesterol in PCOS patients (r = 0.42; P = 0.025) after adjusting for weight. We conclude that hyperandrogenemia in women may result in a male pattern of lipoprotein lipid concentrations. These findings suggest that PCOS patients may have increased atherogenic potential.     

Metformin administration improves leukocyte count in women with polycystic ovary syndrome: a 6-month prospective study

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.     

Metformin therapy improves coronary microvascular function in patients with polycystic ovary syndrome and insulin resistance

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are thought to have increased cardiovascular risk. Metformin therapy reduces whole-body insulin resistance (IR) in patients with type-2 diabetes mellitus (DM). OBJECTIVE: As insulin resistance accompanying PCOS may be reversed by metformin therapy, we hypothesized that metformin therapy might improve coronary microvascular functions in women with PCOS and IR. PATIENTS AND METHODS: We treated 16 women with PCOS and IR with metformin, and measured coronary flow reserve (CFR) at the beginning and after 6 months of metformin therapy using transthoracic second-harmonic Doppler echocardiography. RESULTS: At the end of the 6 months of metformin therapy, baseline coronary diastolic peak flow velocity (DPFV) did not change significantly (from 24.6 +/- 4.3 to 23.0 +/- 3.1, P = 0.106); however, hyperaemic coronary DPFV (from 68.2 +/- 12.7 to 74.5 +/- 9.7, P = 0.08), and CFR (from 2.75 +/- 0.48 to 3.3 +/- 0.5, P = 0.016) was significantly improved by metformin therapy. CONCLUSION: In women with PCOS, coronary microvascular function and CFR are significantly improved by 6 months of therapy with metformin.