Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome

In a previous study we were the first to describe a negative correlation between circulating ghrelin concentrations and androgen levels in human plasma, suggesting an interaction between ghrelin and the endocrine regulation of reproductive physiology. We now investigated a potential direct regulatory influence of circulating androgens on plasma ghrelin levels. Fourteen obese women with polycystic ovary syndrome (PCOS) on a hypocaloric diet were randomly assigned to treatment groups (open-labeled design), receiving either placebo (no.=7) or the antiandrogen flutamide (no.=7) for 6 months. Anthropometry, visceral (VAT) and subcutaneous (SAT) adipose tissue (quantified by computerized tomography), plasma hormone levels, insulin sensitivity indexes (Quantitative Insulin-Sensitivity Check Index-QUICKI) and Homeostatic Model Assessment applied to the oral glucose tolerance test (HOMA(OGTT)) were evaluated at baseline and at the end of the study. Body weight decreased and insulin resistance indexes improved in both groups. A tendency toward a greater loss of VAT was observed in the flutamide group. Only in the flutamide group was a significant reduction of androgens levels observed. Plasma ghrelin levels significantly increased following treatment with flutamide, while ghrelin remained unchanged in the placebo group. We observed a negative correlation between changes of ghrelin levels and changes of androgen plasma concentration in the flutamide-treated group. In the same group a positive correlation was found between plasma ghrelin changes and insulin sensitivity as expressed by HOMA(OGTT). Analysis in a multiple regression model, however, showed that plasma ghrelin changes were mainly due to changes of androgen levels rather than improved insulin sensitivity. We, therefore, conclude that androgens are independent modulators of circulating ghrelin concentrations.     

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.     

Adiponectin levels in women with polycystic ovary syndrome

Serum adiponectin levels were evaluated in 60 women with polycystic ovary syndrome (PCOS), 30 normal-weighted and 30 obese women, and 60 healthy women age and body mass index (BMI) matched with the patients. The homeostasis model assessment (HOMA) score was also calculated. Both in PCOS and controls, serum adiponectin levels were significantly (P < 0.05) lower in obese than normal-weight women, without any difference between PCOS and controls. The HOMA score was significantly (P < 0.05) higher in obese than normal-weight women both in PCOS and controls; additionally, the HOMA score was significantly (P < 0.05) higher in normal-weight PCOS than normal-weight controls. Both in PCOS and controls, adiponectin levels were significantly correlated with BMI (r = -0.51, P < 0.01 in PCOS; r = -0.45, P < 0.01 in controls) and HOMA values (r = -0.39, P < 0.05 in PCOS; r = -0.35, P < 0.05 in controls); HOMA was correlated with BMI (r = 0.51, P < 0.01 in PCOS, r = 0.61, P < 0.001 in controls). In conclusion, our results confirm that adiponectin concentrations change according to variations of fat mass. They further suggest that insulin sensitivity per se probably does not play any pivotal role in the control of adiponectin levels in PCOS women.     

Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease

BACKGROUND: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in development of atherosclerosis and plaque rupture in acute coronary syndromes (ACS). AIM: To determine the relationship between circulating MMPs and symptomatic coronary artery disease. METHODS: Plasma levels of MMP-9 and MMP-2 were measured in patients with ACS, stable angina (SA) and in controls, using a quantitative gelatin zymography. These measurements were correlated with markers of systemic inflammation (hs-CRP) in all subjects and myocardial injury (troponin T) in patients with ACS. RESULTS: Plasma MMP-9 in ACS was greater than in SA, and was greater in SA than in controls (P < 0.01 ACS vs SA and controls, P < 0.01 SA vs control). Plasma MMP-2 was significantly greater in ACS than SA or controls (P < 0.01 vs SA and controls). There was strong overall relationship between hs-CRP and MMP-9 (r = 0.65, P < 0.0001) driven by a significant relationship in ACS patients (r = 0.58, P = 0.02), as there was no significant association in SA or controls. A weaker overall correlation was found between hs-CRP and MMP-2 (r = 0.39, P = 0.02), but no significant relationship was present for either of the two patient subgroups or controls. There was no correlation between levels of troponin T and MMP-9, MMP-2 or hs-CRP in ACS patients. CONCLUSION: Quantitative gelatin zymography identifies increased circulating levels of MMP-9 and MMP-2 in patients with symptomatic coronary disease. MMP-9 and MMP-2 are higher in ACS than SA patients and might have use as markers of plaque rupture or instability. The strong relationship between MMP-9 and hs-CRP in ACS patients suggests MMP-9 might be an additional marker and/or consequence of the inflammatory component in ACS.     

多囊卵巢综合征性激素水平检测

目的：探讨血清性激素各项检测指标与不同年龄段的多囊卵巢综合征（PCOS）患者的关系及其临床意义。方法：以月经周期正常的健康妇女为对照组,采用化学发光法测定30岁以下年龄组和30岁及以上年龄组PCOS患者促黄体生成素（LH）、促卵泡生成素（FSH）、泌乳素（PRL）、雌二醇（E2）、睾酮（TESTO）、孕酮（Prog）水平,通过统计学软件进行比较分析。结果：多囊卵巢综合征患者,30岁以下年龄组和30岁及以上年龄组LH高于对照组（P〈0．01）,E2高于对照组（P〈0．05）,TESTO高于对照组（P〈0．01）。30岁以下PCOS患者组和30岁及以上PCOS患者组各检测指标之间差异无统计学意义（P〉0．05）。结论：血清中LH,E2高水平及TESTO增高可能是多囊卵巢综合征的预示因子,高LH、高E2、高雄激素血症可能是引起PCOS发生的因素之     

Increased levels and activity of matrix metalloproteinase-9 in obstructive sleep apnea syndrome

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cardiovascular diseases. We examined serum levels of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), activity of MMP-9, and the effect of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS). After polysomnography, venous blood was collected at 5:00 A.M. from 44 patients with OSAS and 18 control subjects who were obese, and serum levels of MMP-9, TIMP-1, and enzymatic activity of MMP-9 were measured. In addition, the effects of 1 month of treatment with nCPAP were studied in patients with moderate to severe OSAS. Although serum levels of MMP-9 (p < 0.03) and MMP-9 activity (p < 0.01) were higher in patients with OSAS than in control subjects who were obese, TIMP-1 levels did not differ significantly. In patients with OSAS, the severity of OSAS was the primary factor influencing levels (p < 0.01) and activity (p < 0.01) of MMP-9. nCPAP significantly decreased serum levels (p < 0.01) and activity (p < 0.001) of MMP-9 but did not affect TIMP-1 levels. Therefore, OSAS may increase risks of cardiovascular morbidity, and nCPAP might be useful for decreasing these risks.     

Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy

Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/- 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass index. Moreover, after metformin therapy, hyperandrogenemia and hyperinsulinemia were normalized, and glucose utilization improved [obese before: total T, 0.9 +/- 0.15 ng/ml; fasting insulin, 22.2 +/- 12.1 U/liter; glucose utilization, 2.15 +/- 0.5 mg/kg.min; obese after: total T, 0.5 +/- 0.2 ng/ml; fasting insulin, 11.6 +/- 6 U/liter; glucose utilization, 4.7 +/- 1.4 mg/kg.min 9P < 0.003, P < 0.006, and P < 0.002, respectively); nonobese before: total T, 1 +/- 0.5 ng/ml; fasting insulin, 15.5 +/- 7.6 U/liter; glucose utilization, 3.4 +/- 0.7 mg/kg.min; nonobese after: total T, 0.8 +/- 0.5 ng/ml; fasting insulin, 9 +/- 3.8 U/liter; glucose utilization, 6 +/- 1.7 mg/kg.min (P < 0.04, P < 0.02, and P < 0.0008, respectively)]. In conclusion, our data clearly demonstrate that women with polycystic ovary syndrome, obese and nonobese, have elevated endothelin-1 levels compared with the age-matched control group. In addition, 6 months of metformin therapy reduces endothelin-1 levels and improves their hormonal and metabolic profile.     

Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome

Obstructive Sleep Apnea (OSA) is considerably more common in men than women. Preliminary data suggest that androgens may play a role in the male predominance of apnea. Polycystic Ovary Syndrome (PCOS) is characterized by menstrual disturbances, androgen excess, and frequently obesity. These features suggest that women with PCOS may be at increased risk for OSA. To determine whether obese women with PCOS have an increased prevalence of sleep apnea compared with age and weight-matched reproductively normal women, we performed overnight polysomnography for determination of the apnea-hypopnea index (AHI) in 18 obese women with PCOS and age and weight-matched control women. Additional measurements included waist, hip, and neck circumferences, serum total testosterone, unbound testosterone, and DHEAS. Women with PCOS had a higher AHI than controls (22.5 +/- 6.0, vs. 6.7 +/- 1.0, P = 0.008). Women with PCOS were also more likely to suffer from symptomatic OSA syndrome (44.4% vs. 5.5%, P = 0.008). AHI correlated with waist-hip ratio (r = 0.51, P < 0.03), serum testosterone (r = 0.52, P < 0.03) and unbound testosterone (r = 0.50, P < 0.05) in women with PCOS. We conclude that obese women with PCOS are at increased risk of OSA when compared with matched reproductively normal women. Women with PCOS should be carefully questioned regarding symptoms of sleep apnea.     

Decreased soluble leptin receptor levels in women with polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level. DESIGN: We assessed the correlation of metabolic and endocrine parameters with leptin and sOB-R levels in 122 PCOS women (aged 27 +/- 5.7 years) and 81 healthy controls (aged 25 +/- 4.0 years). METHODS: Leptin and sOB-R levels were measured using ELISA kits. In addition, anthropometric variables, body fat and endocrine parameters were evaluated and a glucose tolerance test performed to assess indices of insulin resistance and glucose metabolism. RESULTS: In PCOS patients, no correlation was found between leptin or sOB-R and parameters of hyper-androgenism. However, as expected, body mass index (BMI), body fat, waist circumference and indices of insulin resistance were significantly correlated with leptin in PCOS subjects and controls. In a subgroup analysis of lean, overweight and obese PCOS patients, significant differences were found in leptin (29.7 +/- 20.7 vs 45.4 +/- 25.0 vs 67.7 +/- 28.8 ng/ml, P < 0.0001) and sOB-R (8.0 +/- 3.4 vs 6.4 +/- 2.5 vs 5.7 +/- 2.3 ng/ml, P < 0.05). Compared with BMI-matched controls, lean PCOS patients had lower sOB-R levels (8.0 +/- 3.4 vs 12.7 +/- 4.7 ng/ml, P < 0.0001) and higher free leptin indices (4.5 +/- 3.9 vs 2.8 +/- 2.2, P = 0.0285). CONCLUSION: Taking into account that low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance.     

Plasma visfatin levels in normal weight women with polycystic ovary syndrome

BACKGROUND: The present study was designed to measure plasma visfatin levels in normal weight women with polycystic ovary syndrome (PCOS) and to assess possible correlations between visfatin and the hormonal or metabolic parameters of the syndrome. METHODS: Twenty-five normal weight [body mass index (BMI)<25 kg/m(2)] women with PCOS, 24 obese and overweight (BMI>25 kg/m(2)) controls (ovulating women without clinical or biochemical hyperandrogenism), and 24 normal weight controls were studied. Blood samples were collected between the 3rd and the 7th days of a menstrual cycle in the control groups and during a spontaneous bleeding episode in the PCOS groups at 9:00 A.M., after an overnight fast. Circulating levels of LH, FSH, prolactin (PRL), testosterone (T), Delta(4)-androstenedione (Delta(4)-Alpha), dehydroepiandrosterone sulfate (DHEA-S), 17alpha-OH-progesterone (17OH-P), sex hormone-binding globulin (SHBG), insulin, glucose, and visfatin were measured. RESULTS: Plasma visfatin levels and the visfatin-to-insulin ratio were significantly lower in normal weight controls than in both normal weight women with PCOS and overweight or obese controls. The visfatin-to-insulin ratio was significantly higher in normal weight women with PCOS than in overweight or obese controls. Plasma visfatin levels were found to be positively correlated with LH and Delta(4)A levels, as well as with free androgen index (FAI) values, and negatively correlated with SHBG. LH and SHBG levels were found to be the only independent significant determinants of circulating visfatin. In the control groups, plasma visfatin levels were significantly correlated with BMI, waist (W) measurement, and waist-to-hip ratio (WHR). CONCLUSIONS: Visfatin levels are positively associated with obesity in healthy women of reproductive age. Moreover, the present study indicates, for the first time, a possible involvement of increased visfatin levels in PCOS-associated metabolic and hormonal disturbances.     

Increased micronucleus frequencies in peripheral blood lymphocytes in women with polycystic ovary syndrome

OBJECTIVE: We aimed to assess possible genomic instability in women with polycystic ovary syndrome (PCOS). DESIGN: The frequency of micronuclei in cultured peripheral lymphocytes was used as a biomarker of genomic instability in somatic cells. METHODS: Nineteen women, diagnosed with PCOS and 19 healthy female volunteers of corresponding ages and body-mass index (BMI) were included in the study. Micronuclei frequencies were assessed in cytokinesis-blocked lymphocytes. RESULTS: The frequency of micronucleated cells (per thousand) was 9.00 (5.00) (interquartile range in parentheses) for patient group and 3.0 (3.0) for the control group (P < 0.0001, Mann-Whitney U-test). The serum levels of follicle-stimulating hormone (FSH), estradiol, prolactin, glucose and dehydroepiandrosterone sulfate (DHEAS) and the homeostasis model of assessment of insulin resistance (HOMA-IR) were not different between the two groups (P > 0.05). Serum total testosterone, luteinizing hormone (LH) and insulin levels and hirsutism score in the PCOS group were significantly (P = 0.007, P < 0.0001, P = 0.009 and P < 0.0001 respectively) higher than those of the control group (2.3 (2.1) nmol/l vs 1.7 (0.4) nmol/l; 8.5 (5.88) mU/ml vs 4.8 (4.4) mU/ml; 6.8 (5.1) microU/ml vs 9.7 (4.2) microU/ml; 19.5 (6.5) vs 4.0 (2.5) respectively). However, the mean level of sex hormone-binding globulin (SHBG) in PCOS group was significantly (P = 0.004) lower than in control group (36.4(22.6) nmol/l vs 48.6(25.2) nmol/l respectively). CONCLUSION: These findings suggest that women with PCOS have a high incidence of genomic instability, and this condition is positively correlated with the hirsutism score, BMI, LH and serum total testosterone and insulin levels, and is negatively correlated with SHBG.     

绝经后妇女MMP-2和TIMP-2水平及其与骨密度和骨代谢指标的关系

目的 探讨绝经后妇女血清基质金属蛋白酶2（MMP-2）和组织金属蛋白酶抑制因子2（TIMP-2）水平及其与骨密度和骨代谢指标的关系。方法 对192名48～65岁绝经后妇女用酶联免疫吸附法（ELISA）测定的血清MMP-2、TIMP-2以及骨碱性磷酸酶（BAP）、骨钙素、Ⅰ型胶原交联C端肽（CTX），尿Ⅰ型胶原交联N端肽（NTX），计算MMP-2／TIMP-2比值，用双能X线吸收法（DEXA）测定腰椎正位，股骨颈，Ward三角和大粗隆的骨密度，按WHO标准将绝经后妇女分为骨密度正常、低骨量和骨质疏松3组。结果 （1）绝经后妇女骨质疏松患者血清MMP-2的水平（1388±121）μg／L高于骨密度正常组（1126±141）μg／L（P〈0．05），而TIMP-2的水平（44．3±38．2）μg／L稍低于骨密度正常组（47、3±30．2）μg／L（P〉0．05）。（2）血清MMP-2和MMP-2／TIMP-2比值与腰椎正位和Ward三角骨密度、血清BAP和骨钙素呈负相关（均P〈0．05），和尿NTx／Cr呈正相关（P〈0．05），MMP-2／TIMP-2比值还与股骨颈骨密度呈负相关（P〈0．05）。TIMP-2与腰椎正位和Ward三角骨密度、血清BAP和骨钙素呈正相关（均P〈0．05），和尿NTX／Cr呈负相关（P〈0．05）。在校正年龄和体重指数后，TIMP-2与腰椎正位骨密度和骨钙素无相关性（P〉0．05）。（3）骨质疏松组中血清MMP-2和MMP-2／TIMP-2比值与腰椎正位、股骨颈和Ward三角骨密度、血清BAP和骨钙素呈负相关（均P〈0．05），和尿NTX／Cr呈正相关（均P〈0．05），TIMP-2和Ward三角骨密度和BAP呈正相关（均P〈0．05）；在低骨量组中仅MMP-2与腰椎正位和Ward三角骨密度、骨钙素呈负相关（P〈0．05），和尿NTX／Cr呈正相关（P〈0．05），MMP-2／TIMP-2比值与Ward三角骨密度和血清BAP呈负相关（均P〈0．05）。结论 绝经后女性尤其是骨质疏松症妇女血清MMP-和MMP-2／TIMP-2比值与骨密度和骨代谢指标BAP、骨钙素和尿NTX／Cr具有关联性，血清MMP-2和MMP-2／TIMP-2比值增高可能为绝经后骨质疏松症伴随骨代谢转换过程增快的表现。     

Increased androgen response to follicle-stimulating hormone administration in women with polycystic ovary syndrome

CONTEXT: In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production. OBJECTIVE: The objective of this study was to determine whether FSH enhances androgen production in women with PCOS compared with that of normal women. DESIGN: A prospective study was conducted to compare androgen production in response to FSH in two groups of women. SETTING: The study was conducted in a General Clinical Research Center in a tertiary academic medical center. PATIENTS: Women with PCOS, 18-35 yr (n = 20), and normal ovulatory controls, 18-35 yr (n = 10), were recruited for study. INTERVENTIONS: Serial blood samples were obtained over a 24-h period after an iv injection of recombinant human FSH (150 IU). MAIN OUTCOME MEASURES: The main outcome measures were serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), dehydroepiandrosterone (DHEA), testosterone (T), and inhibin B (Inh B) responses after FSH administration. RESULTS: Basal serum 17-OHP, A, and T levels were markedly increased in women with PCOS compared with that observed in normal women. Basal DHEA and Inh B levels were similar to those of normal controls. After FSH injection, PCOS women demonstrated enhanced production of 17-OHP, A, DHEA, and Inh B, whereas in normal women no increases were observed. T levels declined slightly in both groups. CONCLUSIONS: These findings provide evidence that, in PCOS women, theca cell androgen production is enhanced by FSH administration and suggest a granulosa-theca cell paracrine mechanism.     

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.     

Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia

Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.     

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.     

Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) develop left ventricular (LV) wall thinning associated with LV dilatation and systolic dysfunction. Recently, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were reported to be involved in ventricular remodeling, however, little is known about MMPs and TIMPs in patients with HCM. METHODS AND RESULTS: Enzyme-linked immunoassays were used to measure the plasma concentrations of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 11 patients with HCM accompanied by systolic dysfunction (fractional shortening (FS) <25%, group A), 17 patients with HCM who had preserved systolic function (FS> or =25%, group B), and 50 age-matched clinically healthy control subjects (mean age: 57 years). The concentration of MMP-2 in group A was significantly higher than in group B and the control subjects (1,124 +/- 84, 792 +/- 49, 809 +/- 26 ng/ml, respectively), whereas there was no significant difference between group B and the control subjects. MMP-2 concentrations significantly increased as the New York Heart Association functional class increased in patients with HCM. TIMP-2 was also significantly higher in group A patients than in group B and the control subjects (45.3 +/- 4.7, 34.6 +/- 2.2, 33.7 +/- 1.8 ng/ml, respectively), but there was no difference between group B and control subjects. TIMP-1 was significantly higher in HCM patients than in control subjects. MMP-3 and MMP-9 concentrations did not differ among the 3 groups. Both MMP-2 and TIMP-2 correlated significantly with FS and LV dimension, negatively and positively, respectively. CONCLUSIONS: These results suggest that changes in the release and activity of MMP-2 and TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with HCM.     

Insulin sensitivity in women with polycystic ovary syndrome

The aim of our study was to compare insulin sensitivity in lean and obese European polycystic ovary syndrome (PCOS) women with lean healthy women. We performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean with body mass index (BMI) of 21.5 +/- 1.8 kg/m2 and 30 obese with BMI of 29.6 +/- 3.7 kg/m2] and in 15 healthy women with BMI of 21.6 +/- 1.8 kg/m2 to determine glucose disposal (M) and the insulin sensitivity index (ISI). Statistical evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis multiple-comparison z-value test. The basal blood glucose was significantly higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin was significantly higher in both lean and obese PCOS women than in controls (P < 0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02 for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M or ISI. Posthepatic insulin delivery was significantly higher in both lean and obese PCOS women compared with controls (P < 0.000008). We conclude that lean PCOS women are not more insulin resistant than healthy controls. Insulin hypersecretion, on the other hand, is present even in lean PCOS women.     

Cardiovascular risk in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women that has received an immense amount of attention in the recent years due to the possible associated risk of cardiovascular disease. Women with PCOS demonstrate an adverse cardiovascular profile characteristic of the cardiometabolic syndrome and an established risk of progression to type 2 diabetes. Despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear if they develop accelerated atherosclerosis. This article summarized the recent development and findings of cardiovascular risk in women with PCOS, and finally the therapeutic options will be discussed.