The metabolic syndrome in polycystic ovary syndrome

Much overlap is present between the polycystic ovary syndrome (PCOS) and the metabolic syndrome. This article reviews the existing data regarding the prevalence, characteristics, and treatment of the metabolic syndrome in women with PCOS. The prevalence of the metabolic syndrome in PCOS is approximately 43-47%, a rate 2-fold higher than that for women in the general population. High body mass index and low serum HDL cholesterol are the most frequently occurring components of the metabolic syndrome in PCOS. The pathogenic link between the metabolic syndrome and PCOS is most likely insulin resistance. Therefore, the presence of the metabolic syndrome in PCOS suggests a greater degree of insulin resistance compared to PCOS without the metabolic syndrome. Obesity, atherogenic dyslipidemia, hypertension, impaired fasting glucose/impaired glucose tolerance, and vascular abnormalities are all common metabolic abnormalities present in PCOS. Lifestyle modification has proven benefit and pharmacological therapy with insulin-sensitizing agents has potential benefit in the treatment of the metabolic syndrome in women with PCOS.     

Role of insulin resistance on fertility – Focus on polycystic ovary syndrome

Several lines of evidence show that gonadal functions and insulin sensitivity display multifaceted relationships, which extend far beyond the well-known association between polycystic ovary syndrome (PCOS), obesity, and metabolic syndrome. In this brief review, we will summarize the main findings showing the pathophysiological role of insulin resistance in impairing reproductive functions. Extreme phenotypes of severe insulin resistance, due to primary defects in insulin receptor or to lipodystrophy syndromes, provide unique opportunities for the modeling of interactions between insulin signaling and ovarian endocrine functions. In addition, recent studies further suggest that common forms of dysfunctional adiposity, as well as altered production of adipokines, could underlie important pathophysiological links between metabolic syndrome and infertility.     

A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a "hyperplastic" theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the syndrome.     

Polycystic ovarian syndrome and insulin resistance: implications for estrogen use in premenopausal and postmenopausal women

Polycystic ovarian syndrome (PCOS) is the most frequent endocrine disorder of reproductive age women, affecting an estimated 8-10% of all women in this age group or approximately six million women. Further, women with PCOS continue to manifest the metabolic alterations inherent in the insulin resistance syndrome after menopause, rendering them more susceptible to type 2 diabetes and cardiovascular disease. Aging and obesity further contribute to these risks. Since estrogen-containing therapy is commonly used for menstrual regulation in premenopausal women with PCOS, it is important to evaluate the possible consequences of hormonal therapy on subsequent metabolic and cardiovascular risk. In postmenopausal women, a consensus regarding the appropriate role of estrogen replacement therapy is currently in evolution. By examining the effects of estrogen with or without progesterone on insulin resistance, insight may be gained about the risk/benefit ratio of this therapy in the subset of women with insulin resistance, PCOS, and type 2 diabetes. The goal of this review, then, is to examine the known effects of estrogen on insulin sensitivity and its implications for cardiovascular and metabolic risk.     

Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is the most common reproductive endocrinopathy of women during their childbearing years. A significant degree of controversy exists regarding the etiology of this syndrome, but there is a growing consensus that the key features include insulin resistance, androgen excess, and abnormal gonadotropin dynamics. Familial and genetic factors cause predisposition to PCOS. Insulin resistance and adiposity put women with PCOS at a higher risk for diabetes, hypertension, dyslipidemia, and cardiovascular disease. Even though the adverse health consequences associated with PCOS are substantial, most women are not aware of these risks. Early recognition and treatment of metabolic sequelae should be the main focus of clinicians. Lifestyle modifications, mainly a balanced diet, weight loss, and regular exercise, are of utmost importance. On the pharmacologic front, various therapies including metformin, thiazolidinediones, and others appear to be very promising in the management of cardiometabolic aspects of PCOS.     

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.     

Adult polycystic ovary syndrome begins in childhood

Polycystic ovary syndrome (PCOS) frequently presents during adolescence and is the commonest cause of menstrual irregularity and hirsutism. The characteristic endocrine abnormalities include hypersecretion of androgens and LH. Metabolic dysfunction is also a feature of many young women with PCOS. Hyperinsulinaemia and insulin resistance, which can be regarded as an exaggeration of the normal metabolic changes that occur during puberty, are further amplified by obesity. The aetiology of PCOS is uncertain but there is evidence for a primary abnormality of ovarian androgen production which is manifest at puberty but may have its origins in childhood or even during fetal development.     

Probiotics and Pregnancy

Polycystic ovary syndrome is a frequent disorder in women of reproductive age that consists of a heterogeneous combination of hyperandrogenism, chronic anovulation, and polycystic ovaries. Hyperandrogenism and anovulation are clearly linked to insulin resistance and compensatory hyperinsulinism, with an ovarian androgenic hyperresponsiveness to circulating insulin. Evidence is increasing that suggests that lipotoxicity, which is a key mechanism in the development of insulin resistance and type 2 diabetes, could also explain the androgen overproduction. During adolescence, diagnosis of polycystic ovarian syndrome (PCOS) may be difficult but is of importance because PCOS increases future risk of type 2 diabetes and metabolic complications. Metabolic perturbations begin early in adolescence and also exist in adolescent relatives of women with PCOS, even before clinical signs of PCOS. Screening for impaired glucose tolerance or type 2 diabetes is also important in this population, and treatment should focus on PCOS clinical manifestations as well as long-term metabolic risk.     

Mitochondrial DNA copy number in peripheral blood in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and various metabolic diseases; and recently, elevated oxidative stress has been detected in PCOS. Mitochondria are highly susceptible to oxidative damage; and disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis, leading to the hypothesis that abnormalities in markers of mitochondrial metabolism are related to PCOS. We compared mitochondrial DNA (mtDNA) copy number in women with and without PCOS and investigated the independent relationship between mtDNA copy number and PCOS after adjustment for metabolic parameters. Fifty women with PCOS and 60 age- and body mass index–matched healthy women were studied. Mitochondrial DNA copy numbers as well as metabolic parameters and indices of insulin resistance were assessed. Mitochondrial DNA copy numbers were significantly lower in women with PCOS (P < .01). In the PCOS group, mtDNA copy number was negatively correlated with indices of insulin resistance, waist circumference, and triglyceride levels and positively correlated with sex hormone–binding globulin levels. In multiple logistic regression, the corresponding odds ratios (95% confidence interval) for PCOS by log-transformed mtDNA copy number and homeostasis model assessment of insulin resistance were 0.15 (0.04-0.56) and 4.26 (1.43-12.68), respectively, after adjustment for age, body mass index, and other metabolic factors. We report decreased mtDNA copy numbers in PCOS patients in relation to controls independently of insulin resistance or other metabolic factors. The pathophysiological and clinical significance of this finding requires further investigation.     

Hemostatic abnormalities and relationships to metabolic and hormonal status in polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS), diagnosed based on hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, is one of the most common disorders of reproductive-aged females. Etiology includes both genetic and environmental/lifestyle factors contributing to both insulin resistance and hyperandrogenism. Clinically, PCOS has reproductive, psychological, and metabolic features, the latter predisposing to cardiovascular disease (CVD). Hemostatic abnormalities have an association with and a demonstrated pathophysiological role in CVD in non-PCOS populations but have not been adequately explored in PCOS. This review focuses on the hemostatic system in PCOS, exploring also relationships to the metabolic and hormonal abnormalities of the syndrome, and aims to identify whether hemostatic abnormalities are present as potential contributors to increased cardiovascular risk. Ultimately, this area may reveal preventative and therapeutic opportunities, which could improve the cardiovascular health of women with PCOS.     

Inherited lipodystrophies and the metabolic syndrome

Lipodystrophies represent a heterogeneous group of diseases characterized by an abnormal subcutaneous fat distribution, the extent of which can vary from localized, to partial, to generalized lipoatrophy. Whereas partial and generalized lipodystrophies are each associated with metabolic abnormalities, the localized form is not. These metabolic changes include insulin resistance with type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed HDL cholesterol, liver steatosis and hypertension. Affected women are often hirsute and this can be associated with the presence of polycystic ovarian syndrome (PCOS). Most of these clinical features are present to some extent in patients with the common metabolic syndrome. As the prevalence of metabolic syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder may often be overlooked with the affected patient diagnosed as merely being 'yet' another case of metabolic syndrome. In this article, we draw attention to the importance of recognizing patients with lipodystrophy who present with metabolic abnormalities, as both the diagnostic as well as the therapeutic approach of these patients differ profoundly from patients with the metabolic syndrome.     

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.     

Obesity and the polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.     

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.     

多囊卵巢综合征α2-HS-糖蛋白水平测定及其意义

目的通过比较多囊卵巢综合征(PCOS)患者与正常对照人群血清中α2-HS-糖蛋白(AHSG)的水平,探讨AHSG在PCOS患者中的临床作用。方法随机选取2007年1～12月在广西医科大学第一附属医院妇科门诊就诊的PCOS患者34例为PCOS组,以月经正常的非PCOS患者27例为对照组。测量其身高、体质量、腰围、臀围、性激素水平、空腹血糖、空腹胰岛素和血脂,计算出体质量指数(BMI)、腰臀比(WHR)、稳态模型的胰岛素抵抗指数(IRI)。ELISA法检测所有研究对象血清中的AHSG水平,并将AHSG与所测临床指标进行多因素分析。结果 P-COS组患者血清AHSG水平高于对照组(P<0.05);IRI值高于对照组(P<0.05)。血清AHSG浓度与IRI、BMI、WHR呈正相关性(P<0.05)。结论 PCOS患者与AHSG、IRI有密切关系,AHSG参与了PCOS患者代谢综合症的发生发展,肥胖的PCOS患者更容易发生胰岛素抵抗。     

Insulin action in the polycystic ovary syndrome.

Research on insulin action in PCOS has been intensive after the identification of insulin resistance as a feature of the syndrome in 1980. It is now clear that PCOS is a metabolic as well as a reproductive disorder and an important cause of type 2 diabetes mellitus in women. The cellular and molecular mechanisms of insulin resistance in PCOS are distinct from those in other insulin resistance syndromes. Elucidating these mechanisms promises to provide considerable insight into insulin receptor signal specificity. Conversely, insulin resistance is now known to have an important role in the pathogenesis of the reproductive disturbances of PCOS. It is thought that one or several genetic defects may cause both the insulin resistance and reproductive abnormalities characteristic of PCOS.     

Polycystic ovary syndrome: syndrome XX?

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic and reproductive disorder. It is associated with substantial defects in insulin action and secretion that confer a markedly increased risk for type 2 diabetes mellitus. Insulin resistance modifies reproductive function both by the direct actions of insulin on steroidogenesis and by disruption of insulin signaling pathways in the central nervous system. These insights have led to a new therapy for PCOS with insulin-sensitizing agents. Hyperandrogenemia and insulin resistance cluster in PCOS families, consistent with a genetic susceptibility to these abnormalities. There is evidence for both linkage and association of the hyperandrogenemia phenotype with an allele of a marker locus on chromosome 19, in the region of the gene encoding the insulin receptor.     

Adipose Tissue Dysfunction in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among premenopausal women. In addition to infertility, PCOS is associated with insulin resistance, features of the metabolic syndrome, and an increased risk for diabetes. Similar to individuals with metabolic syndrome, many women with PCOS manifest abdominal obesity, suggesting adipose tissue dysfunction. The adipose tissue of women with PCOS is characterized by hypertrophic adipocytes and impairments in lipolysis and insulin action. The expression and secretion of a wide variety of adipokines implicated in insulin resistance, including adiponectin and others, are also altered in PCOS. Collectively, the available data indicate that adipose tissue dysfunction plays a central role in the metabolic abnormalities observed in PCOS. Whether these abnormalities are primary or secondary to hyperandrogenism or other abnormalities in PCOS is not yet known.     

Polycystic ovary syndrome and its developmental origins

The prenatal testosterone (T)-treated adult female rhesus monkey is one animal model of polycystic ovary syndrome (PCOS) in women, with early prenatal T excess programming a permanent PCOS-like phenotype characterized by luteinizing hormone (LH) hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess from increased abdominal adiposity. These combined reproductive and metabolic abnormalities are associated with ovarian hyperandrogenism and follicular arrest in adulthood, as well as premature follicle differentiation and impaired embryo development during gonadotropin therapy for in vitro fertilization (IVF). A second animal model for PCOS, the prenatal T-treated sheep also is characterized by LH hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback, persistent follicles and insulin resistance, but also is associated with intrauterine growth retardation and compensatory growth after birth. The ability of prenatal T excess in both species to alter the developmental trajectory of multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programs target tissue differentiation, raising the possibility that T excess in human fetal development promotes PCOS in adulthood. Such a hypothesis must include data from clinical studies of PCOS women to clarify the homology between these PCOS-like animal models and PCOS per se in reproductive and metabolic function. Future studies should develop new clinical strategies that improve pregnancy outcome and minimize pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus as well as minimize transgenerational susceptibility to adult PCOS and its metabolic derangements in male close relatives.     

Insulin-lowering agents in the management of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism, and metabolic disturbances. Women with PCOS should be evaluated for cardiovascular risk factors, such as lipid profile and blood pressure. Modification of diet and lifestyle should be suggested to those who are obese. Several insulin-lowering agents have been tested in the management of PCOS. In particular, metformin is the only drug currently in widespread clinical use for treatment of PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of menstrual cycle, reduction in hyperandrogenism and in cardiovascular risk factors, and improvement in response to therapies for induction of ovulation.