Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome

in Reproduction
View More View Less
  • 1 Gynecological Endocrinology Unit, Laboratory of Molecular Endocrinology, Department of Diagnostic Methods, Division of Endocrinology, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, CEP 90035‐003 Porto Alegre, Rio Grande do Sul, Brazil

Polycystic ovary syndrome (PCOS), a complex condition that affects women of reproductive age, is characterized by ovulatory dysfunction and androgen excess. Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia, and face increased risk of type 2 diabetes. PCOS is closely linked to functional derangements in adipose tissue. Adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by women with PCOS, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance. Hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on metabolism and on sex steroid secretion. Chronic low-grade inflammation in PCOS is also related to hyperandrogenism and to the hypertrophy of adipocytes, causing compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and altered secretion of cytokines. Lifestyle changes are the first-line intervention for reducing metabolic risks in PCOS and the addition of an insulin-sensitizing drug might be required. Nevertheless, there is not sufficient evidence in favor of any specific pharmacologic therapies to directly oppose inflammation. Further studies are warranted to identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

Abstract

Polycystic ovary syndrome (PCOS), a complex condition that affects women of reproductive age, is characterized by ovulatory dysfunction and androgen excess. Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia, and face increased risk of type 2 diabetes. PCOS is closely linked to functional derangements in adipose tissue. Adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by women with PCOS, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance. Hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on metabolism and on sex steroid secretion. Chronic low-grade inflammation in PCOS is also related to hyperandrogenism and to the hypertrophy of adipocytes, causing compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and altered secretion of cytokines. Lifestyle changes are the first-line intervention for reducing metabolic risks in PCOS and the addition of an insulin-sensitizing drug might be required. Nevertheless, there is not sufficient evidence in favor of any specific pharmacologic therapies to directly oppose inflammation. Further studies are warranted to identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

Introduction

Polycystic ovary syndrome (PCOS) is a complex condition that affects women of reproductive age and is characterized by ovulatory dysfunction and androgen excess (Graff et al. 2013). The prevalence of PCOS is high, ranging from 9% according to NIH criteria to 18% according to Rotterdam criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004, March et al. 2010). Current evidence indicates that PCOS is a multifactorial disease, and that individual susceptibility is determined by genetic and environmental risk factors (Jones et al. 2012).

Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia (Toscani et al. 2007, Wiltgen & Spritzer 2010, Wild et al. 2011, Lim et al. 2012), and are at higher risk for type 2 diabetes compared with normal women of the same age (Legro et al. 1999). Data of 240 patients fulfilling the Rotterdam criteria for PCOS show an increased prevalence of obesity, insulin resistance, metabolic syndrome, and diabetes in comparison with control groups (Fig. 1; Wiltgen & Spritzer 2010). These metabolic abnormalities have been primarily linked to insulin resistance (Ciaraldi et al. 2009). In addition, hyperandrogenism, a consequence of increased androgen secretion by the ovaries, may be worsened by a state of insulin resistance. In fact, in PCOS, the insulin resistance-compensatory hyperinsulinemia has a co-gonadotropic effect, stimulating P450c17α enzymatic activity in thecal cells, contributing to androgen secretion. Both insulin resistance and hyperandrogenism influence adipose cell function (Corbould 2007). However, while insulin resistance promotes the differentiation of preadipocytes to adipocytes, especially in the abdominal area, facilitating the development of visceral-type obesity in women with PCOS (Barbosa-Desongles et al. 2013), the role of androgens is not as clear. In fact, there is evidence that androgens may inhibit preadipocyte differentiation in nonobese healthy women (Chazenbalk et al. 2013). Adipose tissue is a dynamic organ, secreting hormones, adipokines, and cytokines, and contributing to endocrine processes that regulate glucose and fatty metabolism, immunity, inflammatory response, and reproduction, among other functions (Lecke et al. 2011a, 2013a).

Figure 1
Figure 1

Prevalence of obesity, insulin resistance, and diabetes in classical and ovulatory PCOS, isolated hirsutism and control groups. PCOS: biochemical and/or clinical hyperandrogenism and ovulatory dysfunction with or without polycystic ovaries (classic PCOS group; n=195); H+PCO: hirsute women with normal androgen levels, ovulatory cycles, and polycystic ovaries (ovulatory PCOS group, n=45); IH: normal androgen levels, ovulatory cycles and normal ovarian volume (isolated hirsutism group, n=68); control: nonhirsute women in the same age range, with proven ovulatory cycles (control group, n=25). DM2, type 2 diabetes mellitus; HOMA, homeostatic model assessment index; IGT, impaired glucose tolerance; LAP, lipid accumulation product; MS, metabolic syndrome. Modified from Wiltgen & Spritzer (2010).

Citation: REPRODUCTION 149, 5; 10.1530/REP-14-0435

The etiopathogenesis of PCOS is not yet well established, but it has been suggested that hyperandrogenism, central obesity, and insulin resistance act together in the development of the syndrome (Glintborg & Andersen 2010). Moreover, emerging data suggest that adipose tissue dysfunction and chronic low-grade inflammation may be involved in the development of metabolic and reproductive dysfunctions of PCOS.

Disturbed adipose tissue function in PCOS

Adipose tissue is regarded as an endocrine organ that plays a major role in the regulation of glucose and lipid metabolism and storage, with impact on energy expenditure, inflammation and immunity, cardiovascular function, and reproduction, among other functions (Lecke et al. 2013a). Adipocytes are the major, but not the sole constituent of adipose tissue, which also contains fibroblasts, macrophages, stromal cells, monocytes (MNCs), and preadipocytes, and is a rich source of stem cells (Vázquez-Vela et al. 2008). Adipogenesis develops as a two-step process: undifferentiated mesenchymal cells convert into preadipocytes, which then differentiate to lipid-filled adipocytes (Lefterova & Lazar 2009).

The location and distribution of adipose tissue are function related. In general, subcutaneous (SC) adipose tissue has been associated with temperature regulation and with specific female and male fat distribution patterns. In turn, visceral or omental (OM) adipose tissue is responsible for maintaining organs in the normal position, occupying the spaces between them (Vázquez-Vela et al. 2008). Greater SC and mainly OM mass and adipocyte size have been linked to hepatic and peripheral insulin resistance as well as metabolic comorbidities such as dyslipidemia, decreased glucose tolerance, diabetes, and hypertension (Vázquez-Vela et al. 2008). In addition, under metabolic stress, adipose tissue expansion is altered, causing hypertrophy rather than hyperplasia (Villa & Pratley 2011). Adipose hypertrophy is associated with lower number of adipocytes than adipose hyperplasia. In fact, the pathophysiological mechanism of fat expansion in hyperplasia is less deleterious, being the adipocytes still functional. In turn, hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids (Baglioni et al. 2012).

Moreover, OM adipose tissue in women with PCOS may present specific functional derangements, related to increased cathecolamine-induced lipolysis and possibly linked to altered stoichiometric properties of the adipose protein kinase hormone-sensitive lipase, as suggested by Ek et al. (2002).

PCOS is closely linked to functional derangements in adipose tissue, although the mechanisms underlying this association are not well established. As described for metabolic stress, adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by PCOS women, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance (Barber & Franks 2013; Fig. 2). Moreover, evidence suggests that reduced catecholamine-induced lipolysis in SC adipocytes may also be associated with adipocyte hypertrophy in PCOS (Villa & Pratley 2011).

Figure 2
Figure 2

Proposed model of inter-relationship among adipose tissue hypertrophy, insulin resistance, and androgen excess in PCOS. Hypertrophic adipose tissue induced by hyperandrogenism and/or weight gain release several adipokines and inflammatory mediators that contribute with insulin resistance/hyperinsulinemia, which promotes additional increase in androgen secretion by the ovary. ↑, Increased; ↔, no alteration; ↓, decreased; CRP, C-reactive protein; IL6, interleukin 6; NFκB, nuclear factor kappa B; TNFα, tumor necrosis factor alpha; CV, cardiovascular. Modified from Escobar-Morreale et al. (2007).

Citation: REPRODUCTION 149, 5; 10.1530/REP-14-0435

Adipokines in PCOS

Adipokines are the product of adipocyte secretion and could be the link between adiposity and PCOS. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on sex steroid secretion. Table 1 presents the most common adipokines studied in PCOS.

Table 1

Main adipokines currently investigated in PCOS.

AdipokineLocal secretionActionFindings in PCOSa
AdiponectinSecreted by adipose tissue and placentaImproves insulin sensitivity, promotes fatty acid oxidation, lowers inflammationDecreased or unchanged circulating levels
LeptinSecreted by adipose tissue, gastric epithelium, hypothalamus, placenta, and gonadsRegulates insulin signaling; implicated in appetite and weight regulationIncreased with body fat content in both overweight/obese PCOS women and in BMI-matched controls
ResistinSecreted by adipose tissue, monocyte, and macrophagesInvolved in lipid metabolism, insulin resistance, and diabetesIncreased or unchanged
VisfatinAdipose tissue, liver, muscle, bone marrow, lymphocytes, trophoblast, and fetal membranesInsulin-mimetic actions; role in insulin sensitivity and secretionIncreased or unchanged
RBP4Secreted by adipocytesInvolved in obesity, glucose metabolism, and insulin resistanceIncreased or unchanged serum levels, higher RBP4 protein levels and RBP4 mRNA expression in adipose tissue in PCOS
PEDFSecreted by adipocytesInvolved in obesity, glucose metabolism, and insulin resistanceUnchanged circulating levels, and PEDF mRNA found in subcutaneous adipose tissue

PCOS, polycystic ovary syndrome; PEDF, pigment epithelium-derived factor; RBP4, retinol-binding protein 4.

vs BMI-matched controls.

Leptin and adiponectin

It is well recognized that leptin is implicated in appetite and weight regulation by acting on the central axis of satiety, while adiponectin acts as an insulin sensitivity enhancer and an anti-atherogenic mediator, promoting fatty acid oxidation in insulin responder tissues and decreasing the number of inflammatory and adhesion molecules within the vascular wall (Pepene 2012, Dong & Ren 2014). We have previously reported that leptin serum levels are higher in overweight/obese PCOS women and also in BMI-matched controls than in normal-weight PCOS and controls (Spritzer et al. 2005, Lecke et al. 2011a, 2013b). In fact, most published studies about circulating leptin levels in PCOS and controls, including adolescents and pre- and post-menopausal women, stratified or not by BMI, have demonstrated that circulating leptin levels are associated with the amount of body fat, being significantly increased in overweight/obese subgroups, independently of the presence of PCOS (Plati et al. 2010, Tan et al. 2013). Increased leptin levels observed in obese PCOS (or non-PCOS) are probably secondary to a leptin-resistance state and linked to insulin resistance and metabolic comorbidities (Dong & Ren 2014).

Concerning adiponectin in PCOS, current data from the literature are still not conclusive. While our group and other authors found similar circulating adiponectin levels in BMI-matched PCOS and control women (Lecke et al. 2011a, 2013b, Pepene 2012, Tan et al. 2013), other studies have reported lower adiponectin levels in PCOS women in comparison with healthy controls, independently of BMI: a meta-analysis including more than 3500 subjects (PCOS women and healthy BMI-matched controls) of various ages with different levels of total testosterone and insulin found that adiponectin was significantly lower in PCOS (Li et al. 2014). Reduced adiponectin levels appear to play a role in promoting insulin resistance increasing triglycerides and small and dense LDL particles (Tan et al. 2006a). The discrepancies among published data may be related to variations in demographic and ethnic features, to the design and sample size of each study, or to methodological differences in the analytical determination of adiponectin. Using high-molecular weight-active adiponectin forms instead of total adiponectin could increase the accuracy of assessments of the relationship between adiponectin and, insulin sensitivity, and glucose tolerance in PCOS.

Few data are available in the literature regarding adipokine gene and protein expression in adipose tissue in PCOS, with differences between OM and SC patterns. Leptin and adiponectin are the best studied adipokines in the context of PCOS. As previously reported by us, leptin gene expression was higher in SC fat of overweight/obese PCOS in comparison with normal-weight controls. In contrast, adiponectin gene expression did not differ between obese and non-obese subgroups (Lecke et al. 2011a, 2013b). These data are in agreement with other reports regarding PCOS and control populations (Wang et al. 2012). Tan et al. (2006a) showed an increase in both adiponectin receptors – 1 and 2 – in isolated SC adipocytes of PCOS, as well as an upregulation of adiponectin receptors by sex steroids, suggesting a role for sex steroids in the regulation of adipose tissue function. Seow et al. (2009) reported that hyperinsulinemia downregulates the gene expression of adiponectin receptors in OM adipose tissue from nonobese PCOS in comparison with age- and BMI-matched healthy controls. These results may indicate a putative sexual dimorphism in some adipose tissue functions, mainly related to differences in androgen levels, which are increased in PCOS.

Resistin

Resistin is an adipokine involved in lipid metabolism, insulin resistance, and diabetes – common metabolic disorders in PCOS women. Resistin also modulate inflammation and may be related to cardiovascular risk. As recently reported, serum resistin levels seemed to be similar in European PCOS and non-PCOS counterparts, irrespective of BMI-status (Pepene 2012). However, serum resistin levels were found to be higher in obese and non-obese Chinese PCOS groups in comparison with controls, suggesting that resistin may be implicated in the regulation of insulin resistance in this PCOS ethnic group (Wang et al. 2010). In terms of gene expression, Seow et al. (2004) reported data on resistin mRNA expression in isolated adipocytes from OM adipose tissue of Taiwanese women with PCOS and age- and weight-matched non-PCOS. An overexpression of the resistin gene was found in adipocytes from PCOS, suggesting that resistin may play a role in the local pathogenesis of PCOS.

Visfatin

Visfatin has been implicated in insulin-mimetic actions, but the relationship between visfatin and obesity has not been clarified (Chen et al. 2013). Studies have shown higher visfatin levels in PCOS women as compared with controls of similar BMI and age (Plati et al. 2010, Yildiz et al. 2010, Cekmez et al. 2011). In those studies, PCOS patients were more insulin resistant than control women, leading to the suggestion that visfatin could be a specific marker of insulin sensitivity, possibly contributing to the pathogenesis of PCOS (Plati et al. 2010, Yildiz et al. 2010, Cekmez et al. 2011). In contrast, recent studies do not confirm the association of visfatin with PCOS. Tan et al. (2013) found similar visfatin values in a cross-sectional study involving obese PCOS and controls. Lajunen et al. (2012) also found similar visfatin levels in PCOS patients and non-obese, normal weight controls of same age, but observed a correlation of visfatin with proinflammatory markers, such as white blood cell (WBC) counts and C-reactive protein (CRP). In addition, Pepene (2012) found that increased visfatin levels could predict endothelial dysfunction in Romanian PCOS patients, independently of obesity status and insulin resistance. Concerning visfatin gene expression in PCOS, Tan et al. (2006b) reported a significant upregulation of visfatin mRNA in both SC and OM adipose tissues in PCOS women from the UK – a finding confirmed by Seow et al. (2011), who showed that visfatin mRNA concentration in OM adipose tissue correlated in a positive manner with BMI and insulin resistance in Taiwanese PCOS women and in age- and BMI-matched controls.

Retinol-binding protein 4 and pigment-epithelium derived factor

Retinol-binding protein 4 (RBP4) and pigment-epithelium derived factor (PEDF) also seem to be involved with obesity, glucose metabolism, and insulin resistance. Yildiz et al. (2010) showed similar RBP4 serum levels in lean Asian PCOS and weight-matched controls. Conversely, Yildizhan et al. (2011) reported significantly higher RBP4 and homeostatic model assessment (HOMA) index in obese PCOS women as compared with nonobese PCOS and control groups. Tan et al. (2007) investigated the expression of RBP4 in SC and OM adipose tissue in overweight women with PCOS and weight-matched controls, and assessed the effects of sex steroids on RBP4 expression in SC and OM fat explants. RBP4 protein levels were significantly higher in PCOS SC and OM adipose tissue. Estradiol significantly increased RBP4 mRNA expression in explants of SC and OM adipose tissue.

Data from our group on circulating PEDF levels reported no difference between obese women with PCOS and age- and BMI-matched controls (Lecke et al. 2013a), in accordance with a previous study with obese PCOS patients (Joham et al. 2012). In normal-weight PCOS Chinese women, higher PEDF values were associated with insulin resistance (Yang et al. 2011) and ultra-sensitive CRP (Cheng et al. 2013). Recently, we have reported that PEDF mRNA in SC adipose tissue of PCOS women was similar to that found in age- and BMI-matched controls. In addition, PEDF mRNA was associated with metabolic risk factors in PCOS (Lecke et al. 2013a).

Other adipokines

The role of adipokines in PCOS has not been completely established. Only inconclusive reports are available regarding some adipokines in PCOS, including a few reports about apelin, among others (Cekmez et al. 2011, Tan et al. 2013).

Sex steroids in adipose PCOS tissue

Adipose tissue also acts as a sex steroid supplier and modulator of hormone conversion (Blouin et al. 2009). Our group has studied aromatase (CYP19) gene expression in SC fat in PCOS women and controls without PCOS, demonstrating a positive correlation of SC CYP19 gene expression with systolic and diastolic blood pressure in PCOS (Lecke et al. 2011b). These results suggest that hyperandrogenism and hyperinsulinemia may be involved in the molecular mechanisms that activate aromatase mRNA transcription in abdominal fat tissue in PCOS. Wang et al. (2012) also inferred that an imbalanced androgen/estrogen ratio and altered progesterone levels may occur in SC fat, and that this disturbance could impact the normal function of adipose tissue. Their data showed significant abnormalities in enzyme gene expression in SC adipose tissue: mRNA of enzymes synthesizing testosterone and inactivating dihydrotestosterone (DHT) and progesterone was increased in PCOS vs matched controls (Wang et al. 2012).

In turn, Mlinar et al. (2011) reported no increase in 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) expression in OM and SC adipose tissue from Slovenian PCOS patients. These results differed from those reported by Li et al. (2013), who demonstrated increased 11βHSD1 mRNA in SC adipose tissue from obese women with PCOS in comparison with age- and BMI-matched controls, suggesting an increase in local active glucocorticoids, which, in turn could induce abnormal changes in cytokine production in adipose tissue.

Low-grade chronic inflammation in PCOS

Adipose tissue releases more than 50 cytokines, acute-phase proteins, and other inflammatory mediators, which have autocrine, paracrine, or systemic function and exert influence on glucose metabolism, energy balance, and proinflammatory or anti-inflammatory activities.

In PCOS, there is evidence of a low-grade chronic inflammation reflected by minor but significant increases in circulating levels of these mediators. These products have been linked to the development of metabolic and ovarian dysfunctions of the syndrome, such as insulin resistance, type 2 diabetes mellitus, cardiovascular risk factors, as well as hyperandrogenism and anovulation. Table 2 gives the markers of low-grade chronic inflammation studied in PCOS.

Table 2

Main inflammatory mediators currently investigated in PCOS.

Inflammatory mediatorLocal secretionActionFindings in PCOSa
CRPSynthesized by the liver in response to factors released by macrophages and adipocytes An acute-phase protein plays a role in acute and chronic inflammatory conditionsIncreased concentration
IL6 Expressed predominantly by adipocytes, but also by macrophages, endothelial cells, skeletal muscle, and fibroblastsRole in development of insulin resistanceIncreased or unchanged
Other IL (1β, 7, 17, and 18)Secreted by adipocytes and macrophages or vascular endothelial cellsRole in immune system, insulin signaling, thermogenesisPossibly increased; few studies available
TNFαMacrophages and adipose tissueAssociated with insulin resistance and stimulates lipolysisIncreased or unchanged
MCP1Adipose tissueIncreased macrophage recruitment in adipose tissue and inflammation; affects insulin sensitivityPossibly increased; few studies available
sE-selectin and sICAMExpressed by endothelial cells; sICAM also expressed by macrophages and lymphocytesProinflammatory effectsPossibly increased; few studies available

CRP, C-reactive protein; IL, interleukin; MCP1, monocyte chemotactic protein 1; PCOS, polycystic ovary syndrome; sE-selectin, soluble endothelial leukocyte adhesion molecule 1; sICAM, soluble intercellular adhesion molecule-1; TNFα, tumor necrosis factor alpha.

vs BMI-matched controls.

Low-grade chronic inflammation in women with PCOS was initially thought to be related to a higher concentration of serum tumor necrosis factor alpha (TNFα), independently of obesity (Gonzalez et al. 1999). However, more recently, a meta-analysis including nine studies has shown similar serum TNFα levels in 726 women with PCOS compared with 328 controls. The same meta-analysis also found no significant differences in serum interleukin 6 (IL6) levels in women with PCOS and controls (Escobar-Morreale et al. 2011). However, evidence of publication bias favoring studies underestimating the differences in the mediator's levels between the groups was observed in that meta-analysis (Escobar-Morreale et al. 2011).

Other studies report increased concentrations of some circulating cytokines, such as: IL18 (Escobar-Morreale et al. 2011), IL1β, IL7, and IL17 (Knebel et al. 2008); monocyte chemotactic protein 1 (MCP1); macrophage inflammatory protein 1α; macrophage migration inhibitory factor (Glintborg & Andersen 2010); matrix metalloproteinases 2 and 9 (Lewandowski et al. 2006); WBC counts (Orio et al. 2005); soluble intercellular adhesion molecule 1; and soluble endothelial leukocyte adhesion molecule 1 (sE-selectin) (Diamanti-Kandarakis et al. 2006).

Regarding serum CRP concentrations, Kelly et al. (2001) showed increased levels in women with PCOS relative to those in healthy women after adjustment for BMI. They also noted that serum CRP concentrations in both PCOS and controls correlated positively with the degree of obesity and inversely with insulin sensitivity, although not with total testosterone concentrations (Kelly et al. 2001). A meta-analysis including 2359 PCOS women and 1289 controls from 31 studies showed that CRP levels are 96% higher in PCOS patients than in healthy women, independently of obesity (Escobar-Morreale et al. 2011). In contrast, CRP levels in obese women are higher (>3.0 mg/dl) than that in normal-weight women (<3.0 mg/l), regardless of PCOS. Thus, CRP elevations attributed to PCOS are obscured by the presence of obesity, and are below the range to predict metabolic or cardiovascular risk (González 2012).

One of the mechanisms of chronic low-grade inflammation in PCOS is related to the hypertrophy of adipocytes that cause compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and, consequently, hypoxia (Fig. 2). Adipose tissue hypoxia stimulates the activation of nuclear factor kappa B – a family of transcription factors that regulates the expression of many critical genes involved in inflammatory reactions, inducing the production and release of many mediators, such as TNFα, ILs (IL1β, IL6, IL10, and IL18), transforming growth factor beta and interferon gamma, factors of the complement cascade, sVCAM1, and MCP1. This results in the recruitment of macrophages into the adipose tissue, maintaining the inflammatory state, impairing adipose cell function, and leading to cell necrosis (Deligeoroglou et al. 2012). IL6 and IL1β stimulate the synthesis of CRP in the liver and promote the uptake of lipids into MNC-derived foamy macrophages within atherosclerotic plaques. Thus, cytokines and acute-phase proteins play a crucial role in the pathophysiological mechanisms of vascular endothelium and the development of atherosclerosis (González et al. 2014a; Fig. 2).

Moreover, in PCOS women, glucose ingestion seems to activate oxidative stress and induce the release of TNFα, IL6, and CRP (González et al. 2014a, b). Similarly to obese subjects, lean women with PCOS present increased reactive oxygen species (ROS) generation compared with lean controls. ROS-induced oxidative stress is a known activator of NFκB, stimulating inflammatory reactions. These findings support the concept that glucose ingestion promotes an obesity-independent pro-atherogenic inflammation with a systemic response in PCOS. Insulin resistance and hyperandrogenism may be the result of inflammation triggered by hyperglycemia and contribute to atherogenesis in PCOS (González 2012, González et al. 2014a).

Low-grade chronic inflammation and its relationship with obesity, insulin resistance, and androgen secretion in PCOS

As mentioned, evidence suggests that PCOS is associated with a proinflammatory state, or else that the syndrome reflects a state of elevated sensitivity of inflammatory cells to cytokines and chemokines, with obesity and especially central adiposity being the most aggravating factors. The proinflammatory state of obesity contributes to the promotion of insulin resistance.

Insulin resistance in PCOS is caused by a post-receptor defect in insulin signaling, with increased serine phosphorylation and decreased protein kinase activity. This intrinsic defect in insulin receptor signaling in PCOS independently of obesity leads to hyperinsulinemia (Dunaif et al. 2001). In addition, TNFα mediates insulin resistance by causing increased serine phosphorylation of insulin receptor substrate 1 (IRS1) in insulin sensitive tissues. This leads to a decrease in the expression of GLUT4 – the insulin sensitive glucose transport protein (González 2012). This knowledge makes TNFα a potential candidate for initiating these molecular events in PCOS.

Hyperinsulinemia and hyperandrogenism are closely related to PCOS. Similarly, inflammation may be directly associated with androgen excess. Infiltration of ovarian tissue by MNC-derived macrophages and increased concentrations of TNFα and IL6 in follicular fluid have been previously demonstrated in women with PCOS. It is, therefore, possible to suppose that MNC recruited into the polycystic ovaries causes a local inflammatory response that stimulates CYP17, the ovarian steroidogenic enzyme, responsible for androgen production. TNFα may also stimulate the in vitro proliferation of androgen, producing theca cells (Glintborg & Andersen 2010).

Glucose induced-inflammation promotes ovarian androgen production and, conversely, hyperandrogenism leads to MNC activation and increases MNC sensitivity to glucose ingestion, inducing inflammation. Oral androgen administration in lean healthy women seem to increase fasting androgen receptor mRNA content and TNFα release, with further increases in response to glucose ingestion. Thus, hyperandrogenism may be the initiating factor of nutrient-induced inflammation and is independent of obesity or excess of abdominal adiposity (González et al. 2014b).

Metabolic repercussions of adipose tissue dysfunction in PCOS

Obesity and metabolic syndrome are more prevalent in PCOS than in nonPCOS women of the same age, and these clinical features are highly associated with adipose tissue dysfunction (Ciaraldi et al. 2009, Lim et al. 2012). In fact, abdominal adiposity, often present even in nonobese PCOS women, is a hallmark of insulin resistance. Thus, clinical markers of abdominal adiposity should be searched in each PCOS woman as a screening for higher metabolic risk and for prevention of metabolic comorbidities (Spritzer 2014). In this sense, we have previously shown that measuring waist circumference (WC), an easy procedure to estimate body fat distribution, in obese PCOS and healthy control women with the same BMI is strongly correlated with truncal fat mass estimated by dual-energy X-ray absorptiometry (Fig. 3; Toscani et al. 2007).

Figure 3
Figure 3

Association between abdominal adiposity measured by waist circumference and truncal fat mass estimated by dual-energy X-ray absorptiometry (DXA) in obese PCOS and BMI-matched controls. r=0.947; P=0.0001 (Pearson's correlation test). Modified from Toscani et al. (2007).

Citation: REPRODUCTION 149, 5; 10.1530/REP-14-0435

In addition, increased triglycerides, one of the components of the metabolic syndrome, have also been regarded as a surrogate marker of cardiovascular risk. Moreover, the lipid accumulation product (LAP), an ordinal scale combining WC and triglycerides, presents a positive association with HOMA index in PCOS, as we have already reported (Wiltgen et al. 2009). In that previous study, we found that a LAP index ≥34.5 could more accurately discriminate insulin resistance in PCOS women when compared with the cutoff points defined for BMI and WC. Actually, if PCOS is regarded as a multifactorial disease, it seems reasonable to use calculation tests with good predictive values such as LAP in order to facilitate clinical decision-making (Wiltgen et al. 2009).

Lifestyle changes are the first-line intervention for reducing metabolic risks, combining behavioral, dietary, and exercise management. Frequently, however, it will be necessary to add an insulin-sensitizing drug (Spritzer 2014). Metformin has been shown to ameliorate cardiometabolic profile by improving insulin sensitivity, lowering blood glucose and androgen levels, possibly through its effects on body weight (Nieuwenhuis-Ruifrok et al. 2009). These effects of metformin are more potent when it is combined with lifestyle interventions (Nieuwenhuis-Ruifrok et al. 2009). In contrast, there is no sufficient information to prescribe any pharmacologic therapies that directly oppose inflammation. Diets with low calorie intake are an integral part of the treatment, and diets with low glycemic index appear to be the best for PCOS patients (Graff et al. 2013). Only few studies have assessed the impact of weight loss on circulating adipokines in women with PCOS, showing a weight loss-related decrease on serum leptin levels both in PCOS and controls (Spanos et al. 2012, Rondanelli et al. 2014). In turn, no changes were found after weight loss on serum adiponectin, resistin, and visfatin levels (Spanos et al. 2012, Rondanelli et al. 2014).

Conclusions

Increasing evidence suggests that there is an important connection between androgen excess, hyperinsulinemia, and adipose tissue hypertrophy and dysfunction in PCOS. In fact, the high leptin serum levels found in obese PCOS seem to be associated rather with the content of body fat mass than with the presence of PCOS. Conversely, current data are still not conclusive in relation to adiponectin, resistin, visfatin, and other adipokines. A low-grade chronic inflammation state is also found in most PCOS women, and has been related to metabolic and ovarian abnormalities, including androgen excess secretion.

While lifestyle changes and individualized prescription of insulin-sensitizing drugs are consensual in managing PCOS, further studies are warranted to eventually identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This work was supported by grants from Brazilian National Institute of Hormones and Women's Health and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq INCT 573747/2008-3), Brazil.

References

  • Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, Borgogni E, Frontera S, Nesi G & Liotta F 2012 Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS ONE 7 e36569. (doi:10.1371/journal.pone.0036569)

    • Search Google Scholar
    • Export Citation
  • Barber TM & Franks S 2013 Adipocyte biology in polycystic ovary syndrome. Molecular and Cellular Endocrinology 373 6876. (doi:10.1016/j.mce.2012.10.010)

    • Search Google Scholar
    • Export Citation
  • Barbosa-Desongles A, Hernández C, Simó R & Selva DM 2013 Testosterone induces cell proliferation and cell cycle gene overexpression in human visceral preadipocytes. American Journal of Physiology. Cell Physiology 305 C355C359. (doi:10.1152/ajpcell.00019.2013)

    • Search Google Scholar
    • Export Citation
  • Blouin K, Nadeau M, Mailloux J, Daris M, Lebel S, Luu-The V & Tchernof A 2009 Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis. American Journal of Physiology. Endocrinology and Metabolism 296 E244E255. (doi:10.1152/ajpendo.00039.2008)

    • Search Google Scholar
    • Export Citation
  • Cekmez F, Cekmez Y, Pirgon O, Canpolat FE, Aydinöz S, Metin Ipcioglu O & Karademir F 2011 Evaluation of new adipocytokines and insulin resistance in adolescents with polycystic ovary syndrome. European Cytokine Network 22 3237. (doi:10.1684/ecn.2011.0279)

    • Search Google Scholar
    • Export Citation
  • Chazenbalk G, Singh P, Irge D, Shah A, Abbott DH & Dumesic DA 2013 Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78 920926. (doi:10.1016/j.steroids.2013.05.001)

    • Search Google Scholar
    • Export Citation
  • Chen X, Jia X, Qiao J, Guan Y & Kang J 2013 Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. Journal of Molecular Endocrinology 50 R21R37. (doi:10.1530/JME-12-0247)

    • Search Google Scholar
    • Export Citation
  • Cheng Q, Xia W, Yang S, Ye P, Mei M, Song Y, Luo M & Li Q 2013 Association of serum pigment epithelium-derived factor with high-sensitivity C-reactive protein in women with polycystic ovary syndrome. Journal of Endocrinological Investigation 36 632635. (doi:10.1007/BF03346755)

    • Search Google Scholar
    • Export Citation
  • Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ & Henry RR 2009 Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. Journal of Clinical Endocrinology and Metabolism 94 157163. (doi:10.1210/jc.2008-1492)

    • Search Google Scholar
    • Export Citation
  • Corbould A 2007 Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. Journal of Endocrinology 192 585594. (doi:10.1677/joe.1.07070)

    • Search Google Scholar
    • Export Citation
  • Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C & Creatsas G 2012 Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecological Endocrinology 28 974978. (doi:10.1677/joe.1.07070)

    • Search Google Scholar
    • Export Citation
  • Diamanti-Kandarakis E, Paterakis T, Alexandraki K, Piperi C, Aessopos A, Katsikis I, Katsilambros N, Kreatsas G & Panidis D 2006 Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Human Reproduction 21 14261431. (doi:10.1093/humrep/del003)

    • Search Google Scholar
    • Export Citation
  • Dong M & Ren J 2014 What fans the fire: insights into mechanisms of leptin in metabolic syndrome-associated heart diseases. Current Pharmaceutical Design 20 652658. (doi:10.2174/138161282004140213160930)

    • Search Google Scholar
    • Export Citation
  • Dunaif A, Wu X, Lee A & Diamanti-Kandarakis E 2001 Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). American Journal of Physiology. Endocrinology and Metabolism 281 E392E399.

    • Search Google Scholar
    • Export Citation
  • Ek I, Arner P, Rydén M, Holm C, Thörne A, Hoffstedt J & Wahrenberg H 2002 A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51 484492. (doi:10.2337/diabetes.51.2.484)

    • Search Google Scholar
    • Export Citation
  • Escobar-Morreale HF & San Millán JL 2007 Abdominal adiposity and the polycystic ovary syndrome. Trends in Endocrinology and Metabolism 18 266272. (doi:10.1016/j.tem.2007.07.003)

    • Search Google Scholar
    • Export Citation
  • Escobar-Morreale HF, Luque-Ramírez M & González F 2011 Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertility and Sterility 95 10481058.e1–2. (doi:10.1016/j.fertnstert.2010.11.036)

    • Search Google Scholar
    • Export Citation
  • Glintborg D & Andersen M 2010 An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome. Gynecological Endocrinology 26 281296. (doi:10.3109/09513590903247873)

    • Search Google Scholar
    • Export Citation
  • González F 2012 Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 77 300305. (doi:10.1016/j.steroids.2011.12.003)

    • Search Google Scholar
    • Export Citation
  • Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M & Dandona P 1999 Elevated serum levels of tumor necrosis factor α in normal-weight women with polycystic ovary syndrome. Metabolism 48 437441. (doi:10.1016/S0026-0495(99)90100-2)

    • Search Google Scholar
    • Export Citation
  • González F, Kirwan JP, Rote NS, Minium J & O'Leary VB 2014a Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome. Journal of Reproductive Immunology 103 3844. (doi:10.1016/j.jri.2014.01.001)

    • Search Google Scholar
    • Export Citation
  • González F, Sia CL, Bearson DM & Blair HE 2014b Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. Journal of Clinical Endocrinology and Metabolism 99 E848E854. (doi:10.1210/jc.2013-4109)

    • Search Google Scholar
    • Export Citation
  • Graff SK, Mário FM, Alves BC & Spritzer PM 2013 Dietary glycemic index is associated with less favorable anthropometric and metabolic profiles in polycystic ovary syndrome women with different phenotypes. Fertility and Sterility 100 10811088. (doi:10.1016/j.fertnstert.2013.06.005)

    • Search Google Scholar
    • Export Citation
  • Joham AE, Teede HJ, Hutchison SK, Stepto NK, Harrison CL, Strauss BJ, Paul E & Watt MJ 2012 Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training. Obesity 20 23902396. (doi:10.1038/oby.2012.135)

    • Search Google Scholar
    • Export Citation
  • Jones MR, Chua AK, Mengesha EA, Taylor KD, Chen YD, Li X, Krauss RM, Rotter JI, Legro RS & Azziz R 2012 Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids 77 317322. (doi:10.1016/j.steroids.2011.12.005)

    • Search Google Scholar
    • Export Citation
  • Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM & Sattar N 2001 Low grade chronic inflammation in women with polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism 86 24532455. (doi:10.1210/jcem.86.6.7580)

    • Search Google Scholar
    • Export Citation
  • Knebel B, Janssen OE, Hahn S, Jacob S, Gleich J, Kotzka J & Muller-Wieland D 2008 Increased low grade inflammatory serum markers in patients with polycystic ovary syndrome (PCOS) and their relationship to PPARγ gene variants. Experimental and Clinical Endocrinology & Diabetes 116 481486. (doi:10.1055/s-2008-1058085)

    • Search Google Scholar
    • Export Citation
  • Lajunen TK, Purhonen AK, Haapea M, Ruokonen A, Puukka K, Hartikainen AL, Savolainen MJ, Morin-Papunen L, Tapanainen JS & Franks S 2012 Full-length visfatin levels are associated with inflammation in women with polycystic ovary syndrome. European Journal of Clinical Investigation 42 321328. (doi:10.1111/j.1365-2362.2011.02586.x)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Mattei F, Morsch DM & Spritzer PM 2011a Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome. Fertility and Sterility 95 20442049. (doi:10.1016/j.fertnstert.2011.02.041)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch DM & Spritzer PM 2011b CYP19 gene expression in subcutaneous adipose tissue is associated with blood pressure in women with polycystic ovary syndrome. Steroids 76 13831388. (doi:10.1016/j.steroids.2011.07.008)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch D & Spritzer PM 2013a Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study. Reproductive Biology and Endocrinology 11 77. (doi:10.1186/1477-7827-11-77)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch DM & Spritzer PM 2013b Association between adipose tissue expression and serum levels of leptin and adiponectin in women with polycystic ovary syndrome. Genetics and Molecular Research 12 42924296. (doi:10.4238/2013.February.28.16)

    • Search Google Scholar
    • Export Citation
  • Lefterova MI & Lazar MA 2009 New developments in adipogenesis. Trends in Endocrinology and Metabolism 20 107114. (doi:10.1016/j.tem.2008.11.005)

    • Search Google Scholar
    • Export Citation
  • Legro RS, Kunselman AR, Dodson WC & Dunaif A 1999 Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Journal of Clinical Endocrinology and Metabolism 84 165169. (doi:10.1210/jcem.84.1.5393)

    • Search Google Scholar
    • Export Citation
  • Lewandowski KC, Komorowski J, O'Callaghan CJ, Tan BK, Chen J, Prelevic GM & Randeva HS 2006 Increased circulating levels of matrix metalloproteinase-2 and -9 in women with the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 91 11731177. (doi:10.1210/jc.2005-0648)

    • Search Google Scholar
    • Export Citation
  • Li S, Tao T, Wang L, Mao X, Zheng J, Zhao A & Liu W 2013 The expression of 11β-HSDs, GR, and H6PDH in subcutaneous adipose tissue from polycystic ovary syndrome subjects. Hormone and Metabolic Research 45 802807. (doi:10.1055/s-0033-1345186)

    • Search Google Scholar
    • Export Citation
  • Li S, Huang X, Zhong H, Peng Q, Chen S, Xie Y, Qin X & Qin A 2014 Low circulating adiponectin levels in women with polycystic ovary syndrome: an updated meta-analysis. Tumour Biology 35 39613973. (doi:10.1007/s13277-013-1595-0)

    • Search Google Scholar
    • Export Citation
  • Lim SS, Davies MJ, Norman RJ & Moran LJ 2012 Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Human Reproduction Update 18 618637. (doi:10.1093/humupd/dms030)

    • Search Google Scholar
    • Export Citation
  • March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ & Davies MJ 2010 The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction 25 544551. (doi:10.1093/humrep/dep399)

    • Search Google Scholar
    • Export Citation
  • Mlinar B, Marc J, Jensterle M, Bokal EV, Jerin A & Pfeifer M 2011 Expression of 11β-hydroxysteroid dehydrogenase type 1 in visceral and subcutaneous adipose tissues of patients with polycystic ovary syndrome is associated with adiposity. Journal of Steroid Biochemistry and Molecular Biology 123 127132. (doi:10.1016/j.jsbmb.2010.12.002)

    • Search Google Scholar
    • Export Citation
  • Nieuwenhuis-Ruifrok AE, Kuchenbecker WK, Hoek A, Middleton P & Norman RJ 2009 Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Human Reproduction Update 15 5768. (doi:10.1093/humupd/dmn043)

    • Search Google Scholar
    • Export Citation
  • Orio F, Palomba S, Cascella T, Di Biase S, Manguso F, Tauchmanovà L, Nardo LG, Labella D, Savastano S & Russo T 2005 The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 90 25. (doi:10.1210/jc.2004-0628)

    • Search Google Scholar
    • Export Citation
  • Pepene CE 2012 Evidence for visfatin as an independent predictor of endothelial dysfunction in polycystic ovary syndrome. Clinical Endocrinology 76 119125. (doi:10.1111/j.1365-2265.2011.04171.x)

    • Search Google Scholar
    • Export Citation
  • Plati E, Kouskouni E, Malamitsi-Puchner A, Boutsikou M, Kaparos G & Baka S 2010 Visfatin and leptin levels in women with polycystic ovaries undergoing ovarian stimulation. Fertility and Sterility 94 14511456. (doi:10.1016/j.fertnstert.2009.04.055)

    • Search Google Scholar
    • Export Citation
  • Rondanelli M, Perna S, Faliva N, Monteferrario M, Repaci E & Allieri F 2014 Focus on metabolic and nutritional correlates of polycystic ovary syndrome and update on nutritional management of these critical phenomena. Archives of Gynecology and Obstetrics 290 10791092. (doi:10.1007/s00404-014-3433-z)

    • Search Google Scholar
    • Export Citation
  • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome Fertility and Sterility 81 2004 1925. (doi:10.1016/j.fertnstert.2003.10.004)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Juan CC, Wu LY, Hsu YP, Yang WM, Tsai YL, Hwang JL & Ho LT 2004 Serum and adipocyte resistin in polycystic ovary syndrome with insulin resistance. Human Reproduction 19 4853. (doi:10.1093/humrep/deh010)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Tsai YL, Juan CC, Lin YH, Hwang JL & Ho LT 2009 Omental fat expression of adiponectin and adiponectin receptors in non-obese women with PCOS: a preliminary study. Reproductive Biomedicine Online 19 577582. (doi:10.1016/j.rbmo.2009.05.003)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Hwang JL, Wang PH, Ho LT & Juan CC 2011 Expression of visfatin mRNA in peripheral blood mononuclear cells is not correlated with visfatin mRNA in omental adipose tissue in women with polycystic ovary syndrome. Human Reproduction 26 28692873. (doi:10.1093/humrep/der267)

    • Search Google Scholar
    • Export Citation
  • Spanos N, Tziomalos K, Macut D, Koiou E, Kandaraki EA, Delkos D, Tsourdi E & Panidis D 2012 Adipokines, insulin resistance and hyperandrogenemia in obese patients with polycystic ovary syndrome: cross-sectional correlations and the effects of weight loss. Obesity Facts 5 495504. (doi:10.1159/000341579)

    • Search Google Scholar
    • Export Citation
  • Spritzer PM 2014 Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances. Arquivos Brasileiros de Endocrinologia e Metabologia 58 182187. (doi:10.1590/0004-2730000003051)

    • Search Google Scholar
    • Export Citation
  • Spritzer PM, Comim FV, Capp E & D'Avila A 2005 Influence of leptin, androgens and insulin sensitivity on increased GH response to clonidine in lean patients with polycystic ovary syndrome. Hormone and Metabolic Research 37 9498. (doi:10.1055/s-2005-861173)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR & Randeva HS 2006a Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome. Diabetologia 49 27232728. (doi:10.1007/s00125-006-0419-9)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR & Randeva HS 2006b Increased visfatin messenger ribonucleic acid and protein levels in adipose tissue and adipocytes in women with polycystic ovary syndrome: parallel increase in plasma visfatin. Journal of Clinical Endocrinology and Metabolism 91 50225028. (doi:10.1210/jc.2006-0936)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Lehnert H, Kennedy R & Randeva HS 2007 Raised serum, adipocyte, and adipose tissue retinol-binding protein 4 in overweight women with polycystic ovary syndrome: effects of gonadal and adrenal steroids. Journal of Clinical Endocrinology and Metabolism 92 27642772. (doi:10.1210/jc.2007-0091)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Hu J, Amar O, Mattu HS, Adya R, Patel V, Ramanjaneya M, Lehnert H & Randeva HS 2013 Metformin increases the novel adipokine cartonectin/CTRP3 in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 98 E1891E1900. (doi:10.1210/jc.2013-2227)

    • Search Google Scholar
    • Export Citation
  • Toscani M, Migliavacca R, Sisson de Castro JA & Spritzer PM 2007 Estimation of truncal adiposity using waist circumference or the sum of trunk skinfolds: a pilot study for insulin resistance screening in hirsute patients with or without polycystic ovary syndrome. Metabolism 56 992997. (doi:10.1016/j.metabol.2007.03.006)

    • Search Google Scholar
    • Export Citation
  • Vázquez-Vela ME, Torres N & Tovar AR 2008 White adipose tissue as endocrine organ and its role in obesity. Archives of Medical Research 39 715728. (doi:10.1016/j.arcmed.2008.09.005)

    • Search Google Scholar
    • Export Citation
  • Villa J & Pratley RE 2011 Adipose tissue dysfunction in polycystic ovary syndrome. Current Diabetes Reports 11 179184. (doi:10.1007/s11892-011-0189-8)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Xie X & Zhu W 2010 Serum adiponectin and resistin levels in patients with polycystic ovarian syndrome and their clinical implications. Journal of Huazhong University of Science and Technology. Medical Sciences 30 638642. (doi:10.1007/s11596-010-0556-8)

    • Search Google Scholar
    • Export Citation
  • Wang L, Li S, Zhao A, Tao T, Mao X, Zhang P & Liu W 2012 The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. Journal of Steroid Biochemistry and Molecular Biology 132 120126. (doi:10.1016/j.jsbmb.2012.02.003)

    • Search Google Scholar
    • Export Citation
  • Wild RA, Rizzo M, Clifton S & Carmina E 2011 Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertility and Sterility 95 10731079.e1–11. (doi:10.1016/j.fertnstert.2010.12.027)

    • Search Google Scholar
    • Export Citation
  • Wiltgen D & Spritzer PM 2010 Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. Fertility and Sterility 94 24932496. (doi:10.1016/j.fertnstert.2010.02.015)

    • Search Google Scholar
    • Export Citation
  • Wiltgen D, Benedetto IG, Mastella LS & Spritzer PM 2009 Lipid accumulation product index: a reliable marker of cardiovascular risk in polycystic ovary syndrome. Human Reproduction 24 17261731. (doi:10.1093/humrep/dep072)

    • Search Google Scholar
    • Export Citation
  • Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, Qing H, Xia W, Luo M & Mei M 2011 Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. Journal of Clinical Endocrinology and Metabolism 96 831836. (doi:10.1210/jc.2010-2140)

    • Search Google Scholar
    • Export Citation
  • Yildiz BO, Bozdag G, Otegen U, Harmanci A, Boynukalin K, Vural Z, Kirazli S & Yarali H 2010 Visfatin and retinol-binding protein 4 concentrations in lean, glucose-tolerant women with PCOS. Reproductive Biomedicine Online 20 150155. (doi:10.1016/j.rbmo.2009.10.016)

    • Search Google Scholar
    • Export Citation
  • Yildizhan R, Ilhan GA, Yildizhan B, Kolusari A, Adali E & Bugdayci G 2011 Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertility and Sterility 96 246250. (doi:10.1016/j.fertnstert.2011.04.073)

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 2802 900 104
PDF Downloads 1104 548 25
  • View in gallery

    Prevalence of obesity, insulin resistance, and diabetes in classical and ovulatory PCOS, isolated hirsutism and control groups. PCOS: biochemical and/or clinical hyperandrogenism and ovulatory dysfunction with or without polycystic ovaries (classic PCOS group; n=195); H+PCO: hirsute women with normal androgen levels, ovulatory cycles, and polycystic ovaries (ovulatory PCOS group, n=45); IH: normal androgen levels, ovulatory cycles and normal ovarian volume (isolated hirsutism group, n=68); control: nonhirsute women in the same age range, with proven ovulatory cycles (control group, n=25). DM2, type 2 diabetes mellitus; HOMA, homeostatic model assessment index; IGT, impaired glucose tolerance; LAP, lipid accumulation product; MS, metabolic syndrome. Modified from Wiltgen & Spritzer (2010).

  • View in gallery

    Proposed model of inter-relationship among adipose tissue hypertrophy, insulin resistance, and androgen excess in PCOS. Hypertrophic adipose tissue induced by hyperandrogenism and/or weight gain release several adipokines and inflammatory mediators that contribute with insulin resistance/hyperinsulinemia, which promotes additional increase in androgen secretion by the ovary. ↑, Increased; ↔, no alteration; ↓, decreased; CRP, C-reactive protein; IL6, interleukin 6; NFκB, nuclear factor kappa B; TNFα, tumor necrosis factor alpha; CV, cardiovascular. Modified from Escobar-Morreale et al. (2007).

  • View in gallery

    Association between abdominal adiposity measured by waist circumference and truncal fat mass estimated by dual-energy X-ray absorptiometry (DXA) in obese PCOS and BMI-matched controls. r=0.947; P=0.0001 (Pearson's correlation test). Modified from Toscani et al. (2007).

  • Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, Borgogni E, Frontera S, Nesi G & Liotta F 2012 Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS ONE 7 e36569. (doi:10.1371/journal.pone.0036569)

    • Search Google Scholar
    • Export Citation
  • Barber TM & Franks S 2013 Adipocyte biology in polycystic ovary syndrome. Molecular and Cellular Endocrinology 373 6876. (doi:10.1016/j.mce.2012.10.010)

    • Search Google Scholar
    • Export Citation
  • Barbosa-Desongles A, Hernández C, Simó R & Selva DM 2013 Testosterone induces cell proliferation and cell cycle gene overexpression in human visceral preadipocytes. American Journal of Physiology. Cell Physiology 305 C355C359. (doi:10.1152/ajpcell.00019.2013)

    • Search Google Scholar
    • Export Citation
  • Blouin K, Nadeau M, Mailloux J, Daris M, Lebel S, Luu-The V & Tchernof A 2009 Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis. American Journal of Physiology. Endocrinology and Metabolism 296 E244E255. (doi:10.1152/ajpendo.00039.2008)

    • Search Google Scholar
    • Export Citation
  • Cekmez F, Cekmez Y, Pirgon O, Canpolat FE, Aydinöz S, Metin Ipcioglu O & Karademir F 2011 Evaluation of new adipocytokines and insulin resistance in adolescents with polycystic ovary syndrome. European Cytokine Network 22 3237. (doi:10.1684/ecn.2011.0279)

    • Search Google Scholar
    • Export Citation
  • Chazenbalk G, Singh P, Irge D, Shah A, Abbott DH & Dumesic DA 2013 Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78 920926. (doi:10.1016/j.steroids.2013.05.001)

    • Search Google Scholar
    • Export Citation
  • Chen X, Jia X, Qiao J, Guan Y & Kang J 2013 Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. Journal of Molecular Endocrinology 50 R21R37. (doi:10.1530/JME-12-0247)

    • Search Google Scholar
    • Export Citation
  • Cheng Q, Xia W, Yang S, Ye P, Mei M, Song Y, Luo M & Li Q 2013 Association of serum pigment epithelium-derived factor with high-sensitivity C-reactive protein in women with polycystic ovary syndrome. Journal of Endocrinological Investigation 36 632635. (doi:10.1007/BF03346755)

    • Search Google Scholar
    • Export Citation
  • Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ & Henry RR 2009 Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. Journal of Clinical Endocrinology and Metabolism 94 157163. (doi:10.1210/jc.2008-1492)

    • Search Google Scholar
    • Export Citation
  • Corbould A 2007 Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. Journal of Endocrinology 192 585594. (doi:10.1677/joe.1.07070)

    • Search Google Scholar
    • Export Citation
  • Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C & Creatsas G 2012 Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecological Endocrinology 28 974978. (doi:10.1677/joe.1.07070)

    • Search Google Scholar
    • Export Citation
  • Diamanti-Kandarakis E, Paterakis T, Alexandraki K, Piperi C, Aessopos A, Katsikis I, Katsilambros N, Kreatsas G & Panidis D 2006 Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Human Reproduction 21 14261431. (doi:10.1093/humrep/del003)

    • Search Google Scholar
    • Export Citation
  • Dong M & Ren J 2014 What fans the fire: insights into mechanisms of leptin in metabolic syndrome-associated heart diseases. Current Pharmaceutical Design 20 652658. (doi:10.2174/138161282004140213160930)

    • Search Google Scholar
    • Export Citation
  • Dunaif A, Wu X, Lee A & Diamanti-Kandarakis E 2001 Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). American Journal of Physiology. Endocrinology and Metabolism 281 E392E399.

    • Search Google Scholar
    • Export Citation
  • Ek I, Arner P, Rydén M, Holm C, Thörne A, Hoffstedt J & Wahrenberg H 2002 A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51 484492. (doi:10.2337/diabetes.51.2.484)

    • Search Google Scholar
    • Export Citation
  • Escobar-Morreale HF & San Millán JL 2007 Abdominal adiposity and the polycystic ovary syndrome. Trends in Endocrinology and Metabolism 18 266272. (doi:10.1016/j.tem.2007.07.003)

    • Search Google Scholar
    • Export Citation
  • Escobar-Morreale HF, Luque-Ramírez M & González F 2011 Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertility and Sterility 95 10481058.e1–2. (doi:10.1016/j.fertnstert.2010.11.036)

    • Search Google Scholar
    • Export Citation
  • Glintborg D & Andersen M 2010 An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome. Gynecological Endocrinology 26 281296. (doi:10.3109/09513590903247873)

    • Search Google Scholar
    • Export Citation
  • González F 2012 Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 77 300305. (doi:10.1016/j.steroids.2011.12.003)

    • Search Google Scholar
    • Export Citation
  • Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M & Dandona P 1999 Elevated serum levels of tumor necrosis factor α in normal-weight women with polycystic ovary syndrome. Metabolism 48 437441. (doi:10.1016/S0026-0495(99)90100-2)

    • Search Google Scholar
    • Export Citation
  • González F, Kirwan JP, Rote NS, Minium J & O'Leary VB 2014a Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome. Journal of Reproductive Immunology 103 3844. (doi:10.1016/j.jri.2014.01.001)

    • Search Google Scholar
    • Export Citation
  • González F, Sia CL, Bearson DM & Blair HE 2014b Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. Journal of Clinical Endocrinology and Metabolism 99 E848E854. (doi:10.1210/jc.2013-4109)

    • Search Google Scholar
    • Export Citation
  • Graff SK, Mário FM, Alves BC & Spritzer PM 2013 Dietary glycemic index is associated with less favorable anthropometric and metabolic profiles in polycystic ovary syndrome women with different phenotypes. Fertility and Sterility 100 10811088. (doi:10.1016/j.fertnstert.2013.06.005)

    • Search Google Scholar
    • Export Citation
  • Joham AE, Teede HJ, Hutchison SK, Stepto NK, Harrison CL, Strauss BJ, Paul E & Watt MJ 2012 Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training. Obesity 20 23902396. (doi:10.1038/oby.2012.135)

    • Search Google Scholar
    • Export Citation
  • Jones MR, Chua AK, Mengesha EA, Taylor KD, Chen YD, Li X, Krauss RM, Rotter JI, Legro RS & Azziz R 2012 Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids 77 317322. (doi:10.1016/j.steroids.2011.12.005)

    • Search Google Scholar
    • Export Citation
  • Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM & Sattar N 2001 Low grade chronic inflammation in women with polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism 86 24532455. (doi:10.1210/jcem.86.6.7580)

    • Search Google Scholar
    • Export Citation
  • Knebel B, Janssen OE, Hahn S, Jacob S, Gleich J, Kotzka J & Muller-Wieland D 2008 Increased low grade inflammatory serum markers in patients with polycystic ovary syndrome (PCOS) and their relationship to PPARγ gene variants. Experimental and Clinical Endocrinology & Diabetes 116 481486. (doi:10.1055/s-2008-1058085)

    • Search Google Scholar
    • Export Citation
  • Lajunen TK, Purhonen AK, Haapea M, Ruokonen A, Puukka K, Hartikainen AL, Savolainen MJ, Morin-Papunen L, Tapanainen JS & Franks S 2012 Full-length visfatin levels are associated with inflammation in women with polycystic ovary syndrome. European Journal of Clinical Investigation 42 321328. (doi:10.1111/j.1365-2362.2011.02586.x)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Mattei F, Morsch DM & Spritzer PM 2011a Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome. Fertility and Sterility 95 20442049. (doi:10.1016/j.fertnstert.2011.02.041)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch DM & Spritzer PM 2011b CYP19 gene expression in subcutaneous adipose tissue is associated with blood pressure in women with polycystic ovary syndrome. Steroids 76 13831388. (doi:10.1016/j.steroids.2011.07.008)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch D & Spritzer PM 2013a Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study. Reproductive Biology and Endocrinology 11 77. (doi:10.1186/1477-7827-11-77)

    • Search Google Scholar
    • Export Citation
  • Lecke SB, Morsch DM & Spritzer PM 2013b Association between adipose tissue expression and serum levels of leptin and adiponectin in women with polycystic ovary syndrome. Genetics and Molecular Research 12 42924296. (doi:10.4238/2013.February.28.16)

    • Search Google Scholar
    • Export Citation
  • Lefterova MI & Lazar MA 2009 New developments in adipogenesis. Trends in Endocrinology and Metabolism 20 107114. (doi:10.1016/j.tem.2008.11.005)

    • Search Google Scholar
    • Export Citation
  • Legro RS, Kunselman AR, Dodson WC & Dunaif A 1999 Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Journal of Clinical Endocrinology and Metabolism 84 165169. (doi:10.1210/jcem.84.1.5393)

    • Search Google Scholar
    • Export Citation
  • Lewandowski KC, Komorowski J, O'Callaghan CJ, Tan BK, Chen J, Prelevic GM & Randeva HS 2006 Increased circulating levels of matrix metalloproteinase-2 and -9 in women with the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 91 11731177. (doi:10.1210/jc.2005-0648)

    • Search Google Scholar
    • Export Citation
  • Li S, Tao T, Wang L, Mao X, Zheng J, Zhao A & Liu W 2013 The expression of 11β-HSDs, GR, and H6PDH in subcutaneous adipose tissue from polycystic ovary syndrome subjects. Hormone and Metabolic Research 45 802807. (doi:10.1055/s-0033-1345186)

    • Search Google Scholar
    • Export Citation
  • Li S, Huang X, Zhong H, Peng Q, Chen S, Xie Y, Qin X & Qin A 2014 Low circulating adiponectin levels in women with polycystic ovary syndrome: an updated meta-analysis. Tumour Biology 35 39613973. (doi:10.1007/s13277-013-1595-0)

    • Search Google Scholar
    • Export Citation
  • Lim SS, Davies MJ, Norman RJ & Moran LJ 2012 Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Human Reproduction Update 18 618637. (doi:10.1093/humupd/dms030)

    • Search Google Scholar
    • Export Citation
  • March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ & Davies MJ 2010 The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction 25 544551. (doi:10.1093/humrep/dep399)

    • Search Google Scholar
    • Export Citation
  • Mlinar B, Marc J, Jensterle M, Bokal EV, Jerin A & Pfeifer M 2011 Expression of 11β-hydroxysteroid dehydrogenase type 1 in visceral and subcutaneous adipose tissues of patients with polycystic ovary syndrome is associated with adiposity. Journal of Steroid Biochemistry and Molecular Biology 123 127132. (doi:10.1016/j.jsbmb.2010.12.002)

    • Search Google Scholar
    • Export Citation
  • Nieuwenhuis-Ruifrok AE, Kuchenbecker WK, Hoek A, Middleton P & Norman RJ 2009 Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Human Reproduction Update 15 5768. (doi:10.1093/humupd/dmn043)

    • Search Google Scholar
    • Export Citation
  • Orio F, Palomba S, Cascella T, Di Biase S, Manguso F, Tauchmanovà L, Nardo LG, Labella D, Savastano S & Russo T 2005 The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 90 25. (doi:10.1210/jc.2004-0628)

    • Search Google Scholar
    • Export Citation
  • Pepene CE 2012 Evidence for visfatin as an independent predictor of endothelial dysfunction in polycystic ovary syndrome. Clinical Endocrinology 76 119125. (doi:10.1111/j.1365-2265.2011.04171.x)

    • Search Google Scholar
    • Export Citation
  • Plati E, Kouskouni E, Malamitsi-Puchner A, Boutsikou M, Kaparos G & Baka S 2010 Visfatin and leptin levels in women with polycystic ovaries undergoing ovarian stimulation. Fertility and Sterility 94 14511456. (doi:10.1016/j.fertnstert.2009.04.055)

    • Search Google Scholar
    • Export Citation
  • Rondanelli M, Perna S, Faliva N, Monteferrario M, Repaci E & Allieri F 2014 Focus on metabolic and nutritional correlates of polycystic ovary syndrome and update on nutritional management of these critical phenomena. Archives of Gynecology and Obstetrics 290 10791092. (doi:10.1007/s00404-014-3433-z)

    • Search Google Scholar
    • Export Citation
  • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome Fertility and Sterility 81 2004 1925. (doi:10.1016/j.fertnstert.2003.10.004)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Juan CC, Wu LY, Hsu YP, Yang WM, Tsai YL, Hwang JL & Ho LT 2004 Serum and adipocyte resistin in polycystic ovary syndrome with insulin resistance. Human Reproduction 19 4853. (doi:10.1093/humrep/deh010)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Tsai YL, Juan CC, Lin YH, Hwang JL & Ho LT 2009 Omental fat expression of adiponectin and adiponectin receptors in non-obese women with PCOS: a preliminary study. Reproductive Biomedicine Online 19 577582. (doi:10.1016/j.rbmo.2009.05.003)

    • Search Google Scholar
    • Export Citation
  • Seow KM, Hwang JL, Wang PH, Ho LT & Juan CC 2011 Expression of visfatin mRNA in peripheral blood mononuclear cells is not correlated with visfatin mRNA in omental adipose tissue in women with polycystic ovary syndrome. Human Reproduction 26 28692873. (doi:10.1093/humrep/der267)

    • Search Google Scholar
    • Export Citation
  • Spanos N, Tziomalos K, Macut D, Koiou E, Kandaraki EA, Delkos D, Tsourdi E & Panidis D 2012 Adipokines, insulin resistance and hyperandrogenemia in obese patients with polycystic ovary syndrome: cross-sectional correlations and the effects of weight loss. Obesity Facts 5 495504. (doi:10.1159/000341579)

    • Search Google Scholar
    • Export Citation
  • Spritzer PM 2014 Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances. Arquivos Brasileiros de Endocrinologia e Metabologia 58 182187. (doi:10.1590/0004-2730000003051)

    • Search Google Scholar
    • Export Citation
  • Spritzer PM, Comim FV, Capp E & D'Avila A 2005 Influence of leptin, androgens and insulin sensitivity on increased GH response to clonidine in lean patients with polycystic ovary syndrome. Hormone and Metabolic Research 37 9498. (doi:10.1055/s-2005-861173)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR & Randeva HS 2006a Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome. Diabetologia 49 27232728. (doi:10.1007/s00125-006-0419-9)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR & Randeva HS 2006b Increased visfatin messenger ribonucleic acid and protein levels in adipose tissue and adipocytes in women with polycystic ovary syndrome: parallel increase in plasma visfatin. Journal of Clinical Endocrinology and Metabolism 91 50225028. (doi:10.1210/jc.2006-0936)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Lehnert H, Kennedy R & Randeva HS 2007 Raised serum, adipocyte, and adipose tissue retinol-binding protein 4 in overweight women with polycystic ovary syndrome: effects of gonadal and adrenal steroids. Journal of Clinical Endocrinology and Metabolism 92 27642772. (doi:10.1210/jc.2007-0091)

    • Search Google Scholar
    • Export Citation
  • Tan BK, Chen J, Hu J, Amar O, Mattu HS, Adya R, Patel V, Ramanjaneya M, Lehnert H & Randeva HS 2013 Metformin increases the novel adipokine cartonectin/CTRP3 in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 98 E1891E1900. (doi:10.1210/jc.2013-2227)

    • Search Google Scholar
    • Export Citation
  • Toscani M, Migliavacca R, Sisson de Castro JA & Spritzer PM 2007 Estimation of truncal adiposity using waist circumference or the sum of trunk skinfolds: a pilot study for insulin resistance screening in hirsute patients with or without polycystic ovary syndrome. Metabolism 56 992997. (doi:10.1016/j.metabol.2007.03.006)

    • Search Google Scholar
    • Export Citation
  • Vázquez-Vela ME, Torres N & Tovar AR 2008 White adipose tissue as endocrine organ and its role in obesity. Archives of Medical Research 39 715728. (doi:10.1016/j.arcmed.2008.09.005)

    • Search Google Scholar
    • Export Citation
  • Villa J & Pratley RE 2011 Adipose tissue dysfunction in polycystic ovary syndrome. Current Diabetes Reports 11 179184. (doi:10.1007/s11892-011-0189-8)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Xie X & Zhu W 2010 Serum adiponectin and resistin levels in patients with polycystic ovarian syndrome and their clinical implications. Journal of Huazhong University of Science and Technology. Medical Sciences 30 638642. (doi:10.1007/s11596-010-0556-8)

    • Search Google Scholar
    • Export Citation
  • Wang L, Li S, Zhao A, Tao T, Mao X, Zhang P & Liu W 2012 The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. Journal of Steroid Biochemistry and Molecular Biology 132 120126. (doi:10.1016/j.jsbmb.2012.02.003)

    • Search Google Scholar
    • Export Citation
  • Wild RA, Rizzo M, Clifton S & Carmina E 2011 Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertility and Sterility 95 10731079.e1–11. (doi:10.1016/j.fertnstert.2010.12.027)

    • Search Google Scholar
    • Export Citation
  • Wiltgen D & Spritzer PM 2010 Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. Fertility and Sterility 94 24932496. (doi:10.1016/j.fertnstert.2010.02.015)

    • Search Google Scholar
    • Export Citation
  • Wiltgen D, Benedetto IG, Mastella LS & Spritzer PM 2009 Lipid accumulation product index: a reliable marker of cardiovascular risk in polycystic ovary syndrome. Human Reproduction 24 17261731. (doi:10.1093/humrep/dep072)

    • Search Google Scholar
    • Export Citation
  • Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, Qing H, Xia W, Luo M & Mei M 2011 Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. Journal of Clinical Endocrinology and Metabolism 96 831836. (doi:10.1210/jc.2010-2140)

    • Search Google Scholar
    • Export Citation
  • Yildiz BO, Bozdag G, Otegen U, Harmanci A, Boynukalin K, Vural Z, Kirazli S & Yarali H 2010 Visfatin and retinol-binding protein 4 concentrations in lean, glucose-tolerant women with PCOS. Reproductive Biomedicine Online 20 150155. (doi:10.1016/j.rbmo.2009.10.016)

    • Search Google Scholar
    • Export Citation
  • Yildizhan R, Ilhan GA, Yildizhan B, Kolusari A, Adali E & Bugdayci G 2011 Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertility and Sterility 96 246250. (doi:10.1016/j.fertnstert.2011.04.073)

    • Search Google Scholar
    • Export Citation