多囊卵巢综合征胰岛素抵抗的发生机制

多囊卵巢综合征（PCOS）是一种发病多因性、临床表现多态性的综合征，以慢性持续的无排卵和高雄激素血症为基本病理生理改变。研究证实胰岛素抵抗（IR）可能是PCOS发生发展的主要因素之一，本文就PCOS-IR发生机制的研究进展作一综述。     

Tissue insulin sensitivity and body weight in polycystic ovary syndrome

OBJECTIVE: Polycystic ovarian syndrome (PCOS) and obesity both affect insulin sensitivity. This study was designed to investigate the biochemical indices of PCOS and tissue insulin sensitivity in groups of lean and obese women with clinically equivalent degrees of the syndrome, relative to control subjects. DESIGN: A prospective study of in vivo parameters and in vitro study of adipocytes to assess insulin sensitivity. PATIENTS: Six lean and 14 overweight patients fulfilling formal diagnostic criteria for PCOS were studied. The degree of hirsutism and amenorrhoea was similar in each group. Eight control subjects were also studied. MEASUREMENTS: Endocrine and metabolic parameters were measured in lean and overweight patients with PCOS and control subjects. In vitro studies of adipocyte insulin receptor binding and adipocyte insulin action were performed. RESULTS: The mean plasma LH level was elevated in both groups of PCOS but was significantly higher in the lean group (LH levels were 25.1 +/- 3.1 and 14.5 +/- 1.6 iu/l in lean PCOS and obese PCOS, respectively (P = 0.01)). There was a strong inverse correlation between BMI and LH levels (R = - 0.70, P = 0.001). Fasting insulin levels were elevated in both lean and obese groups (11.5 +/- 2.8 and 26.8 +/- 8.1 mU/l, respectively; P = 0.068). Mean serum testosterone and serum androstenedione levels were also elevated in PCOS compared to control subjects but there was no difference between the two groups of PCOS subjects. Insulin receptor binding in amenorrhoeic subjects with PCOS was low in both lean and obese patients with PCOS but was not significantly different between the two groups (0.79 +/- 0.17% and 0.66 +/- 0.07% per 10 cm2 cell membrane, respectively). Maximally insulin-stimulated rates of 3-O-methylglucose transport were low in both groups compared to previously studied normal subjects (0.96 +/- 0.21 and 0.64 +/- 0.07 pmol per 10 cm2 membrane in lean and obese PCOS subjects, respectively; P = NS). CONCLUSIONS: Lean subjects with a given phenotypic expression of PCOS have an equivalent degree of tissue insulin resistance compared to obese PCOS subjects. This implies that the insulin resistance may be a primary feature of PCOS. If this is so, a similar clinical degree of the syndrome may be brought about by genetically determined insulin resistance in lean subjects or by insulin resistance which is secondary to obesity.     

不同胰岛素抵抗状态下多囊卵巢综合征患者内分泌指标与卵巢超声特征的相关性研究

目的 探讨伴或不伴IR的多囊卵巢综合征(PCOS)患者内分泌指标与超声特征的相关性.方法 将195例PCOS患者分为IR(PCOS-IR)组和非IR(PCOS-NIR)组,另选健康对照(NC)组50名.检测各组FIns、睾酮(T)、黄体生成素(LH)、卵泡刺激素(FSH)、卵巢体积(OV)、卵泡最大直径等指标.结果 PCOS-IR组BMI[(22.73±2.35)vs(20.97±2.33)kg/m2,P＜0.01]、FIns[(39.22±28.30)vs (6.13±3.59)μU/ml,P＜0.01]、胰岛素抵抗指数(HOMA-IR)[(8.40±7.15)vs(1.26±0.75),P＜0.01]、T[(0.74±0.21) vs (0.53±0.11) ng/ml,P＜0.01]和OV[(12.76±3.78)vs(11.43±4.01)ml,P＜0.05]大于PCOS-NIR组,卵泡最大直径[(5.08±1.63)vs(7.05±1.72)mm,P＜0.01]小于PCOS-NIR组.PCOS患者OV与BMI、HOMA-IR、T、LH/FSH呈正相关,卵泡最大直径与BMI、HOMA-IR、T呈负相关. 结论 PCOS合并IR患者OV增大,卵泡最大直径减小.OV与IR、高雄激素血症呈正相关,卵泡大小与其呈负相关.IR影响卵巢形态.     

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.     

Selective insulin resistance in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia that is amplified by insulin in the presence of resistance to insulin's action to stimulate glucose uptake in muscle and fat. To explore the mechanisms for this paradox, we examined the metabolic and mitogenic actions of insulin and insulin-like growth factor I (IGF-I) in cultured skin fibroblasts from PCOS (n = 16) and control (n = 11) women. There were no significant decreases in the number or affinity of insulin- or IGF-I-binding sites in PCOS compared to control fibroblasts. Basal rates were similar, but there were significant decreases in insulin-stimulated (control, 51.8 +/- 7.0; PCOS, 29.5 +/- 2.9 nmol/10(6) cells x 2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stimulated (control, 48.9 +/- 6.7; PCOS, 33.0 +/- 3.2 PCOS nmol/10(6) cells x 2 h at 100,000 pmol/L IGF-I; P < 0.05) glucose incorporation into glycogen in PCOS fibroblasts, a metabolic action of insulin. Stimulation of thymidine incorporation, a mitogenic action of insulin, was similar in PCOS and control fibroblasts in response to both insulin and IGF-I. There were also no significant differences in insulin- or IGF-I-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in PCOS compared to control fibroblast cells. We conclude that 1) there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mitogenic, signaling pathways; 2) there is a similar defect in IGF-I action, suggesting that insulin and IGF-I stimulate glycogen synthesis by the same postreceptor pathways; and 3) insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activation by insulin and IGF-I is similar to the control value, suggesting that the metabolic signaling defect is in another pathway or downstream of this signaling step in PCOS fibroblasts.     

The management of insulin resistance in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) has reproductive and metabolic implications. Insulin resistance (IR), secondary to genetic and lifestyle factors, is integral in the pathogenesis, metabolic, clinical features and the long-term sequelae in the majority of people with PCOS. Therapeutic strategies targeting IR in PCOS ameliorate clinical features and might reduce long-term sequelae including diabetes. The mainstay for improving IR is lifestyle change; however, feasibility and sustainability remain concerns. In PCOS, metformin reduces IR, improves ovarian function, regulates cycles, lowers androgens, improves clinical hyperandrogenism and potentially improves fertility. Metformin is also likely to delay diabetes onset and has a role in PCOS in those at high risk of diabetes; however, further research is needed to clarify specific target subgroups and clinical indications.     

Lean mass and insulin resistance in women with polycystic ovary syndrome

Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Muscle is the major tissue utilizing glucose while excess adipose tissue relates to insulin resistance. Thus, body composition is likely to be an important regulator of insulin sensitivity. Thirty-nine PCOS patients (age: 29.9 ± 1.0 years; BMI: 33.8 ± 1.2 kg/m²) participated in a cross sectional study. Body composition was measured by dual energy x-ray absorptiometry (DEXA). Insulin resistance and secretion were assessed using oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FS-IVGTT). In contrast with the conventional expectations, lean mass correlated directly (P < .05) with the insulin resistance measure HOMA (r = 0.440); and inversely with the insulin sensitivity index QUICKI (r = ?0.522) independent of fat mass. In 11 pairs of subjects matched for fat mass (35.6 ± 2.2 and 35.6 ± 2.4 kg) but with discordant lean mass (52.8 ± 1.8 vs 44.4 ± 1.6 kg), those with higher lean mass had a higher glucose response during OGTT (AUC_Glucose; P = .034). In contrast, 17 pairs matched for lean mass (48.7 ± 1.7 and 48.9 ± 1.6 kg) but discordant for fat mass (43.3 ± 2.6 vs 30.3 ± 8.9 kg) showed no differences in insulin resistance parameters. These novel findings indicate that lean mass relates directly to insulin resistance in PCOS.     

PCOS患者血浆抵抗素与胰岛素抵抗的关系

目的探讨血浆抵抗素水平与多囊卵巢综合征（PCOS）患者胰岛素抵抗（IR）的关系。方法对35例PCOS患者及40例健康者（对照组）采用ELISA方法检测血浆抵抗素,放免法检测促黄体生成素（LH）、卵泡刺激素（FSH）及空腹胰岛素（FIN）,氧化酶法检测空腹血糖（FPG）,计算胰岛素抵抗指数（HOMA—IR）。结果PCOS组血浆抵抗素、LH、LH／FSH、FIN、HOMA—IR显著高于对照组（P均〈0．05）;PCOS组血浆抵抗素与FPG、FIN、HOMA—IR、LH及LH／FSH呈显著正相关（P均〈0．05）。结论抵抗素参与PCOS患者的IR发生过程,可作为一种新的敏感指标评价PCOS患者的IR程度。     

Cardiometabolic features of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.     

Insulin resistance and polycystic ovary syndrome

Insulin resistance plays a central role in the pathogenesis of the reproductive as well as metabolic aberrations that characterize the syndrome. Many women with polycystic ovary syndrome (PCOS) manifest a phenotype that overlaps substantially with the so-called “metabolic syndrome” or “syndrome X.” These manifestations include obesity, glucose intolerance, hypertension, macrovascular disease, and dyslipidemia. The etiology and manifestations of insulin resistance in PCOS are reviewed in this article.     

Insulin resistance and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.     

Relationship between homocysteine and insulin resistance in women with polycystic ovary syndrome

Hyperhomocysteinemia is a risk factor for atherosclerotic vascular diseases. It is known that plasma homocysteine levels are higher in polycystic ovary syndrome (PCOS) patients than in healthy subjects. The aim of our study was to determine the relationship between plasma homocysteine level and insulin resistance in women with PCOS. Twenty-nine patients (age, 23.90 +/- 5.86 years) and twenty-five healthy subjects (age, 25.24 +/- 4.28 years) were involved in the study. Plasma levels of fasting insulin, glucose, homocysteine, FSH, and LH levels were measured. A statistically significant difference in plasma concentrations of HOMA index, homocysteine, basal insulin levels and LH/FSH ratios was observed between groups (P = 0.001, P = 0.001, P = 0.001, and P = 0.01, respectively). There was no relationship between Hcy and the other variables. In multiple logistic regression analysis, age, BMI and insulin resistance were not predictors of Hcy.     

Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome

OBJECTIVE The relationship between insulin resistance and hyperandrogenism led us to study insulin resistance in polycystic ovary syndrome (PCOS) in order to determine its prevalence and pathogenesis. DESIGN Blood samples were taken on the 8th day after menses commenced. PATIENTS Sixty-one women with PCOS, 30 with normal weight (BMK25 kg/m²) (group 1) and 31 with obesity (BMI<26 kg/m₂) (group 2) were studied. They were divided also according to LH level: group A, low or normal LH (n==23) and group B, high LH (n= 38). Twenty lean control women and 16 obese control women were studied. MEASUREMENTS Serum LH, testosterone, free testosterone, dehydroepiandrosterone, sex-hormone binding globulin, androstenedione, and fasting insulin were measured. Insulin sensitivity was explored by the insulin tolerance test (ITT). ITT was performed by bolus i.v. insulin of 0 1 IU/kg. Blood glucose was measured before (– 5, 0) and after injection (3, 5, 7, 10, 15 minutes). Insulin sensitivity was given by the ratio of glycaemic variation to initial blood glucose (AG/G index). RESULTS ΔG/G was correlated with other insulin resistance parameters, particularly fasting insulin r=–0.40, P<0.01. The PCOS groups had the following insulin resistances (mean ± SEM) compared to matched groups: ΔG/G lean PCOS vs lead controls: 0.45 ± 0.02 vs 0.61 ± 0.01, P< 0.001; ΔG/G obese PCOS vs obese controls: 0.32 ± 0.02 vs 0.40 ± 0.01, P<0.02. Insulin resistance was higher in group A than in group B: ΔG/G 0 29 ± 002 vs 0 45 ± 0 02, P < 0.001. The prevalence of insulin resistance was 63% in lean PCOS and 51% in obese PCOS. Positive correlations between AG/G index and LH were found in group 1 and 2, respectively r= 0.45, P<0.01 and r= 0.55, P<0.01. CONCLUSION PCOS was associated with a significant decrease of insulin sensitivity, independent of obesity. The correlation between LH and insulin sensitivity suggests a complementary action in PCOS.     

The relationship of epicardial adipose tissue thickness to clinical and biochemical features in women with polycystic ovary syndrome

The amount of epicardial adipose tissue (EAT), a component of body visceral adiposity, has been linked to the presence and severity of cardiovascular disease through multiple mechanisms. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and subclinical inflammation, which participate in the mechanism of atherosclerosis. We searched if the patients with PCOS have increased EAT thickness (EATT), along with its relation to the measures of adiposity and insulin sensitivity. A total of 41 subjects with PCOS and 46 age and body mass index (BMI) matched healthy controls were enrolled. EAT was measured by echocardiography above the free wall of the right ventricle. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) formula, and plasma adiponectin level was measured by ELISA. Compared to healthy controls EATT and HOMA-IR score were significantly higher (p=0.0001 for both) while plasma adiponectin concentration was significantly lower (p=0.048) in women with PCOS. EATT correlated positively with total cholesterol, triglyceride, luteinizing hormone (LH) and negatively with sex hormon binding globuline (p<0.05 for all), whereas it displayed no correlation to plasma adiponectin level (p=0.924). Triglyceride level was the significant determinant of EATT in logistic regression analysis (p=0.035). Thickness of the EAT is increased in patients with PCOS in conjunction with hyperandrogenity. Prospective studies are required to identify the relation of EAT and cardiovascular risk in patients with PCOS.     

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.     

Insulin resistance and polycystic ovary syndrome]

The causes and consequences of the insulin resistance that accompanies the polycystic ovary Syndrome (PCOS) are still controversial. The hyperandrogenism does not appear any more as a causal factor but on the contrary is likely to be a consequence, via the ovarian effects of hyperinsulinism. These are still not clearly understood in their molecular aspects, but their reality is undoubtful in view of some clinical studies which showed an improvement following by the reduction of hyperinsulinism. Therefore, the aetiopathogenic role of the insulin resistance in PCOS becomes more and more obvious but it cannot be split from the likely implication of the intra-ovarian growth factors, and more especially the IGF 1 which could act synergistically with it. Moreover, the presence of LH seems to be still a pre-requisite to the ovarian action of insulin. The therapeutical incidences of these hypothesis are obvious and should improve in the next future the medical management of PCOS.     

Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome

The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.