The effects of metformin on metabolic and cardiovascular risk factors in nonobese women with polycystic ovary syndrome

Objective There are conflicting data regarding the effects of metformin in lean women with polycystic ovary syndrome (PCOS). Thus, our aim was to evaluate the effects of 6 months of metformin therapy on various metabolic and cardiovascular risk factors in lean women with PCOS. Design This was a prospective clinical study performed in a University hospital. Patients Twenty nonobese PCOS women and 20 age‐ and BMI‐matched healthy women were included in the study. Metformin (2550 mg/day) was administered for 6 months in women with PCOS. The hormonal and metabolic parameters were evaluated before and after metformin treatment. Measurements The main outcome measures were serum androgens, FSH, LH, oestradiol, 17‐hydroxyprogesterone, glucose, insulin, lipid profile, lipoprotein(a) [Lp(a)] and homocysteine levels. In addition 24‐h ambulatory blood pressure monitoring (ABPM) and carotid intima‐media thickness (IMT) were taken. Results After 6 months of metformin therapy, women with PCOS had decreased LH, total testosterone, free androgen index and slightly increased SHBG levels. Metformin treatment resulted in resumption of regular menses in 12 (60%) patients, and in 8 (40%) of them serum progesterone level was compatible with ovulation. Glucose and insulin responses to oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA‐IR) did not improve after the metformin therapy. There were no significant changes in terms of cardiovascular risk factors such as lipids and homocysteine, IMT and ABPM. Conclusion Metformin may have beneficial effects in lean PCOS women in terms of resumption of menses without any remarkable effect on metabolic and cardiovascular risk factors.     

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.     

Risk of atherosclerosis in women with polycystic ovary syndrome: a study from South India

Women with polycystic ovary syndrome (PCOS) often present for cosmetic and or reproductive symptoms; attention is generally not paid to the future risk of atherosclerosis for these women. Given that Asian Indians are insulin resistant and prone to metabolic syndrome at an earlier age, we assessed glucose/insulin ratio and intimal medial thickness (IMT) in young women with PCOS from south India. In this cross-sectional case control study, we assessed insulin resistance and carotid IMT in 40 women presenting with hyperandrogenic features of PCOS. Insulin resistance was assessed by fasting glucose/insulin ratio and IMT by the Doppler system with electrical linear transducer midfrequency of 12 MHz. Women with PCOS had higher fasting insulin levels (36.58 +/- 17.81 muU/mL, vs. 16.60 +/- 3.22 muU/mL in controls; p < 0.001), higher insulin resistance (glucose/insulin ratio 2.81 +/- 1.47 vs. 5.47 +/- 1.46 in controls; p < 0.001), and greater IMT (0.53 +/- 0.14 mm vs. 0.39 +/- 0.06 mm in controls; p < 0.001). Women with PCOS had a higher body mass index (BMI) (26.46 +/- 5.24 vs. 23.24 +/- 3.05 in controls; p < 0.001), and the differences between PCOS and controls persisted, even among those who had a BMI of less than 25. We concluded that South Indian women with the reproductive abnormalities of PCOS have greater insulin resistance and IMT, and therefore they must be advised about lowering the risk of future vascular disease.     

Vascular dysfunction and metabolic parameters in polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and the metabolic syndrome; however, the cardiovascular (CV) manifestations of PCOS remain unclear. OBJECTIVE: The objective of this study was to examine the relationships between IR, metabolic parameters, androgens, and markers of early CV disease in PCOS. DESIGN: We conducted an observational study examining noninvasive markers of early CV disease in women with PCOS including structural [carotid intimal media thickness (IMT)] and functional measures (arterial function with pulse wave velocity and endothelial function with brachial arterial flow-mediated vasodilation). Metabolic parameters included insulin and glucose during an oral glucose tolerance test and lipid and androgen levels. SETTING: Participants were recruited from the general community. PATIENTS: Eighty overweight women with PCOS who were nonsmokers and not on oral contraceptives or other medications known to affect IR participated in the study. RESULTS: Stepwise regression analysis showed that after adjustment for age and body mass index, IMT was significantly correlated with blood pressure (BP) load (P = 0.03) and inversely with dehydroepiandrosterone sulfate (DHEAS) (P = 0.01). After correction for androgen status, IMT was correlated with fasting glucose and area under curve (AUC) insulin. Flow-mediated vasodilation was inversely related to lipids (P = 0.02), whereas pulse wave velocity was related to BP (P < 0.001), AUC insulin (P = 0.04), and AUC glucose (P = 0.035). CONCLUSION: In overweight women with PCOS, insulin resistance and BP interacted negatively with arterial structural and functional measures. DHEAS correlated inversely with arterial structure, suggesting possible cardioprotective effects of endogenous DHEAS in women with PCOS. Additional research is needed to clarify these findings.     

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.     

Circulating ghrelin levels in patients with polycystic ovary syndrome

The syndrome of polycystic ovaries (PCOS) is associated with adiposity and metabolic changes predisposing to insulin resistance and diabetes mellitus. Because the recently discovered GH secretagogue, ghrelin, is intimately involved in the control of appetite and weight regulation, we studied ghrelin levels in a group of 26 otherwise healthy women with PCOS. They were compared with 61 healthy female control subjects and 5 gastrectomized women. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and continuous infusion of glucose with model assessment (CIGMA) in all patients. In PCOS women, serum ghrelin levels were significantly lower than in healthy lean or obese controls (P < 0.001). In insulin-sensitive PCOS women, ghrelin concentrations compared well with the healthy controls, whereas in insulin-resistant PCOS ghrelin levels were significantly lower and indistinguishable from the low levels found in the gastrectomized women. There was a close correlation of ghrelin to insulin sensitivity (HOMA, r(2) = 0.330, P < 0.002; CIGMA, r(2) = 0.568, P < 0.0001). Treatment of 10 insulin-resistant PCOS women with metformin significantly increased circulating fasting ghrelin concentrations (P < 0.02). Ghrelin levels did not correlate to any of the parameters of hyperandrogenemia, to the LH/FSH ratio, to body mass index, or to fasting insulin and glucose concentrations. In summary, ghrelin levels are decreased in PCOS women and are highly correlated to the degree of insulin resistance. This suggests that ghrelin could be linked to insulin resistance in PCOS women. However, whether low ghrelin in PCOS is a cause or the consequence of insulin resistance awaits further investigations.     

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.     

Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit risk factors for cardiovascular diseases such as abdominal obesity, insulin resistance and dyslipidemia. Insulin sensitizers, especially metformin, have been shown to improve these metabolic disturbances, but there are only a few studies on their effects on serum lipids in polycystic ovary syndrome. METHODS: Thirty-five women with PCOS (18 obese and 17 non-obese) were randomized to 6-month treatments with metformin or ethinyl estradiol-cyproterone acetate oral contraceptive pills. RESULTS: In the whole-study population (non-obese and obese women) serum levels of high-density lipoprotein cholesterol increased from 1.4+/-0.2 to 1.6+/-0.1 mmol/l (means +/-S.E. throughout) at 3 and 6 months (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased significantly from 3.8+/-0.3 to 3.3+/-0.2 at 6 months (P < 0.001) and a similar trend was observed in serum triglyceride levels during metformin treatment. In the oral contraceptive group, serum levels of total cholesterol increased from 4.9+/-0.3 to 5.4+/-0.3 mmol/l (P < 0.05), high-density lipoprotein cholesterol increased from 1.2+/-0.1 to 1.5+/-0.1 mmol/l (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased from 4.6+/-0.4 to 3.7+/-0.2 (P < 0.001) and triglycerides increased from 1.3+/-0.1 to 1.9+/-0.2 mmol/l at 6 months of treatment (P < 0.001). Serum low-density lipoprotein cholesterol levels remained unchanged during both treatments. Milder but similar changes in the subgroups of obese and non-obese women were observed during both treatments. Moreover, in the whole-study population both systolic (P = 0.02) and diastolic (P = 0.05) blood pressures decreased over the 6 months of metformin treatment. CONCLUSION: In women with PCOS, metformin treatment had beneficial effects on lipid profile and blood pressure, and therefore it could be useful in the prevention of cardiovascular complications in these women.     

Homocysteine and steroids levels in metformin treated women with polycystic ovary syndrome.

Risk for atherosclerosis is increased in women with polycystic ovary syndrome (PCOS). Homocysteine (Hcy) is one of the independent risk factors for ischemic heart disease. We examined the effect of metformin (M) treatment on Hcy levels, steroids and glycide tolerance in PCOS. MATERIAL AND METHODS: 9 women with PCOS (defined as hyperandrogenemia and chronic anovulation); age 20 +/- 3.8 yrs, BMI 28.1 +/- 6.5 kg/m(2); examined in the follicular phase of spontaneous menstrual cycle before and after 27 +/- 4 weeks of treatment with M 1000 mg/day. The plasma concentrations of Hcy, DHEA, DHEA-S, cortisol (F), allopregnanolone (HPO), 17OHpregnenolone (17OHPl), insulin (I) and blood glucose (G) before and after the course of M were measured. RESULTS: After the course of M, Hcy significantly increased (10.1 +/- 2.6 to 13.4 +/- 5.1 micromol/l, p < 0.05.). There was no significant change in levels of I, HPO, F, DHEA-S and 17OHPl. DHEA levels increased significantly (from 26.9 +/- 15.7 to 44.4 +/- 24.6 nmol/l, p < 0.05). A borderline significant trend towards reduction in waist-hip ratio was seen (from 0.986 +/- 0.042 to 0.951 +/- 0.085; p < 0.06). CONCLUSIONS: Treatment with metformin in women with PCOS can lead to the increase in homocysteine levels--a risk factor for atherosclerosis.     

Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation

In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.     

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.     

Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity

This study was performed to determine whether the sisters of women with polycystic ovary syndrome (PCOS) have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligo- or amenorrhea, n = 39], HA with regular menses (n = 36), unaffected (UA; n = 122), and unknown (n = 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P = 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P = 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P = 0.04) compared with control women, which suggested pancreatic beta-cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. We conclude that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity.     

Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by obesity, hyperandrogenism, and insulin resistance. An adverse lipid profile has also been observed in PCOS-affected women, suggesting that these individuals may be at increased risk for coronary heart disease at a young age. The objective of the present study was to evaluate subclinical atherosclerosis among women with PCOS and age-matched control subjects. A total of 125 white PCOS cases and 142 controls, aged >/=30 years were recruited. Collection of baseline sociodemographic data, reproductive hormone levels, and cardiovascular risk factors was conducted from 1992 to 1994. During follow-up (1996 to 1999), these women underwent B-mode ultrasonography of the carotid arteries for the evaluation of carotid intima-media wall thickness (IMT) and the prevalence of plaque. A significant difference was observed in the distribution of carotid plaque among PCOS cases compared with controls: 7.2% (9 of 125) of PCOS cases had a plaque index of >/=3 compared with 0.7% (1 of 142) of similarly aged controls (P=0.05). Overall and in the group aged 30 to 44 years, no difference was noted in mean carotid IMT between PCOS cases and controls. Among women aged >/=45 years, PCOS cases had significantly greater mean IMT than did control women (0.78+/-0.03 versus 0.70+/-0.01 mm, P:=0. 005). This difference remained significant after adjustment for age and BMI (P:<0.05). These results suggest that (1) lifelong exposure to an adverse cardiovascular risk profile in women with PCOS may lead to premature atherosclerosis, and (2) the PCOS-IMT association is explained in part by weight and fat distribution and associated risk factors. There may be an independent effect of PCOS unexplained by the above variables that is related to the hormonal dysregulation of this condition.     

The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome

The present study was designed in order to: (a) compare ET-1 and ADMA levels, between women with PCOS (n=106) and healthy controls (n=30); (b) determine the effects of treatment with estrogens and anti-androgens on the hormonal features of PCOS, insulin resistance, ET-1 and ADMA levels. Women with PCOS were randomized in five therapeutic protocols: (I) 17beta-estradiol+cyproterone acetate 50mg; (II) conjugated estrogen+CA 50 mg; (III) ethinyl estradiole+CA 2mg; (IV) EE+CA 52 mg; (V) EE+desogestrel. In all women, gonadotropin, PRL, androgen, SHBG, insulin, glucose, ET-1 and ADMA levels were determined; in women with PCOS, testosterone, SHBG, ET-1 and ADMA levels were measured again after 3, 6, 12 months of treatment and insulin and glucose levels after 12 months. ET-1 and ADMA concentrations were higher in women with PCOS, and they were positively correlated with each other. ADMA levels were decreased and IR was increased with treatment. Treatment with synthetic estrogens (EE) resulted in a more pronounced increase in SHBG and a more pronounced decrease in FAI, compared to natural estrogens. Conclusively, PCOS is associated with endothelial dysfunction, which is ameliorated by the administration of estrogens and anti-androgens, independent of IR.     

Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease

We hypothesized that the administration of rosiglitazone, an insulin-sensitizing agent of the thiazolidinedione class, would improve the ovulatory dysfunction, hirsutism, hyperandrogenemia, and hyperinsulinemia of polycystic ovary syndrome (PCOS) patients. Forty women with PCOS and impaired glucose tolerance test (IGT) were randomly assigned to the 8-month treatment with rosiglitazone at either 2 mg/day or 4 mg/day. We compared changes in ovulatory function, hirsutism, hormonal levels (total and free testosterone, estradiol, estrone, androstenedione, LH and FSH), and measures of glycemic parameters (fasting and post-challenge levels of glucose and insulin, HOMA-IR, hemoglobin A1c), between the study groups. The patients' baseline characteristics were similar across all treatment arms. Fifteen of 20 women in the 2 mg group and 19 of 20 women in the 4 mg group achieved normal glucose tolerance; 14 of 20 women in the 2 mg group and 17 of 20 women in the 4 mg group achieved ovulatory menses at the end of the study period. The decreases of free testosterone levels were better in the 4 mg group than the 2 mg rosiglitazone group (-1.89+/-0.35 pg/ml vs. -2.21+/-0.39 pg/ml; P<0.01). There were neither any serious adverse events nor any liver enzyme elevations in our study patients during the treatment period. This study demonstrated that rosiglitazone improves the ovulatory dysfunction, hirsutism, hyperandrogenemia, and insulin resistance of PCOS in a dose-related fashion, with minimal adverse effects. This drug may be a good choice for lifetime treatment of patients with PCOS, especially for the ones who failed to show satisfactory results in metformin therapy.     

Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), a common endocrinopathy of women of reproductive age, is associated with the early appearance of multiple risk factors for cardiovascular disease, such as abdominal obesity, dyslipidemia, and diabetes mellitus. However, premature atherosclerosis of the carotid artery has not yet been demonstrated in young women with PCOS. Measurement of carotid intima-media thickness (IMT) is considered an easy and reliable index of subclinical atherosclerosis, which is predictive of subsequent myocardial infarction and stroke. To evaluate the cardiovascular risk of PCOS and the participation of the hyperandrogenemic and metabolic pattern, we measured carotid IMT by B-mode ultrasound as well as hormonal and several cardiovascular disease-associated parameters in 75 young women with PCOS and 55 healthy, age- and body mass index-matched women. The PCOS women had significantly increased carotid IMT (0.58 vs. 0.47 mm, P < 0.001) and abdominal adiposity; higher levels of androgens, insulin, homeostasis model assessment score of insulin sensitivity, and total and low-density lipoprotein-cholesterol; and significantly lower levels of SHBG and high-density lipoprotein-cholesterol. In the studied population (n = 130), PCOS status, age, body mass index, and parental history of coronary heart disease were strong positive predictors of carotid IMT, whereas dehydroepiandrosterone sulfate was a strong negative predictor. In PCOS patients lower delta4-androstenedione and high-density lipoprotein-cholesterol levels were additionally strong positive predictors of carotid IMT, whereas in control women only total cholesterol was the additional positive predictor of carotid IMT. In conclusion, young women with PCOS have an early increase of cardiovascular risk factors and greater carotid IMT, both of which may be responsible for subclinical atherosclerosis. The hyperandrogenemic phenotype of the syndrome may attenuate the consequences of the dysmetabolic phenotype on the vascular wall.