Dissociation of endothelial function and arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS)

Objective Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk but it is not clear if this is independent of obesity and insulin resistance. This study therefore investigates endothelial function and arterial stiffness in nonobese, noninsulin resistant women with PCOS. Design This is cross‐sectional case–control study. Patients A total of 19 young women with PCOS, with body mass index (BMI) <30 kg/m², and 19 healthy controls matched for age and BMI were included in the study. Measurements Endothelial function was assessed with flow mediated dilatation (FMD) of the brachial artery, while arterial stiffness was assessed with pulse wave velocity (PWV) and augmentation index (AI). Results There were no significant differences between PCOS and control subjects when assessing the following clinical and biochemical variables: blood pressure, homeostasis model assessment insulin‐resistance index, lipids and oestradiol. Women with PCOS had higher free androgen index scores (5·14 ± 3·47 vs. 3·25 ± 1·42, P = 0·036). The PCOS subjects had significantly lower FMD of the brachial artery compared with the controls (6·5 ± 2·9%vs. 10·5 ± 4·0%, P < 0·01). There were no significant differences in markers of arterial stiffness (PWV 5·8 ± 1·1 vs. 6·0 ± 1·0, P = 0·58, AI 16·5 ± 10·2 vs. 20·3 ± 10·2, P = 0·25). Conclusions Women with polycystic ovary syndrome who are young, nonobese, and have no biochemical evidence of insulin resistance, have abnormal vascular function, but normal arterial stiffness, when compared with age and weight matched control subjects. Whether this leads to a greater risk of cardiovascular disease requires further investigation.     

大样本中国人PCOS临床特点分析

目的 为多囊卵巢综合征(PCOS)的临床诊治提供依据.方法 回顾性分析1 040例PCOS患者的临床特征及内分泌、血糖、血脂、胰岛素等检查指标.结果 ①1 040例PCOS患者中,月经稀发占62.60%,闭经占19.71%,所有成年患者的月经紊乱史均可追溯到青春期初潮后;450例存在肥胖(259例为腹部型);158例存在黑棘皮症(肥胖型103例,非肥胖型55例).②PCOS患者中高甘油三酯血症占5.58%、高胆固醇血症占7.02%、HDL异常占0.10%、LDL异常占12.69%,其中肥胖患者胆固醇、低密度脂蛋白明显高于非肥胖患者,P＜0.05.173例符合糖尿病诊断标准,179例糖耐量减低(IGT),27例空腹葡萄糖异常(IFG),9例IFG IGT;平均空腹及口服葡萄糖耐量试验(OGTT)30、60、120和180 min血糖超过正常范围的人次分别为19、74、110、42和12,如果不取空腹血糖值有10例患者被漏诊,分别略去30、60、120和180 min的血糖值,依次有16、50、28和1例被漏诊,5次抽血及3次抽血(空腹 60 min 120 min)的血糖及胰岛素曲线下面积有显著差异;体质量指数(BMI)和腰臀比(WHR)均与胰岛素抵抗指数(HOMA-IR)呈正相关(r=0.29987、P＜0.01,r=0.12441、P＜0.000 1).结论 PCOS患者肥胖发生率较高,肥胖型PCOS患者较非肥胖型存在更严重的内分泌及代谢紊乱;阻断肥胖、IR,打破内分泌代谢间的恶性循环,不但对阻断PCOS的进程具有重要意义,更是预防2型糖尿病、心血管疾病等远期并发症的关键.     

Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS)

Objective To determine serum adiponectin concentrations in adolescent girls with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin levels with insulin and androgen levels. Design Prospective case–control study. Setting Endocrine clinics in the community. Patients Forty‐four adolescent girls were grouped as follows: 14 were overweight [body mass index (BMI) standard deviation score >1·645] with PCOS; 16 were lean (BMI SDS <1·036) with PCOS; and 14 were lean (BMI SDS <1·036) without PCOS. Intervention Blood samples were collected from all girls between 8 and 11 am , after an overnight fast. Main outcome measures Serum levels of adiponectin, leptin, insulin, Müllerian‐inhibiting substance, luteinizing hormone, follicle‐stimulating hormone, testosterone, 17‐alpha‐hydroxyprogesterone, androstendione, dehydroepiandrosterone sulphate (DHEAS) and 17β‐oestradiol. Results Adiponectin concentrations were significantly decreased in obese adolescents with PCOS (10·5 ± 5·5 μg/ml) compared with that in lean girls with or without PCOS (16·9 ± 8·64 and 18·0 ± 7·4 μg/ml respectively). Leptin levels were significantly elevated in obese adolescents with PCOS compared with the levels in normal weight adolescents with PCOS, and compared with that in normal weight controls. Insulin levels were markedly higher in obese adolescents with PCOS compared with that in normal weight adolescents (12·3 ± 12·2 vs. 4·5 ± 2·9, P < 0·05), and compared with that in normal weight PCOS adolescents (7·4 ± 4·9); however, this difference was not statistically significant. Insulin levels did not differ between normal weight adolescents with PCOS and normal controls. Adiponectin concentrations correlated inversely with BMI, leptin and insulin. Conclusions Hypoadiponectinaemia is evident only in obese adolescents with PCOS and therefore does not seem to be involved in the pathogenesis of PCOS in this age group.     

Long term complications of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women “at-risk” to detect and prevent complications as soon as possible.     

Association of insulin resistance with anti-Mullerian hormone levels in women without polycystic ovary syndrome (PCOS)

Objective  To explore the relationship of insulin resistance (IR) and adipokines (leptin, adiponectin, RBP4) to anti-Mullerian hormone (AMH) levels in women without polycystic ovary syndrome (PCOS).
Design/patients/measurements  We recruited 120 healthy, reproductive age women without PCOS. An overnight fasting blood draw, anthropometric measurements, analyses of serum levels of AMH, adipokines (leptin, adiponectin and RBP4) and total testosterone, a homeostasis model assessment for insulin resistance (HOMA-IR) and a transvaginal ultrasound scan were performed between the third and fifth day of their spontaneous menstrual cycles.
Results  Higher HOMA-IR levels were associated with lower levels of AMH. After adjustment for age, serum AMH levels negatively correlated with insulin, fasting glucose, HOMA-IR and RBP4. However, a positive correlation was identified between serum AMH and adiponectin. A final multiple stepwise linear regression demonstrated that HOMA-IR was independently associated with AMH.
Conclusion  An independent relationship exists between HOMA-IR and AMH in women without PCOS, possibly due to the effect of abnormal insulin action on AMH secretion by granulosa cells.     

Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS

BACKGROUND: The phenotypic spectrum of PCOS has been broadened but the prevalence and clinical significance of PCOS phenotypes continue to challenge the scientific community. OBJECTIVE: Analysis of the phenotypic spectrum of PCOS and determination of the association between metabolic, hormonal and new ultrasonographic criteria. DESIGN: Clinical prospective study. PATIENTS: Six hundred and thirty-four women with PCOS (18-35 years) and comparable body mass index (BMI), diagnosed by ESHRE/ASRM criteria, were categorized into two major groups of phenotypes: classic (NIH) and nonclassic (ESHRE/ASRM), and then subdivided into phenotypes with all possible combinations of diagnostic characteristics. One hundred and eight healthy women of reproductive age, matched for BMI, were recruited as the control group. MEASUREMENTS: Ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters. RESULTS: Classic PCOS phenotype was more frequent (85.96%) than the nonclassic phenotype (14.04%). The patients were also classified according to the presence of biochemical (80.60%) or clinical hyperandrogenaemia (12.62%), and, in the newly introduced group, to absence of evidence of hyperandrogenaemia (6.78%). Subjects with classic PCOS with biochemical hyperandrogenaemia (74.76%) were more insulin resistant than controls. In women with PCOS, follicle number was positively related to both insulin resistance and biochemical hyperandrogenaemia. Additionally, women with PCOS had a 6.58-fold increased relative risk (RR) of > 12 follicles on intravaginal ultrasound and a 2.94-fold increased RR of ovarian volume > 10 cm(3) compared to controls. CONCLUSION: The most frequent PCOS phenotype is the subgroup with biochemical hyperandrogenaemia only within the classic phenotype, which is more insulin resistant than the control group. The follicle number, a newly introduced ultrasonographic marker, is related to both metabolic and hormonal features of PCOS.     

Should physicians prescribe metformin to women with polycystic ovary syndrome PCOS?

1. Metformin is not efficient enough in order to regulate menstrual cycles.2.Metformin is not efficient enough in order to treat hyperandrogenism.3. Metformin should not be used as a first-line treatment in order to treat infertility. Clomiphene citrate (CC) is the reference treatment.4. Metformin in addition to CC is not recommended as a second line treatment, after the failure of CC alone.5. Metformin should not be used during pregnancy in non diabetic women with PCOS, in order to prevent the risk of gestational diabetes.6. Metformin should be prescribed to PCOS women when they are diabetic, in order to prevent their cardiovascular risk, after lifestyle modification.7. Metformin should not be used in PCOS non diabetic women in order to lose weight. Metformin should not be used in order to treat dyslipidemia in women with PCOS.8. In PCOS women, without diabetes, but with fasting hyperglycemia or carbohydrate intolerance, metformin should be prescribed if: BMI > 35.     

Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome

Obese women with polycystic ovary syndrome (PCOS) exhibit impaired endothelial function, which is strongly and directly correlated with both testosterone levels and insulin resistance. Endothelial dysfunction is considered a potent risk factor for macrovascular disease. Because troglitazone (Tgz) improves both hormonal profiles and insulin sensitivity, we tested whether Tgz treatment ameliorates endothelial function in these patients. We studied leg blood flow (LBF) responses to graded intrafemoral artery infusion of the endothelium-dependent vasodilator methacholine chloride (MCh) and to a 4-h hyperinsulinemic euglycemic clamp (120 mU/m(2) x min) in 10 PCOS, before and after 3 months treatment with Tgz (600 mg/d). A group of 13 obese women (OBW) matched for age, weight, body fat (>40% in both groups), blood pressure, and total cholesterol served as controls. PCOS patients exhibited elevated free testosterone (fT) and triglycerides (TG) and lower high density lipoprotein cholesterol levels compared with OBW [14.0 +/- 1.0 vs. 3.7 +/- 0.6 pmol/liter (P < 0.0001), 1.60 +/- 0.28 vs. 0.94 +/- 0.09 mmol/liter (P < 0.02), and 0.91 +/- 0.04 vs. 1.1 +/- 0.04 mmol/liter (P < 0.005), respectively]. Tgz treatment reduced fT levels, but did not improve the TG and high density lipoprotein profile [to 9.7 +/- 2.8 pmol/liter (P < 0.007), 1.49 +/- 0.34 mmol/liter (P = NS), and 0.93 +/- 0.07 mmol/liter (P = NS), respectively]. Basal LBF was unchanged after Tgz. In PCOS compared with OBW, insulin stimulated glucose disposal (52.7 +/- 6.6 vs. 85.5 +/- 4.4 micromol/kg fat-free mass x min; P < 0.0005) and vasodilation (increase in LBF, 22 +/- 14% vs. 59 +/- 15%; P < 0.05) were significantly improved after Tgz treatment to 68.8 +/- 7.2 micromol/kg fat-free mass x min (P < 0.0001) and 101 +/- 48% (P < 0.03), respectively. The increase in LBF in response to MCh in PCOS was markedly more pronounced after treatment (P < 0.01, by ANOVA) and was similar to that observed in OBW. Before Tgz treatment, maximal LBF increments in response to MCh were 130 +/- 25% and 233 +/- 29% in PCOS and OBW, respectively (P < 0.01). After Tgz treatment, PCOS values improved, achieving increments similar to those in OBW (245 +/- 45%; P < 0.04). Tgz treatment in PCOS improves both hormonal and metabolic features. These modifications are associated with improvement of endothelial function, suggesting that Tgz could be a useful tool to reduce the risk of macrovascular disease in women with PCOS and perhaps in other insulin-resistant syndromes.     

Altered vascular function in young women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinemic insulin resistance, a metabolic disorder that in other circumstances is associated with increased cardiovascular risk. We compared macrovascular and microvascular function in 19 women with PCOS with 12 control subjects matched as a group for body mass index. Macrovascular function was assessed by recording pulse wave velocity (PWV) across the aorta and brachial artery. Microvascular function was studied by wire myography, by measuring the concentration response curve to norepinephrine (NE) before and after incubation with insulin (100 and 1,000 pM). PWV at the level of the brachial artery was found to be significantly elevated in the PCOS group [9.08 (range, 8.34-11.15) m/sec(-1) vs. 8.27 (range, 7.5-9.01) m/sec(-1); P = 0.03]. In contrast, PWV measured in the aorta did not differ between the two groups [7.49 +/- 1.21 vs. 7.84 +/- 1.44 m/sec(-1); P = 0.8]. In vessels from control subjects, insulin reduced the contraction response to NE. At an insulin concentration of 100 pM, NE negative log EC50 (pD(2)) was 6.2 +/- 0.24 vs. 6.7 +/- 0.15 (P = 0.02). At a concentration of 1,000 pM, NE pD(2) was 6.4 +/- 0.14 vs. 6.9 +/- 0.19 (P = 0.0006). Both concentrations also caused attenuation in maximal tension developed in response to NE (insulin 100 pM, 12 +/- 3%, P = 0.002; insulin 1,000 pM, 17 +/- 5%, P = 0.009). In contrast, there was no change in the PCOS group with insulin at 100 pM for either pD(2) (6.7 +/- 0.24 vs. 6.8 +/- 0.27; P = 0.3) or maximum contraction (-0.4 +/- 2%; P = 0.8). At 1,000 pM, there was a change in pD(2) (6.4 +/- 0.2 vs. 6.8 +/- 0.2; P = 0.003) but not maximum contraction (4 +/- 3%; P = 0.2). In conclusion, this study is the first to demonstrate increased vascular stiffness and a functional defect in the vascular action of insulin ex vivo in patients with PCOS. We suggest that these findings are indicative of insulin resistance at a vascular level in women without overt cardiovascular disease.     

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS)

Background Nonenzymatic advanced glycation and oxidation end‐products, advanced glycation end‐products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. Objective To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Design Clinical trial. Patients One hundred and ninety‐three age‐ and BMI‐matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty‐eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Measurements Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. Results The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7·96 ± 1·87 U/ml, P < 0·001) compared with those with isolated hyperandrogenaemia (5·61 ± 0·61 U/ml), anovulation (5·53 ± 1·06 U/ml), US‐PCO morphology (5·26 ± 0·25 U/ml) and controls (5·86 ± 0·89 U/ml). Conclusions In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS)

OBJECTIVE: To determine the prevalence of adrenal androgen (AA) excess in the polycystic ovary syndrome (PCOS) using age- and race-specific normative values. DESIGN: Cross-sectional observational study. PATIENTS: One hundred and eight-two (88 Black and 94 White) age-matched healthy eumenorrhoeic nonhirsute women (controls) and 213 (27 Black and 186 White) women with PCOS were recruited. MEASUREMENTS: Total testosterone (T), free T, androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS) and SHBG, as well as fasting insulin and glucose, were measured in plasma. RESULTS: The mean total T, free T, A4, DHEAS and body mass index (BMI) were higher in women with PCOS than in control women. DHEAS levels were significantly lower in Black controls than White controls, whereas fasting insulin and BMI were higher in Black controls. In control and Black PCOS women, DHEAS levels did not correlate with BMI, waist-to-hip ratio (WHR) or fasting insulin. Among White women with PCOS, DHEAS levels correlated negatively with BMI and fasting insulin. DHEAS levels decreased similarly with age in control and PCOS women of either race. For each race and age group the upper 95% normative values for log DHEAS was calculated, and the number of PCOS subjects with log DHEAS values above this level were assessed. The prevalence of supranormal DHEAS levels was 33.3% and 19.9%, respectively, among Black and White women with PCOS. CONCLUSIONS: The prevalence of DHEAS excess is approximately 20% among White and 30% among Black PCOS patients, when using age- and race-adjusted normative values. This study also indicates that the age-associated decline in DHEAS levels is observable and similar in both control and PCOS women, regardless of race. While BMI and fasting insulin had little impact on circulating DHEAS levels in healthy women, among White PCOS patients these parameters were negatively associated with circulating DHEAS levels.