多囊卵巢综合征伴胰岛素抵抗的研究进展

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是国内外研究者、医患人员非常关心的育龄期妇女常见的内分泌代谢疾病,其主要表现为闭经、月经量减少、肥胖、不孕、体多毛等。多数伴有胰岛素抵抗（insulin resistance,IR）的发生,胰岛素抵抗（insulin resistance,IR）是指正常水平的胰岛素促进葡萄糖摄取及利用能力下降,机体各组织、器官代偿性分泌胰岛素以维持机体血糖稳定的一种代谢状态。近年来的研究不断证实PCOS患者2型糖尿病、血脂代谢紊乱及代谢综合征（metabolicsyndrome,MS）等并发症的发病率明显增高。运动能够改善2型糖尿病患者胰岛素抵抗的说法已经得到了共识,其分子机制也逐渐分明。PCOS患者胰岛素抵抗的研究目前仍处于进一步探讨阶段,但是经过近几年的努力已经有了新的进展,若在PCOS胰岛素抵抗患者的治疗过程中给予一定的运动干预,相信一定能够有新的突破。本文就PCOS患者胰岛素抵抗研究的机制、诊断及治疗方法的新进展简单做一综述。     

Premicroalbuminuria in Women with Polycystic Ovary Syndrome: A Metabolic Risk Marker

ObjectiveTo determine the relationship between urinary albumin excretion and features of the metabolic syndrome in women with polycystic ovary syndrome (PCOS).MethodsWe retrospectively analyzed the medical records of 189 premenopausal women (mean age ± SD, 28.9 ± 7.7 years) with PCOS and 81 control patients (mean age ± SD, 37.9 ± 8.6 years) from a single endocrinology practice. Exclusion criteria were diabetes, heart disease, kidney disease, use of lipid-lowering agents, and use of antihypertensive agents (except spironolactone). The urine albumin-to-creatinine ratio (ACR) was measured in a random single-voided urine sample. Premicroalbuminuria was defined as an ACR > 7 mg/g.ResultsThe prevalence of ACR > 7 mg/g was 31.2% in the PCOS group (N = 189) and 35.8% in the control group (N = 81). The metabolic syndrome was noted in 16.3% (27 of 166) of patients with PCOS and in 2.9% (2 of 69) of control subjects. Nine percent of patients with PCOS who had an ACR ≤ 7 mg/g but 30.9% of those with an ACR > 7 mg/g had the metabolic syndrome. Patients with PCOS who had an ACR > 7 mg/g had significantly higher blood pressure and alanine aminotransferase levels than did those with an ACR ≤ 7 mg/g. In the patients with PCOS who had an ACR ≤ 7 mg/g versus those who had an ACR > 7 mg/g, no significant difference was found in frequency of use of metformin, spironolactone, or oral contraceptives.ConclusionIn women with PCOS, an ACR > 7 mg/g was strongly associated with the metabolic syndrome, high blood pressure, and elevated alanine aminotransferase levels. It may be useful to consider ACR > 7 mg/g as an associated sign of the presence of metabolic syndrome in women with PCOS. (Endocr Pract. 2008;14: 193-200)     

13-cis-Retinoic Acid (Isotretinoin) Unmasking of Clinical Polycystic Ovary Syndrome

ObjectiveTo describe a woman in whom polycystic ovary syndrome manifested during treatment with 13-cis-retinoic acid (isotretinoin) for severe acne.MethodsWe present serial clinical and biochemical findings for a several month period before, during, and after therapy with 13-cis-retinoic acid. Homeostasis model assessment of insulin resistance was calculated from the fasting plasma glucose and insulin concentrations.ResultsA 32-year-old woman with some past features suggestive of metabolic syndrome took 13-cis-retinoic acid for 20 weeks as treatment of nodulocystic acne. During therapy, amenorrhea and hirsutism developed, as well as biochemical evidence of hyperandrogenemia and insulin resistance, as assessed by homeostasis model assessment of insulin resistance. After discontinuation of the medication, both the clinical features and the laboratory abnormalities resolved.Conclusion13-cis-Retinoic acid likely causes insulin resistance through its role as an agonist of retinoid A and X receptors. Although elevated levels of serum triglycerides are well documented with use of this drug, to the best of our knowledge this is the first report of a patient in whom polycystic ovary syndrome, a condition known to be associated with insulin resistance, manifested during isotretinoin therapy. (Endocr Pract. 2007;13: 776-779)     

Association Study of Gene LPP in Women with Polycystic Ovary Syndrome

Background

Previous genome-wide association study (GWAS) of polycystic ovary syndrome (PCOS) in Han Chinese population has found that SNPs in LPP gene were nominally significant in PCOS patients (P around 10E-05). Replication of the GWAS was applied to further confirm the relationship between LPP gene and PCOS.

Methods

Three polymorphisms of LPP gene (rs715790, rs4449306, rs6782041) were selected and replicated in additional 1132 PCOS cases and 1142 controls. Genotyping of LPP gene was carried out by Taqman-MGB method.

Results

In rs715790, the allele frequency is significantly different between the PCOS group and the control group. Meta-analysis showed that the allele frequencies of the three SNPs rs715790 (P_meta = 1.89E-05, OR = 1.23), rs4449306 (P_meta = 3.0E-04, OR = 1.10), rs6782041 (P_meta = 2.0E-04, OR = 1.09), were significantly different between PCOS cases and controls.

Conclusions

Our results suggest that LPP gene might be a novel candidate for PCOS.     

高雄激素相关的慢性炎症与多囊卵巢综合征的研究进展

多囊卵巢综合征是育龄妇女常见的慢性炎症代谢性疾病,70%以上患者出现高雄激素血症。下丘脑-垂体-性腺相关激素是月经周期和卵巢活动的调节器,脑神经元分泌的Kisspeptin、褪黑素通过下丘脑-垂体-卵巢轴调节Gn RH神经元AMH、Gn RH的表达,卵巢促性腺激素、雄激素水平增高,有利于慢性炎症的形成,促进多囊卵巢综合征的发生发展。本文综述了近几年多囊卵巢综合征中雄激素相关的慢性炎症研究,并根据相关研究提出了一些见解,希望能为多囊卵巢综合征的研究提供一些新的思路。     

肥胖对多囊卵巢综合征的影响

多囊卵巢综合征(Polycystic Ovary syndrome,PCOS)是女性最常见的生殖内分泌紊乱性疾病,严重影响女性健康。PCOS患者中有50%-70%存在肥胖,肥胖严重影响女性生殖功能,目前关于肥胖对PCOS影响的临床和实验研究很多,但是关于肥胖对PCOS女性生殖影响方面尚未进行系统的归纳总结,本文就肥胖影响PCOS女性生殖障碍的机制、肥胖对PCOS促排卵和辅助生殖技术的应用效果的影响等进行综述,目的是进一步明确肥胖本身及肥胖的治疗在PCOS生殖方面的影响,为PCOS的临床诊疗提供依据。     

Risk of Cardiovascular Events in Mothers of Women with Polycystic Ovary Syndrome

ObjectiveTo assess the prevalence of cardiovascular events in an older population of women with polycystic ovary syndrome (PCOS).MethodsWe took advantage of the high heritability of PCOS and determined the probable PCOS status of mothers of women with PCOS. The prevalence of cardiovascular events was then determined in these mothers with and without PCOS. In a single endocrine clinic, 308 women with PCOS were interviewed about their mothers’ medical history, and the mothers themselves were interviewed if available. The interview addressed menstrual history, fertility, clinical signs of hyperandrogenism, age at incident cardiovascular event, and age at death as reported by daughters. Presence of PCOS in the mothers was defined as a history of infertility, irregular menses, or clinical signs of hyperandrogenism. A cardiovascular event was defined as fatal or nonfatal myocardial infarction, any coronary intervention, angina necessitating emergency department visits, or a cerebrovascular event.ResultsThe mothers were predominantly postmenopausal. Among 182 interviewed (n = 157) or deceased (n = 25) mothers, 59 had probable PCOS. Cardiovascular events were more common (P = .011) among mothers with PCOS (11 of 59 or 18.6%) than among non-PCOS mothers (5 of 123 or 4.1%). After adjustments were made for age and race, probable PCOS was an independent predictor of cardiovascular events (odds ratio, 5.41; 95% confidence interval, 1.78 to 16.40). Cardiovascular events occurred at an early age in mothers of women with PCOS, particularly mothers with probable PCOS themselves.ConclusionPCOS-affected mothers of women with PCOS have a higher risk for cardiovascular events in comparison with non-PCOS mothers, and cardiovascular events appear to occur at an earlier than expected age in mothers with PCOS. (Endocr Pract. 2008;14:1084-1094)     

达必佳治疗91 例多囊卵巢综合征临床分析

目的：探索一种有效的药物治疗多囊卵巢综合征的方法。方法：19例多囊卵巢综合征的病人每月肌注长效促性腺激素释放激素类似物达必佳3,75mg,共三月。结果：19例病人治疗后LH均降低,LH／FSH正常,卵巢恢复正常大小,卵巢多囊征明显好转。结论：达必佳治疗多囊卵巢综合征是有效的。     

Serum Macroelement and Microelement Concentrations in Patients with Polycystic Ovary Syndrome: a Cross-Sectional Study

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine diseases. However, its pathogenesis is unclear. We aim to explore the potential relationships between serum macroelements/microelements and PCOS. A total of 1137 women were involved in the current study. PCOS was defined according to ESHRE/ASRM, and complete blood samples were collected. Serum macroelements (calcium and magnesium) and microelements (copper, zinc, and iron) were assayed through atomic absorption spectrophotometry. PCOS patients had significantly higher copper concentrations than patients without PCOS (P < 0.001). By contrast, PCOS patients had lower serum calcium levels than patients without PCOS (P < 0.001). No significant differences were observed in the levels of serum zinc, magnesium, and iron between PCOS and non-PCOS patients. PCOS patients with acne had higher magnesium levels than those without acne (P = 0.020), and PCOS patients with hirsutism had lower magnesium levels than those without hirsutism (P = 0.037). High serum copper and low calcium levels may be correlated with PCOS. Magnesium concentrations are correlated with acne and hirsutism in PCOS patients. These results provide clues to explore the mechanism of PCOS and guidance for element treatments in PCOS patients.     

Interleukin-6 Levels in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

Background

The change of serum interleukin-6(IL-6) levels in women with polycystic ovary syndrome (PCOS), as well as the relations between IL-6 levels and body mass index (BMI), insulin resistance(IR) and androgen status of PCOS patients, are not fully understood.

Methods

A literature search was performed in October 2015 using PubMed, Embase and the Cochrane Library databases to identify studies. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs).

Results

Twenty articles with 25 case-control studies included 1618 women (922 PCOS patients and 696 controls) were included in this study. IL-6 levels in controls were significantly lower than that of PCOS patients (SMD = 0.78, 95%CI = 0.41–1.16, P<0.001), with significant heterogeneity across studies (I² = 91% and P<0.001). Meta-regression analysis model indicated IR status was the main source of heterogeneity (P = 0.005). Results from group analysis suggested that high IL-6 levels in PCOS were significantly associated with Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR) ratio and total testosterone ratio (T ratio), and was found in both lean and obese women with PCOS. Cumulative meta-analysis results indicated the total effect size (SMD) had tend to be stable since 2012(0.79 to 0.92).

Conclusions

A high IL-6 level is not an intrinsic characteristic of PCOS, but may be a useful monitoring biomarker for the treatment of PCOS.     

Polycystic Ovary Syndrome,Depression, and Affective Disorders

ObjectiveTo assess the prevalence of depression and psychologic disorders and their effect on the quality of life in women with polycystic ovary syndrome.MethodsWe performed a PubMed search of major relevant articles published during the period from 1985 to 2009 dealing with polycystic ovary syndrome, associated psychologic morbidity, and the relationship to clinical and biochemical changes affecting the quality of life.ResultsIn patients with polycystic ovary syndrome, the presence of depression and allied disorders was frequently noted to diminish mental well-being, affect, and self-worth. The symptoms often associated with this syndrome, such as hirsutism, obesity, irregular menses, and subfertility, were a major source of psychologic morbidity. Obesity was the most prevalent cause of mental distress, whereas other features such as hirsutism and infertility were less well defined as major factors. Although the findings in some studies have been inconclusive, the presence of clinically significant eating disorders and a 7-fold increase in the suicide rate have been reported in women with polycystic ovary syndrome.ConclusionWomen with polycystic ovary syndrome have a high risk for depression and affective disorders that impair their quality of life. The presence of obesity, eating disorders, hirsutism, poor self-image, and a significant suicide rate makes evaluation of their emotional state an integral part of their assessment and treatment. For adequate treatment of the woman with polycystic ovary syndrome, a biopsychosocial model should be used, with all aspects of the patient’s mental status considered before implementation of optimal intervention. (Endocr Pract. 2009;15:475-482)     

Impact of Treatment with Metformin on Adipocytokines in Patients with Polycystic Ovary Syndrome: A Meta-Analysis

Background

Metformin is effective for the treatment of polycystic ovary syndrome, but conflicting results regarding its effect on adipocytokine levels (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving metformin treatment have been reported. To provide high-quality evidence about the effect of metformin treatment on adipocytokines in patients with polycystic ovary syndrome, relevant studies that assessed the levels of adipocytokines (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving treatment with metformin administration were reviewed and analyzed.

Methods

A literature search was conducted in the SCI, PUBMED, EMBASE, and Elsevier databases, and personal contact was made with the authors. Standard mean differences and 95% confidence intervals were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed.

Results

A total of 34 data sets were included in 4 different outcomes, involving 744 women with polycystic ovary syndrome and adipocytokine levels measured both before and after metformin administration. Metformin treatment was associated with significantly elevated serum adiponectin concentrations (standard mean differences [95% confidence interval], −0.43 [−0.75 to −0.11]) and decreased serum leptin concentrations (0.65 [0.26 to 1.04]), whereas no significant difference in resistin level (−0.01 [−0.49 to 0.45]) or visfatin level (−0.04 [−1.55 to 1.46]) was found.

Conclusions

Metformin administration was associated with increased serum adiponectin concentrations and decreased serum leptin levels. Further study is needed to elucidate whether this apparent effect decreases the incidence of type 2 diabetes and other metabolic diseases in patients with polycystic ovary syndrome later in life.     

Hypothalamic Neuroendocrine Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome: Effects of Low-Frequency Electro-Acupuncture

Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5α-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4–5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS.     

Pancreatic β-CELL Dysfunction in Polycystic Ovary Syndrome: the Role of Metformin

ObjectiveTo determine whether the administration of 6 months of daily metformin treatment in women with polycystic ovary syndrome (PCOS) would significantly improve pancreatic β-cell function as measured by an increase in the disposition index.MethodsWe enrolled women with PCOS from a private practice and from the Mount Sinai Hospital Endocrinology Clinic. All patients underwent frequently sampled intravenous glucose tolerance tests both on and off 500 to 1000 mg of twice daily metformin. Values of insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index were calculated for each test. The product of acute insulin response to glucose and insulin sensitivity yielded the disposition index and estimated the degree of β-cell compensation for insulin resistance.ResultsWe enrolled 14 women. We observed no significant changes in insulin sensitivity, glucose effectiveness, or acute insulin response to glucose, disposition index, or distributed glucose at time 0 before or after metformin treatment. Patients with PCOS treated with metformin remained statistically on the same hyperbolic curve, which is consistent with previously reported results of the effect of metformin on β-cell function. In contrast, the proportional change in disposition index correlated significantly with the proportional change in insulin sensitivity. Patients whose insulin sensitivity decreased after treatment showed a proportional decrease in disposition index, while patients whose insulin sensitivity increased showed a proportional increase in disposition index.ConclusionsOur findings suggest that acute insulin response to glucose does not proportionately change to match change in insulin sensitivity. Thus, there may be a β-cell defect in women with PCOS. (Endocr Pract. 2012;18:685-693)     

Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens.     

Blood Trace Element Concentrations in Polycystic Ovary Syndrome: Systematic Review and Meta-analysis

Polycystic ovary syndrome (PCOS) is a prevalent condition in women of reproductive age. PCOS is characterized by androgen excess and chronic anovulation and associated with low-grade inflammation and metabolic comorbidities. Some trace elements have been linked to pathophysiological mechanisms of oxidative stress and inflammation in different disorders. Therefore, we conducted a systematic review and meta-analysis of the available evidence regarding trace element concentrations in PCOS. We reviewed MEDLINE and EMBASE in search of case-control, cross-sectional, and cohort studies published until September 2015. Of 183 studies identified, six were selected for systematic review. All used the Rotterdam criteria for the diagnosis of PCOS. Two studies evaluating chromium and one assessing cobalt levels did not observe differences between PCOS and controls. Another study recorded similar nickel and vanadium levels between the groups, but lower selenium concentrations in women with PCOS compared to controls. Four studies were included in the random effects model meta-analysis, for a total of 264 PCOS and 151 control women. Copper levels were found to be higher in women with PCOS than in controls [mean difference 0.12 ppm (95 % CI 0.07; 0.17 ppm); I ²?=?0 %]. Manganese [mean difference 0.04 ppm (95 % CI ?0.05; 0.13 ppm); I ²?=?94.4 %] and zinc concentrations [mean difference 0.02 ppm (95 % CI ?0.12; 0.16 ppm); I ²?=?92.4 %] were similar between the groups. The present results suggest a relationship between increased copper concentration and PCOS. This systematic review and meta-analysis is registered in PROSPERO under number CRD42016034036.     

慢性炎症因子在多囊卵巢综合征中的作用机制

目的通过构建多囊卵巢综合征(PCOS)大鼠模型,探讨慢性炎症在PCOS发病过程中的作用机制。方法皮下埋置17-炔诺酮硅胶棒联合皮下注射HCG(Bogovich法)诱导PCOS大鼠模型。测定血清肿瘤坏死因子-α(TNF-α)、睾酮(T)空腹血糖(FPG)及空腹胰岛素(FIns)水平。结果模型组于6d形成PCO大鼠,24d构建PCOS大鼠模型成功。模型组血清TNF-α,T,FIns,FPG,胰岛素抵抗指数(Homa-IR)均高于对照组,胰岛素敏感指数(ISI)低于对照组。结论 Bogovich法诱导PCOS大鼠模型是研究PCOS发病机制的理想动物模型,慢性炎症可能诱导IR参与PCOS的发生与发展。