The pluripotential effects of hypolipidemic treatment for polycystic ovary syndrome (PCOS): dyslipidemia, cardiovascular risk factors and beyond

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenemia and polycystic ovaries. Clinical expression is determined by both genetic and environmental factors. Dyslipidemia is very common in lean as well as in obese women with PCOS and should be considered in the therapeutic management of the syndrome. Additionally to dyslipidemia, other risk factors for cardiovascular disease strongly associated with PCOS include insulin resistance, impaired glucose tolerance and metabolic syndrome. Therefore, the ideal therapeutic approach for PCOS would be multi targeted treatment ameliorating not only ovarian dysfunction but also cardiometabolic aspects, including dyslipidemia. Recently, a new era of hypolipidemic agents like statins has been initiated with regard to PCOS. The spectrum of statins' targets has been expanded and in vitro and in vivo studies have explored the specific effect of statins on androgen production, insulin resistance and inflammatory markers in PCOS. Statins are potentially promising therapeutic agents targeting hormonal and metabolic disturbances in PCOS, though conclusive results are still pending. Since several hormonal and metabolic aberrations characterizing this multifaceted syndrome cluster and interact with each other, their effects on the lipid profile are interweaving and the therapeutic modalities targeting dyslipidemia appear to have a more broad beneficial effect.     

Genetic Basis of Metabolic Abnormalities in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. The syndrome is frequently associated with an increased risk for insulin resistance and type 2 diabetes mellitus; obesity exacerbates insulin resistance and favors the progression from impaired glucose tolerance to diabetes in these patients. In young women, precocious pubarche and hyperinsulinemia are early manifestations of PCOS. The familial clustering of women with PCOS suggests that heredity is implicated in the origin of the syndrome. However, genetic approaches to its pathogenesis have been hampered by the heterogeneity of phenotypic features within families, and the lack of uniform criteria for diagnosis. Currently, PCOS is considered a polygenic trait that might result from the interaction of susceptibility and protective genomic variants under the influence of environmental factors. Both linkage analysis and association studies are valid tools for the study of the genetics of PCOS. Candidate genes for PCOS include those related to androgenic pathways and metabolic associations of the syndrome. More recently, genes encoding inflammatory cytokines have been identified as target genes for PCOS, as proinflammatory genotypes and phenotypes are also associated with obesity, insulin resistance, type 2 diabetes, PCOS, and increased cardiovascular risk. This paper reviews the candidate genes involved in the metabolic pathways that are altered in patients with PCOS. Despite a significant amount of research in this area, none of the genes studied so far has been identified as the PCOS susceptibility gene for the majority of cases. PCOS is the first component of the metabolic syndrome to be detected in many women, so the identification and correct diagnosis of PCOS has important preventive and therapeutic implications for the affected women and their families. In the future, new therapeutic approaches to PCOS will rely on knowing the genes, environmental influences, and etiologic mechanisms associated with the disorder.     

The obesogen tributyltin induces features of polycystic ovary syndrome (PCOS): a review

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by abnormal reproductive cycles, irregular ovulation, and hyperandrogenism. This complex disorder has its origins both within and outside the hypothalamic-pituitary-ovarian axis. Cardio-metabolic factors, such as obesity and insulin resistance, contribute to the manifestation of the PCOS phenotype. Polycystic ovary syndrome is one of the most common endocrine disorders among women of reproductive age. Growing evidence suggested an association between reproductive and metabolic features of PCOS and exposure to endocrine-disrupting chemicals (EDC), such as bisphenol A. Further, the environmental obesogen tributyltin (TBT) was shown to induce reproductive, metabolic and cardiovascular abnormalities resembling those found in women and animal models of PCOS. However, the causal link between TBT exposure and PCOS development remains unclear. The objective of this review was to summarize the most recent research findings on the potential association between TBT exposure and development of PCOS-like features in animal models and humans.     

Phenotypes and enviromental factors: their influence in PCOS

Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals.     

Insulin-sensitisers in the treatment of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine condition with reproductive and metabolic implications. In the current setting there is an evolving, yet inadequate, understanding of the pathophysiology, long-term health implications and ideal therapies for women with PCOS. Insulin resistance, secondary to both genetic and lifestyle factors, is integrally involved in the pathogenesis, the metabolic and clinical features and the long-term sequelae of PCOS in a majority of patients. Therapeutic strategies targeting insulin resistance ameliorate clinical features and may reduce long-term sequelae of PCOS, including diabetes. The main benefit of improved insulin resistance is to improve fertility and potentially to improve clinical features of hyperandrogenism and lower androgen levels. Insulin sensitisers also have the potential to delay the development of diabetes and cardiovascular disease in PCOS. Lifestyle therapy is indicated as the first intervention; however, metformin as an insulin sensitising agent has a role in first-line medical therapy in women with PCOS. Further research is needed to define the role of insulin sensitisers in PCOS and to determine the long-term risks and benefits of these therapies.     

Insulin-sensitisers in the treatment of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine condition with reproductive and metabolic implications. In the current setting there is an evolving, yet inadequate, understanding of the pathophysiology, long-term health implications and ideal therapies for women with PCOS. Insulin resistance, secondary to both genetic and lifestyle factors, is integrally involved in the pathogenesis, the metabolic and clinical features and the long-term sequelae of PCOS in a majority of patients. Therapeutic strategies targeting insulin resistance ameliorate clinical features and may reduce long-term sequelae of PCOS, including diabetes. The main benefit of improved insulin resistance is to improve fertility and potentially to improve clinical features of hyperandrogenism and lower androgen levels. Insulin sensitisers also have the potential to delay the development of diabetes and cardiovascular disease in PCOS. Lifestyle therapy is indicated as the first intervention; however, metformin as an insulin sensitising agent has a role in first-line medical therapy in women with PCOS. Further research is needed to define the role of insulin sensitisers in PCOS and to determine the long-term risks and benefits of these therapies.     

Vascular abnormalities and low-grade chronic inflammation in women with polycystic ovary syndrome: Relationships with insulin resistance,obesity and hyperandrogenemia

Polycystic ovary syndrome (PCOS) is possibly the most common endocrinopathy of reproductive age, characterized by hyperandrogenism and oligomenorrhea. Additionally, approximately one-third to one-half of all women and adolescent girls with PCOS tend to fulfill many of the metabolic syndrome criteria, and many view PCOS as a premetabolic syndrome condition, predisposing to a high risk for cardiovascular disease. Endothelial dysfunction, impaired arterial structure, or proinflammatory markers are early features of atherosclerosis, and can be used as surrogate indicators of future coronary artery disease in women with PCOS. However, as the latest studies show, these symptoms are the result of deleterious effects that cardiovascular risk factors, in particular insulin resistance and obesity, produce on the vascular wall, rather than to the presence of PCOS per se. The relationship between hyperandrogenemia and the risk of cardiovascular disease is controversial and needs to be clarified. Further research is warranted to understand the pathogenesis of cardiovascular disease in PCOS, and to identify subtypes of PCOS in which the presence of cardiovascular risk factors may result in increased cardiovascular events, leading to high morbidity or mortality rates caused by cardiovascular disease.     

Pharmacotherapeutic management of comorbid polycystic ovary syndrome and diabetes

ABSTRACT

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women. Insulin resistance and glucose intolerance are very prevalent metabolic complications in women with PCOS, especially in those presenting with weight excess. Therapeutic strategies targeting insulin resistance in PCOS are of interest because of their overall safety and their beneficial effects on metabolic and reproductive features.

Areas covered: The authors review systematically all of the available therapeutic interventions targeting insulin resistance and/or disturbances of glucose metabolism in women with PCOS.

Expert opinion: The diagnosis of glucose tolerance disorders in women with PCOS requires an oral glucose tolerance test. Strategies addressing weight excess and abdominal adiposity, from lifestyle modification to insulin sensitizers, may improve insulin resistance and glucose tolerance in women with PCOS. However, amelioration of signs and symptoms of PCOS usually requires the loss of large amounts of weight for it to be noticeable. Bariatric surgery has emerged as the most successful approach for obese patients with PCOS, because glucose intolerance, diabetes, and PCOS resolve in most cases through follow-ups. At present, the role of novel drugs targeting insulin resistance and/or diabetes such as inositols, berberine, resveratrol, and incretin-based therapies are yet to be properly established.     

Treatment of polycystic ovary syndrome with insulin-lowering agents

Early diagnosis and therapy of the underlying insulin resistance of heritable polycystic ovary syndrome (PCOS), often manifested at menarche, facilitate the reduction and/or reversal of the reproductive and metabolic morbidity of PCOS, as well as reduce the risk factors for cardiovascular disease. PCOS is characterised by oligoamenorrhoea, clinical and biochemical hyperandrogenism, infertility, recurrent miscarriage, insulin resistance, hyperinsulinaemia, gestational diabetes, impaired glucose tolerance, Type 2 diabetes, morbid obesity, hypertension, hypofibrinolysis, hypertriglyceridaemia, low levels of high density lipoprotein-cholesterol and a sevenfold risk increase in cardiovascular disease. Insulin sensitising-lowering agents reduce insulin resistance and hyperinsulinaemia, reverse PCOS endocrinopathy and ameliorate the reproductive, metabolic and cardiovascular morbidity of the disorder. The largest literature on the subject discusses metformin. Improved pregnancy outcomes in women with PCOS receiving metformin may be attributed to its ability to reduce insulin resistance, hyperinsulinaemia and hypofibrinolytic plasminogen activator inhibitor activity by the enhancement of folliculogenesis and improvement of oocyte quality.     

Ceftaroline fosamil for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection

Early diagnosis and therapy of the underlying insulin resistance of heritable polycystic ovary syndrome (PCOS), often manifested at menarche, facilitate the reduction and/or reversal of the reproductive and metabolic morbidity of PCOS, as well as reduce the risk factors for cardiovascular disease. PCOS is characterised by oligoamenorrhoea, clinical and biochemical hyperandrogenism, infertility, recurrent miscarriage, insulin resistance, hyperinsulinaemia, gestational diabetes, impaired glucose tolerance, Type 2 diabetes, morbid obesity, hypertension, hypofibrinolysis, hypertriglyceridaemia, low levels of high density lipoprotein-cholesterol and a sevenfold risk increase in cardiovascular disease. Insulin sensitising-lowering agents reduce insulin resistance and hyperinsulinaemia, reverse PCOS endocrinopathy and ameliorate the reproductive, metabolic and cardiovascular morbidity of the disorder. The largest literature on the subject discusses metformin. Improved pregnancy outcomes in women with PCOS receiving metformin may be attributed to its ability to reduce insulin resistance, hyperinsulinaemia and hypofibrinolytic plasminogen activator inhibitor activity by the enhancement of folliculogenesis and improvement of oocyte quality.     

Updates on the myo-inositol plus D-chiro-inositol combined therapy in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. It is characterized by chronic anovulation, hyperandrogenism, and insulin resistance. It is the main cause of infertility due to the menstrual dysfunction and metabolic disorders. Women with PCOS also have an increased cardiovascular risk because of dyslipidemia and insulin resistance. So far, we have a lot of information about the etiology of PCOS, and many steps forward have been made about the diagnosis of this syndrome, but there is still no certainty about the therapy. Myo-inositol (MI) and D-chiro-inositol, two inositol stereoisomers, have been proven to be effective in PCOS treatment. However, only MI has been shown to have beneficial effects on reproductive function, whereas the administration of MI/D-chiro-inositol, in the physiological plasma ratio (i.e., 40:1) ensures better clinical results, such as the reduction of insulin resistance, androgens’ blood levels, cardiovascular risk and regularization of menstrual cycle with spontaneous ovulation.     

线粒体功能障碍与多囊卵巢综合征相关性的研究进展

多囊卵巢综合征（PCOS）是以生殖、内分泌和代谢异常为特征的常见疾病,其发病机制不明确。线粒体在能量代谢等多种生命活动中发挥关键作用,线粒体相关调控机制受损可导致其功能障碍,常见有线粒体基因组异常、能量代谢异常、氧化应激、钙稳态失衡、生物合成减少、细胞增殖凋亡失衡、线粒体动力学紊乱及自噬异常等。PCOS作为多种疾病的相关因素被广泛认可,线粒体基因调控和功能紊乱与PCOS的发生发展密切相关,基于线粒体功能修复的治疗方法是PCOS治疗的新方向。该文就线粒体功能障碍与PCOS相关性的研究进展进行综述。     

Advances in the treatment of polycystic ovary syndrome

Current treatment of polycystic ovary syndrome (PCOS) in women is essentially symptomatic. However, there is growing evidence that this disorder is an evolving condition and that it may be associated with major medical outcomes later in life. As a consequence, effective treatments should be instituted as soon as PCOS is diagnosed. Insulin resistance with associated hyperinsulinaemia and increased luteinising hormone (LH)-dependent androgen secretion from the ovary seem to play a central role in the pathogenesis of PCOS. Accordingly, the effects of attenuation of hyper-insulinaemia, LH excess or hyperandrogenism were recently assessed, with promising results. A consistent finding was that attenuation of insulin resistance and hyperinsulinaemia may correct the entire spectrum of endocrine, metabolic and reproductive abnormalities of PCOS in many subjects.     

多囊卵巢综合征与胰岛素抵抗

多囊卵巢综合征（PCOS）作为一种生殖内分泌紊乱性疾病,与胰岛素抵抗（IR）关系密切,可引起空腹血糖异常、糖耐量异常、高血压、血脂紊乱等代谢综合征的表现,增加2型糖尿病、妊娠糖尿病、心血管疾病与子宫内膜癌发生的危险性。本文从流行病学、临床表现、分子机制、PCOS患者不同组织中的IR表现及药物治疗等方面综述PCOS与IR的关系。     

多囊卵巢综合征与致密性髂骨炎相关性的临床研究

目的探讨多囊卵巢综合征与致密性髂骨炎的关系。方法连续收集本中心2012年7月至2012年11月558例行子宫输卵管造影（HsG）的不孕症患者,并排除有干扰性因素的患者如肥胖、结核和风湿等。临床诊断为多囊卵巢综合征（Polycystic ovary syndrome,PCOS）为A组,余下为B组。观察两组不孕症患者罹患致密性髂骨炎（0steitis condensans ilii,OCI）的情况。结果患有多囊卵巢综合征A组230例,造影过程中表现为典型致密性髂骨炎X线特点的患者有53（23．04％）例,其中仅有两例为单侧髂骨耳状关节部分骨质密度增高。无PCOS的B组328例,造影过程中表现为典型致密性髂骨炎x线特点的患者有16（4．88％）例,均为双侧髂骨耳状关节部分骨质密度增高。多囊卵巢综合征患者患有致密性髂骨炎的几率明显高于B组,差异有统计学意义（P〈0．05）。结论多囊卵巢综合征患者自身代谢内分泌的紊乱可能对骨代谢产生一定影响。     

多囊卵巢综合征患者抗苗勒氏管激素与相关临床指标的关系

【摘要】目的 探讨多囊卵巢综合征（PCOS）患者抗苗勒氏管激素（AMH）水平与体质指数（BMI）、激素及代谢指标的关系。方法 将60例PCOS患者和30例不孕患者分为PCOS组1（BMI≥25 kg/m2）、PCOS组2（BMI<25 kg/m2）,每组30例;对照组1（BMI≥25 kg/m2）、对照组2（BMI<25 kg/m2）,每组15例。空腹采血并测定血清卵泡刺激素（FSH）、黄体生成素（LH）、雌二醇、睾酮、血清AMH、空腹血糖和空腹血清胰岛素,计算稳态模型胰岛素抵抗指数（HOMA-IR）,比较4 组的上述指标并进行相关性分析。结果 PCOS 组AMH、LH、LH/FSH、睾酮、空腹胰岛素及 HOMA-IR均高于对照组,PCOS组1和PCOS组2 AMH差异无统计学意义,PCOS组1 LH、LH/FSH低于PCOS组2,空腹胰岛素、HOMA-IR高于PCOS组2。PCOS组AMH与BMI无相关性。PCOS组1 AMH与睾酮、空腹血糖、空腹胰岛素、 HOMA-IR呈正相关,与雌二醇、FSH呈负相关;PCOS组2 AMH与LH、LH/FSH、睾酮呈正相关（均P < 0.05）。结论 PCOS患者血清AMH显著升高,其升高与体质量无关,可能与激素紊乱和糖代谢紊乱有关。     

Polycystic ovary syndrome: treatment strategies and management

Background: The polycystic ovary syndrome (PCOS) is possibly the most common endocrine disorder in premenopausal women, with prevalences in the 6 – 7% range reported worldwide. Although PCOS is primarily a disorder of androgen excess, affected women frequently present with abdominal adiposity and insulin resistance, explaining the association of PCOS with metabolic comorbidities and an increased cardiovascular risk. Abdominal adiposity, and very especially the compensatory hyperinsulinism resulting from insulin resistance, further contribute to hyperandrogenism. These pathophysiological mechanisms must be considered when deciding the optimal therapy for PCOS patients. Objective: To review the impact of the current approaches to the treatment of PCOS on the metabolic associations and the cardiovascular risk of these women. Methods: Review of published studies addressing the effects of different treatment strategies of PCOS. Results: The resolution of PCOS after the marked and sustained weight loss attained after bariatric surgery makes this therapeutic option a first-line strategy in women presenting with severe obesity. In patients with lesser grades of obesity who desire fertility, a short trial of metformin, followed by classic ovulation induction and/or assisted reproductive techniques in case pregnancy is not achieved in a few months, is a reasonable approach. If fertility is not an immediate concern, third generation oral contraceptive pills containing a neutral or antiandrogenic progestin remains the drug of choice, considering their efficacy, their excellent tolerability, and their overall metabolic safety. Conclusion: Strategies targeting obesity and abdominal adiposity, insulin resistance and hyperandrogenism, alone or in combination, are effective in ameliorating the signs and symptoms of hyperandrogenism while improving the metabolic comorbidities and the cardiovascular risk of these patients in most cases.     

葡萄糖转运体-4与多囊卵巢综合征相关性的研究进展

葡萄糖转运体(GLUTs)是外周组织摄取葡萄糖的主要载体,目前发现共有14个成员。其中GLUT4被称为胰岛素敏感性转运蛋白,广泛分布于骨骼肌、心肌、脂肪等组织,是胰岛素作用下发挥主要转运能力的载体蛋白,与多种代谢性疾病密切相关。多囊卵巢综合征(polycystic ovary syndrome,PCOS)是一种以闭经、不孕、肥胖、多毛为主要特征的内分泌紊乱性疾病,其发病机制不详。据报道,GLUT4与PCOS的生殖功能障碍及代谢异常密切相关,本综述主要概括GLUT4表达和功能变化与PCOS病理状态的关系,及这些改变对疾病产生的影响,并初步探讨了相关机制。     

The role of obesity in the development of polycystic ovary syndrome

Polycystic Ovary Syndrome (PCOS) is one of the common endocrine diseases that affects women in their reproductive age. PCOS has diverse clinical implications that include reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, cardiovascular diseases) and psychological features (increased anxiety, depression and worsened quality of life). The exact patho-physiology of PCOS is complex and remains largely unclear. The prevalence of PCOS is estimated at 4-18%, depending on diverse factors discussed ahead. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and body weight. During the last decades, obesity and excess weight are major chronic diseases all around the word. Obesity increases some features of PCOS such as hyperandrogenism, hirsutism, infertility and pregnancy complications. Both obesity and insulin resistance increase diabetes mellitus type 2 and cardiovascular diseases. Moreover, obesity impairs insulin resistance and exacerbates reproductive and metabolic features of PCOS. It is well known that obesity is associated with anovulation, pregnancy loss and late pregnancy complications (pre-eclampsia, gestational diabetes). Obesity in PCOS is also linked to failure or delayed response to the various treatments including clomiphene citrate, gonadotropins and laparoscopic ovarian diathermy. It has been reported that, after losing as little as 5 % of initial body weight obese women with PCOS improved spontaneous ovulation rates and spontaneous pregnancy. Therefore, the weight loss prior to conception improves live birth rate in obese women with or without PCOS. The treatment of obesity may include lifestyle therapy (diet and exercise), pharmacological treatment and bariatric surgery. In summary, weight loss is considered the first-line therapy in obese women with PCOS. In the present review, the consequence and treatment of obesity in women with PCOS are discussed.     

Soy but not bisphenol A (BPA) induces hallmarks of polycystic ovary syndrome (PCOS) and related metabolic co-morbidities in rats

Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder with a prevalence as high as 8–15% depending on ethnicity and the diagnostic criteria employed. The basic pathophysiology and mode of inheritance remain unclear, but environmental factors such as diet, stress and chemical exposures are thought to be contributory. Developmental exposure to endocrine disrupting compounds (EDCs) have been hypothesized to exacerbate risk, in part because PCOS hallmarks and associated metabolic co-morbidities can be reliably induced in animal models by perinatal androgen exposure. Here we show that lifetime exposure to a soy diet, containing endocrine active phytoestrogens, but not developmental exposure (gestational day 6–lactational day 40) to the endocrine disrupting monomer bisphenol A (BPA), can induce key features of PCOS in the rat; results which support the hypothesis that hormonally active diets may contribute to risk when consumed throughout gestation and post-natal life.