多囊卵巢综合征患者血清对氧磷酯酶1活性、氧化应激与胰岛素抵抗的关系

目的探讨对氧磷酯酶1（PON-1）活性、氧化应激在多囊卵巢综合征（PCOS）患者发生胰岛素抵抗（IR）中的作用。方法41例PCOS患者分为肥胖组17例和非肥胖组24例,另有20名健康女性纳入正常对照组。所有研究对象均行口服糖耐量试验（OGTT）和胰岛素释放试验,使用稳态模型评价IR及胰岛B细胞分泌功能,空腹静脉取血检测丙二醛（MDA）、超氧化物歧化酶（SOD）活性及PON-1活性。结果（1）PCOS非肥胖组和PCOS肥胖组的空腹胰岛素、餐后2小时血糖及胰岛素、HOMA—IR及HOMA-β均高于正常组（P〈0．05）,且PCOS肥胖组的空腹胰岛素、餐后2小时血糖及胰岛素、HOMA—IR均高于PCOS非肥胖组（P％0．05）。（2）PCOS非肥胖组和PCOS肥胖组的MDA、SOD及PON-1与正常组比较差异有统计学意义（P〈0．05）;PCOS肥胖组的SOD显著低于PCOS非肥胖组（P％0．01）,而MDA及PON-1两组之间差异无统计学意义（P〉0．05）。（3）相关分析显示：在PCOS非肥胖组,SOD与PON—1正相关（r=0．417,P〈0．05）,SOD与IR负相关（r=0．492,P〈0．05）。结论PCOS患者无论肥胖与否,均存在餐后血糖升高、PON-1活性降低、氧化应激、IR,且肥胖患者更为严重;PCOS患者的氧化应激与IR相关。     

QT dispersion in patients with polycystic ovary syndrome

Cardiac risk factors are observed more frequently in patients with polycystic ovary syndrome (PCOS). On the other hand, increased QT dispersion, which is a risk factor for cardiac arrhythmias and sudden death, has not been investigated in this syndrome. In this study, we evaluated QT dispersion in PCOS patients without overt heart disease. Thirty-six consecutive women with PCOS (mean age 24+/-5 years) and 36 healthy women of similar ages (mean age 24+/-4 years) participated in this study. PCOS was diagnosed if there were polycystic ovaries by ultrasound (enlarged ovaries with > or =8 cysts 2-8 mm in diameter), oligoamenorrhea (intermenstrual interval >35 days), hirsutism (Ferriman-Gallwey score, > or =7) and elevated serum levels of testosterone (> or =2.7 nmol/L). Electrocardiograms were recorded at a paper speed of 50 mm/s. QT intervals were manually measured by a cardiologist. All intervals were corrected for heart rate according to Bazett's formula: QTc interval=QT interval/square root of the RR interval. Mean values of body mass index, heart rate, and blood pressure were not significantly different between the two groups (P>0.05). No significant differences in QT intervals (maximum QT, minimum QT, QT dispersion, minimum corrected QT, maximum corrected QT, and corrected QT dispersion) were observed between the two groups (P>0.05). Our results suggest that the risk of ventricular arrhythmias or sudden cardiac death is not increased in PCOS patients.     

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.     

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.     

多囊卵巢综合征卵巢局部胰岛素抵抗的生物学效应

多囊卵巢综合征(PCOS)是生殖功能障碍与代谢异常并存的一种特殊疾病.生殖功能障碍包括卵巢排卵功能障碍和雄激素过多,是PCOS患者临床表现的核心内容;代谢异常主要表现为胰岛素抵抗和高胰岛素血症.近期研究发现PCOS患者除胰岛素作用的经典靶组织--骨骼肌、脂肪和肝脏存在胰岛素抵抗之外,卵巢局部也存在胰岛素抵抗 [1].同时2型糖尿病患者存在胰岛素抵抗和外周高胰岛素血症的表现,但并不常见卵巢功能障碍,很显然以卵巢组织外的胰岛素抵抗和外周的高胰岛素血症来解释卵巢本身的功能异常是不确切的.因此,卵巢本身的胰岛素抵抗对PCOS患者卵巢功能改变有更重要的意义.     

Risk of cardiovascular events in patients with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have increased prevalence of cardiovascular (CV) risk factors. However, data on the incidence of CV events are lacking in this population. Using Rochester Epidemiology Project resources, we conducted a retrospective cohort study comparing CV events in women with PCOS with those of women without PCOS in Olmsted County, Minnesota. Between 1966 and 1988, 309 women with PCOS and 343 without PCOS were identified. Mean (SD) age at PCOS diagnosis was 25.0 (5.3) years; mean age at last follow-up was 46.7 years. Mean (SD) follow-up was 23.7 (13.7) years. Women with PCOS had a higher body mass index (29.4 kg÷m2 vs 28.3 kg÷m2; p=.01). Prevalence of type 2 diabetes mellitus and hypertension and levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were similar in the two groups. We observed no increase in CV events, including myocardial infarction (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.32 to 1.72; p=.48); coronary artery bypass graft surgery (adjusted HR 1.52; 95% CI 0.42 to 5.48; p=.52); death (adjusted HR 1.03; 95% CI, 0.29 to 3.71; p=.96); death due to CV disease (adjusted HR 5.67; 95% CI 0.51 to 63.7; p=.16); or stroke (adjusted HR 1.05; 95% CI 0.28 to 3.92; p=.94). Although women with PCOS weighed more than controls, there was no increased prevalence of other CV risk factors. Furthermore, we found no increase in CV events. While prospective studies are needed to confirm these findings, women with PCOS do not appear to have adverse CV outcomes in midlife.     

Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome

CONTEXT: Insulin resistance and chronic low level inflammation are often present in women with polycystic ovary syndrome (PCOS). OBJECTIVE: The purpose of this study was to determine the effects of hyperglycemia on reactive oxygen species (ROS) generation from mononuclear cells (MNCs) in PCOS. DESIGN: This was a prospective controlled study. SETTING: The study was conducted at an academic medical center. PATIENTS: The study population consisted of 16 women with PCOS (eight lean, eight obese) and 15 age- and body composition-matched controls (eight lean, seven obese). MAIN OUTCOME MEASURES: Insulin sensitivity was derived from a 2-h, 75-g oral glucose tolerance test (IS(OGTT)). ROS generation and p47(phox) protein expression were quantitated from MNCs obtained from blood drawn fasting and 2 h after glucose ingestion. RESULTS: IS(OGTT) was lower in PCOS, compared with controls (3.1 +/- 0.3 vs. 6.3 +/- 0.9, P < 0.003). The percent change in ROS generation from MNCs was higher in lean and obese PCOS, compared with lean controls (138.8 +/- 21.3 and 154.2 +/- 49.1 vs. 0.6 +/- 12.7, P < 0.003). The percent change in ROS generation from MNCs correlated positively with glucose area under the curve (r = 0.38, P < 0.05), and plasma levels of testosterone (r = 0.59, P < 0.002) and androstenedione (r = 0.50, P < 0.009). The percent change in p47(phox) from MNCs was also higher in lean and obese PCOS, compared with lean controls (36.2 +/- 18.2 and 39.1 +/- 8.0 vs. -13.7 +/- 8.7, P < 0.02), and correlated negatively with IS(OGTT) (r = -0.39, P < 0.05). CONCLUSION: ROS generation from MNCs in response to hyperglycemia is increased in PCOS independent of obesity. The resultant oxidative stress may contribute to a proinflammatory state that induces insulin resistance and hyperandrogenism in women with this disorder.     

Altered multihormone synchrony in obese patients with polycystic ovary syndrome

Luteinizing hormone (LH) concentrations and pulsatility are increased in obese women with polycystic ovary syndrome (PCOS). In addition, patients have hyperandrogenemia and insulin resistance. The mechanisms involved in aberrant hormone regulation in PCOS are still unclear. We investigated 15 obese PCOS women with a body mass index between 30 and 54 kg/m² and 9 healthy obese controls (body mass index, 31-60 kg/m²) with regular menstrual cycles. Subjects underwent 24-hour blood sampling at 10-minute intervals for later measurements of LH, leptin, testosterone, and insulin concentrations. Data were analyzed with a new deconvolution program, approximate entropy (and bivariate approximate entropy), and a cross-correlation network. Patients had increased LH pulse frequency and more than 2-fold greater daily LH secretion, with diminished pattern regularity. Testosterone secretion was increased 2-fold, but pattern regularity was similar to that in controls. In the network construct, insulin was correlated positively with LH, whereas leptin and testosterone were correlated negatively with LH. Bivariate synchrony of LH with insulin was decreased. Short-term caloric restriction paradoxically increased LH secretion by 1.5-fold and pattern irregularity, and reduced interpulse variability. Testosterone secretion and fasting concentrations of estradiol and sex hormone-binding globulin levels remained unchanged. Correlations between LH and insulin, leptin, and calculated free testosterone decreased. This study demonstrates marked alterations in the control of LH secretion in PCOS in the fed and calorie-restricted states. The ensemble results point to abnormal feedback control of not only the GnRH-gonadotrope complex, but also LH's relationships with leptin, insulin, and testosterone.     

Melatonin reduces oxidative stress in erythrocytes and plasma of senescence-accelerated mice

It has been suggested that oxidative stress is a feature of aging. The goal of the present study was to assess the oxidant effects related to aging and the protective role of exogenous melatonin in senescence-accelerated mice (SAMP8). Two groups of SAMP8 mice (males and females) were compared with their respective control groups of SAMR1 mice (senescence-resistant inbred strain) to determine their oxidative status without melatonin treatment. Four other groups of the same characteristics were treated with melatonin (10 mg/kg/day) in their drinking water. The melatonin concentration in the feeding bottles was titrated according to water consumption and body weight (i.e. 0.06 mg/mL for 30 g of body weight and 5 mL/day of water consumption). The treatment began when animals were 1-month old and continued for 9 months. When mice were 10-month old, they were anesthetized and blood was obtained. Plasma and erythrocytes were processed to examine oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), thiobarbituric acid reactive substances (TBARS), and hemolysis. The results showed greater oxidative stress in SAMP8 than in SAMR1, largely because of a decrease in GSH levels and to an increase in GSSG and TBARS with the subsequent induction of the antioxidant enzymes GPX and GR. Melatonin, as an antioxidant molecule, improved the glutathione-related parameters, prevented the induction of GPX in senescent groups, and promoted a decrease in SOD and TBARS in almost all the groups.     

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.     

Thyroidal effect of metformin treatment in patients with polycystic ovary syndrome

Objective Metformin is widely used for the treatment of type 2 diabetes. Growing evidence supports the beneficial effects of metformin also in patients with polycystic ovary syndrome (PCOS). It was recently reported that metformin has a TSH‐lowering effect in hypothyroid patients with diabetes being treated with metformin. Design Aim of this study was to evaluate the effect of metformin treatment on the thyroid hormone profile in patients with PCOS. Patients and measurements Thirty‐three patients with PCOS were specifically selected for being either treated with levothyroxine for a previous diagnosis of hypothyroidism (n = 7), untreated subclinically hypothyroid (n = 2) or euthyroid without levothyroxine treatment (n = 24) before the starting of metformin. The serum levels of TSH and FT₄ were measured before and after a 4‐month period of metformin therapy. Results Thyroid function parameters did not change after starting metformin therapy in euthyroid patients with PCOS. In the 9 hypothyroid patients with PCOS, the basal median serum levels of TSH (3·2 mIU/l, range = 0·4–7·1 mIU/l) significantly (P < 0·05) decreased after a 4‐month course of metformin treatment (1·7 mIU/l, range = 0·5–5·2 mIU/l). No significant change in the serum levels of FT4 was observed in these patients. The TSH‐lowering effect of metformin was not related to the administered dose of the drug, which was similar in euthyroid as compared with hypothyroid patients with PCOS (1406 ± 589 vs 1322 ± 402 mg/day, respectively; NS). Conclusions These results indicate that metformin treatment has a TSH‐lowering effect in hypothyroid patients with PCOS, both treated with l ‐thyroxine and untreated.     

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

OBJECTIVE: To investigate the prevalence of autoimmune thyroiditis (AIT) in patients with polycystic ovary syndrome (PCOS). DESIGN: Over a period of 30 months, 175 patients with PCOS were recruited to a prospective multicenter study to evaluate thyroid function and morphology; 168 age-matched women without PCOS were studied as a control group. METHODS: PCOS was defined as a- or oligomenorrhea, hyperandrogenism and exclusion of other disturbances of estrogen or androgen synthesis. All laboratory parameters were determined with automated immunoassays. Thyroid morphology was assessed by ultrasound. RESULTS: PCOS patients were characterized by an increased LH/FSH ratio, low progesterone, elevated testosterone and a high prevalence of hirsutism (PCOS 83%, control 3%; mean hirsutism score 12+/-5 and 3+/-2 respectively), but no differences in estrogen levels were found. Thyroid function and thyroid-specific antibody tests revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of 168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%; P<0.001). On thyroid ultrasound, 42.3% of PCOS patients, but only 6.5% of the controls (P<0.001) had a hypoechoic tissue typical of AIT; while thyroid hormone levels were normal in all subjects, PCOS patients had a higher mean TSH level (P<0.001) and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%, controls 1.8%; P<0.001). CONCLUSION: This prospective study demonstrates a threefold higher prevalence of AIT in patients with PCOS, correlated in part with an increased estrogen-to-progesterone ratio and characterized by early manifestation of the disease.     

Assessment of atrial conduction time in patients with polycystic ovary syndrome

Background

Polycystic ovary syndrome (PCOS) is closely related to increased cardiovascular risk in women of reproductive age. Atrial conduction abnormalities in these patients have not been investigated in terms of atrial electromechanical delay measured by tissue Doppler imaging (TDI) as an early predictor of atrial fibrillation development. The aim of this study was to evaluate whether TDI-derived atrial conduction time is prolonged in PCOS.

Methods

The study included 51 patients with PCOS and 48 age-matched healthy controls. P-wave dispersion (PWD) was calculated on the 12-lead surface electrocardiogram. Systolic and diastolic left ventricular (LV) functions, atrial electromechanical coupling, intraatrial and interatrial electromechanical delays were measured with conventional echocardiography and TDI.

Results

PWD was higher in PCOS women (50.45?±?3.7 vs 34.73?±?6.7 ms, p?=?0.008). Interatrial and intraatrial electromechanical delay were found longer in patients with PCOS compared to controls (41.9?±?9.0 vs 22.2?±?6.6 ms, p?p?r?=?0.54, p?C-reactive protein levels (r?=?0.68, p?r?=?0.53, p?r?=?0.31, p?=?0.04; r?=?0.37, p?=?0.021, respectively) and negatively correlated with flow propagation velocity (r?=??0.38, p?=?0.014).

Conclusion

This study shows that atrial electromechanical delay is prolonged in PCOS patients. Atrial electromechanical delay prolongation is related to low-grade inflammation, insulin resistance, and LV diastolic dysfunction in PCOS.     

未发现多囊样卵巢的多囊卵巢综合征的临床特征

选择2004年9月至2006年10月在本中心就诊的多囊卵巢综合征(PCOS)患者876例,根据B超检查分为两组:多囊样卵巢组800例,无多囊样卵巢组76例.结果 发现无多囊样卵巢组多毛评分、睾酬、胆固醇和低密度脂蛋白明显高于多囊样卵巢组,差异有统计学意义.无多囊样卵巢组一级亲属中糖尿病、高血压病史的患病率明显增高.     

Role of ovary and adrenal glands in hyperandrogenemia in patients with polycystic ovary syndrome.

Ovary is the main source of the hyperandrogenism in polycystic ovary syndrome (PCOS). Adrenal glands may also be involved in the pathogenesis of the development of PCOS. To investigate this possibility and to find out if buserelin test is able to distinguish PCOS patients from the patients with idiopathic hirsutism (IH), ACTH and buserelin tests were performed in 29 women with PCOS, 21 women with IH, and 20 control subjects (CS). We also aimed to determine the role of dysregulation of 17 hydroxylase in the development of PCOS. Basal and stimulated dehydroepiandrosterone sulfate (DHEA-S) and stimulated cortisol (F) levels after ACTH administration were significantly higher in PCOS group than in IH and CS groups (p<0.0001 and p<0.05, respectively). PCOS patients also possessed significantly higher basal and stimulated 17-hydroxyprogesterone (17-OH P) levels, including the peak levels (p<0.02), during buserelin testing when compared with IH patients and CS. There was no significant correlation between the ACTH-stimulated and the buserelin-stimulated peak 17-OH P values. In conclusion, significantly higher basal and ACTH-stimulated levels of F and DHEA-S in PCOS compared with controls and patients with IH, reflect that adrenal hyperactivity also plays a role in hyperandrogenemia seen in PCOS. Because of the lack of the correlation between ACTH-stimulated and buserelin-stimulated 17-OH P levels, it is hard to say that adrenal hyperactivity seen in PCOS is the result of the dysregulation of cytochrome P450c17-alpha enzyme. Our results suggest that buserelin test which is an GnRH analogue could distinguish at least some of the patients with PCOS from the other patients presenting with the common symptoms of hyperandrogenemia.     

Hypertension in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors. The aims of this study are to investigate the prevalence of hypertension in a female population with PCOS and to correlate hypertension with her clinical and hormonal profile. MATERIALS AND METHODS: it is a transversal study of 79 PCOS patients with mean age of 25 +/- 7 years (range 13-44). PCOS diagnosis is made by Rotterdam consensus criteria's (2003). WHO definition of hypertension is used (BP 140/90 mmHg). Blood pressure is measured three times in each patient. Ovarian echography and biochemical assays (GnRH test, androgens, cholesterol, triglycerides, and oral glucose tolerance test) are made before the 5th day of the menstrual cycle. RESULTS: 12% of PCOS women have hypertension. Family history of hypertension is not a predictive factor of hypertension in our study. PCOS patients with hypertension are not significantly older than those without hypertension (28.4 +/- 6.5 vs. 25.2 +/- 7; p = 0.12). If compared to PCOS women without hypertension, those with hypertension have a significantly higher BMI (39.2 +/- 7 vs. 29.6; p = 0.0004). PCOS patients with and without hypertension do not differ significantly in their level of androgens and total cholesterol. Triglycerides level is higher in PCOS patients with hypertension (p = 0.06). In oral glucose tolerance test, areas under the curve of insulin and glucose are significantly higher in PCOS patients with hypertension (respectively p = 0.06 and 0.02). The area under the curve of LH during GnRH test is lower in PCOS patients with hypertension (p = 0.04).