Funding sources
This work was supported by the Brazilian National Institute of Hormones and Women’s Health/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq INCT grant number 465482/2014-7) and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS INCT grant number 17/2551-0000519-8). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Declarations of interest
All authors declare no conflict of interest.
Introduction
Polycystic ovary syndrome (PCOS) is a multifactorial condition with different phenotypes, characterized by clinical or biochemical hyperandrogenism, ovarian dysfunction, and/or polycystic ovaries. Insulin resistance and central adiposity are often present , and women with PCOS are at higher risk for prediabetes and type 2 diabetes ; these clinical features are highly associated with adipose tissue dysfunction . Obesity is also a common finding in patients with PCOS, with a reported prevalence ranging from 30% to 60% and a pooled estimated prevalence of 49%, as shown by a metaanalysis . Obesity, through insulin resistance, may exacerbate the metabolic comorbidities associated with the syndrome . In this sense, insulin resistance is a common finding even in lean women with PCOS, reaching about 45% in a previous study conducted by our group ( Fig. 1 ). In turn, the prevalence of metabolic syndrome is much higher in obese women compared to those with body mass index (BMI) lower than 25.
Hyperinsulinemia resulting from insulin resistance also stimulates androgen production by ovarian theca cells and suppresses the hepatic production of sex hormone-binding globulin (SHBG), increasing the availability of free androgens . In addition, the adipose tissue provides storage and is a site of androgen metabolism, which contributes further to hyperandrogenism . Besides, the development of insulin resistance in these patients leads to defects in lipolysis and to a state of chronic low-grade inflammation, free fatty acid metabolism dysregulation, adipocytokine dysfunction and epigenetic abnormalities . Finally, insulin resistance induces preadipocytes in the abdominal region to differentiate into adipocytes, leading to central obesity in women with PCOS .
Adipose tissue is as an endocrine organ involved in the regulation of multiple processes, including glucose and fatty metabolism, immunity, inflammatory response, and reproduction. Current evidence indicates that dysfunctional adipose tissue is implicated in pathophysiological mechanisms of metabolic and reproductive disturbances in PCOS.
Intrinsic abnormalities of adipose tissue and adipose tissue dysfunction in PCOS
Adipose tissue is a major site for storage and metabolism of energy sources and sex steroids and contributes to regulation of endocrine processes. It is composed mainly of adipocytes and preadipocytes, with the rest represented by fibroblasts, endothelial cells, macrophages, stromal cells and immune cells.
There are two main types of functional adipose tissue: brown and white. Despite being primarily involved in thermogenesis in newborns, brown adipose tissue responds to cold and sympathetic nervous system activation in adult humans as well . White adipose tissue plays a pivotal role in the regulation of physiological and pathological processes, synthetizing and secreting specific adipokines and other pro and antiinflammatory factors . Depending on their anatomical location, white adipose depots are broadly classified into the subcutaneous (located under the skin) and the visceral/omental (located intra-abdominally, over the internal organs in the omentum, mesentery and retroperitoneal space) . Subcutaneous adipose depots provide energy storage and protection against mechanical damage and heat loss, while visceral fat is highly metabolically active, constantly releasing free fatty acids into the portal circulation . In fact, the accumulation of visceral fat has been linked to the onset of metabolic syndrome as the protagonist of an unfavorable metabolic profile in obesity . Obesity is associated with anatomic and functional derangements in adipose tissue: enlarged volume and increased number of adipocytes (hypertrophy and hyperplasia of adipocytes), immune cell infiltration, impaired adipogenesis, and abnormal inflammatory responses—characterizing the low-grade inflammation of obesity . Farkhondeh et al. suggested that an altered adipokine secretion profile is probably the cause of chronic low-grade inflammation of obesity.
Adipokines consist of hormones, cytokines, growth factors, vasodilators, and several other substances with a variety of functions, including important signaling molecules . Adipokines have been linked to the development of insulin resistance and other obesity-associated abnormalities, influencing blood pressure, lipid profile and degree of inflammation. Moreover, they are involved in several disease states, including cardiovascular disease, type 2 diabetes, cancer, immune diseases, and metabolic syndrome . Secretion of these adipose tissue-derived molecules appears to be compartment-specific, varying according to the adipose tissue depot and leading to variable effects of adipokines within particular depots .
Adipokines and PCOS
Patients with PCOS are at increased risk of developing insulin resistance and visceral obesity. In fact, elevated visceral adiposity has been found in obese and nonobese patients with PCOS in comparison with age- and BMI-matched healthy controls ; this has been associated with worse metabolic profile . The regulatory mechanism of adipokines may differ according to BMI status between healthy populations and women with PCOS. Adipokines may be a connecting factor between obesity and PCOS, with a role in the pathogenesis of the syndrome. In recent years, studies involving new adipokines and PCOS have advanced knowledge in the field ( Table 1 ).
| Adipokine | Source | Effects | Serum levels in PCOS a |
|---|---|---|---|
| Adiponectin | Adipose tissue, placenta | Antiproliferative, antidiabetic, antiinflammatory, and antiatherogenic | ↓ or ↔ |
| Leptin | Adipose tissue, gastric epithelium, hypothalamus, placenta, gonads | Appetite and weight regulation, pro-diabetic, and pro-inflammatory | ↑ with body fat |
| Resistin | Adipose tissue, monocyte, macrophages | Insulin resistance, pro-inflammatory | ↑ or ↔ |
| PEDF | Adipose tissue | Antiangiogenic, antiinflammatory, and antidiabetic | ? |
| RBP4 | Adipose tissue | Insulin resistance | ? |
| Visfatin | Adipose tissue, liver, muscle, bone marrow, lymphocytes, trophoblast, fetal membranes | Insulin-mimetic, pro-inflammatory | ↑ or ↔ |
| Apelin | Adipose tissue, brain, peripheral tissues | Insulin resistance | ↑ |
Adiponectin
Adiponectin is a 244 amino acid protein with a molecular weight of 28 kDa. It is the product of the APM1 gene transcript, encoded on chromosome 3q27—close to a known locus for type 2 diabetes and adiposity . This adipokine is mainly produced by adipocytes, and also detected in skeletal muscle, cardiomyocytes, osteoblasts, lymphocytes, adrenal gland, placenta, testis, ovary, pituitary gland, and liver tissue .
Adiponectin is well recognized for its antiproliferative, antidiabetic, antiinflammatory, and antiatherogenic properties . Adiponectin inhibits gluconeogenesis, improving insulin sensitivity through peroxisome proliferator-activated receptor (PPAR)-α activation in the liver. Moreover, it promotes adipogenesis and oxidation of free fatty acids in the skeletal muscles and adipose tissue through AMP-activated protein kinase (AMPK) signaling .
It has been suggested that overweight and obesity are characterized by low adiponectin concentrations . Indeed, this adipocyte product correlates negatively with BMI. An altered leptin/adiponectin ratio is also associated with BMI, impaired insulin signaling, and inflammatory state .
The existing data are not as conclusive regarding the role of adiponectin in PCOS. Previous reports from our group and other authors found similar circulating adiponectin levels in BMI-matched PCOS and control women . In contrast, some studies have reported lower adiponectin levels in women with PCOS than in healthy controls, independently of BMI . Recently, Asian studies showed significantly lower serum levels of adiponectin in lean women with PCOS than that in age- and BMI-matched controls . A metaanalysis conducted by Toulis et al. including 36 articles with more than 3000 subjects (PCOS women and BMI-matched healthy controls), of various ages and different levels of total testosterone and insulin, found that adiponectin was significantly lower in those with PCOS. Li et al. analyzed 38 articles with more than 3500 women (PCOS and BMI-matched healthy controls) and concluded that pooled adiponectin levels in PCOS women were significantly reduced compared with those of healthy controls. As reported by Groth in a systematic review of 15 articles, the majority of studies support the finding of low adiponectin levels in women with PCOS, irrespective of BMI. The disagreement among published data may be related to heterogeneity across studies, including variations in subject ethnicity, study design and sample size, or methodological techniques used to measure adiponectin, since this adipokine can be secreted by adipose tissue as a low-molecular-weight trimer, as a combination of two intermediate-molecular-weight trimers, or as six high-molecular-weight (HMW) trimers, and circulates either as a trimer or as an oligomer . These issues notwithstanding, the current evidence strongly reinforces that PCOS is accompanied by a state of adipose tissue dysfunction.
Leptin
Leptin, the product of the OB gene, located at 7q31.3, is implicated in energy balance through the central control of satiety, and consequently, of body weight, playing a key role in decreasing food intake and increasing energy expenditure . This hormone participates in the regulation of lipid and carbohydrate metabolism. It also acts on the immune system to modulate the inflammatory response .
Leptin serum levels are associated with adiposity; they are significantly increased in overweight and obese subjects, regardless of whether PCOS is present . However, despite elevated leptin concentrations in obesity, the effect of leptin is reduced due to a leptin-resistance state which is linked to insulin resistance and metabolic comorbidities .
We have previously reported higher leptin serum levels in overweight/obese PCOS and BMI-matched controls than in normal-weight PCOS and control women . Other published studies showed similar levels of circulating leptin in women with PCOS and BMI-matched controls , as well as higher leptin levels in overweight/obese women compared with nonoverweight controls . In turn, some studies showed higher levels of leptin in overweight/obese Iranian women and Russian adolescents with PCOS in comparison to a healthy control group, and one study reported elevated concentrations of leptin in normal weight and overweight Croatian PCOS in relation to age- and WHR-matched controls.
Resistin
Resistin is implicated in modulating insulin resistance and inflammatory responses. While it is an established adipokine and has been shown to be associated with adverse health conditions such as obesity and cardiovascular risk, it is not clear whether resistin is increased or suppressed in obesity .
Likewise, the role of resistin in PCOS is unclear, and published data are still controversial. While European studies showed similar resistin serum levels in patients with PCOS and non-PCOS counterparts irrespective of BMI , one Iranian report demonstrated decreased resistin levels in overweight/obese patients with PCOS in relation to normal-weight PCOS and controls groups . Conversely, other studies reported significantly higher resistin serum concentrations among women with PCOS than in age- and BMI-matched healthy subjects .
Pigment epithelium-derived factor
Pigment epithelium-derived factor (PEDF) has potent antiangiogenic and antiinflammatory effects. Moreover, it appears to be involved in obesity, glucose metabolism, and insulin resistance.
Data from our group reported similar circulating PEDF levels in obese women with PCOS and age- and BMI-matched controls , which is consistent with a previous study of obese patients with PCOS . In normal-weight Chinese women with PCOS, higher PEDF values were associated with insulin resistance and high-sensitivity C-reactive protein (CRP) levels . Other studies concerning PEDF have used experimental animal models to explore therapeutic alternatives PCOS .
Retinol-binding protein 4
Retinol-binding protein 4 (RBP4) appears to act through a detrimental effect on insulin sensitivity, modifying insulin signaling in muscle, inhibiting glucose uptake and interfering with insulin-mediated suppression of gluconeogenesis .
Similar RBP4 serum levels have been shown in lean Turkish and overweight postmenopausal Greek women with PCOS and in weight-matched controls. Conversely, Yildizhan et al. reported significantly higher RBP4 and homeostatic model assessment for insulin resistance (HOMA) index in obese women with PCOS as compared to nonobese PCOS and control groups. While Weiping et al. suggested an important link between circulating RBP4, adipose tissue and insulin resistance in PCOS, others noted that RBP4 was associated with obesity and glucose metabolism but was not a marker of insulin resistance in PCOS . Recently, Olszanecka-Glinianowicz et al. reported significantly higher RBP4 concentrations in women with PCOS over a range of normal weight to obesity, with an inverse correlation between RBP4 and HOMA-IR and insulin levels, as a compensatory effect of deterioration in obese PCOS patients.
Visfatin
Visfatin is a multifunctional protein with potential involvement in the obese-related insulin resistance and inflammation processes . Studies have shown higher serum visfatin levels in women with PCOS than in controls of similar age and BMI . In contrast, similar visfatin levels were reported in overweight/obese women with PCOS and controls , as well in normal-weight PCOS and control groups of same age . Lajunen et al. showed that circulating visfatin correlates with white blood cells and CRP, but is not associated with PCOS, obesity, or metabolic markers, suggesting that visfatin may act as a proinflammatory cytokine. Pepene found that increased visfatin levels could predict endothelial dysfunction in Romanian patients with PCOS, independently of obesity status and insulin resistance. A metaanalysis conducted by Sun et al. , evaluating 17 articles which enrolled more than 1300 European and Asian subjects, reported that high visfatin levels were not related to BMI, insulin resistance, or total testosterone ratio, but were an intrinsic characteristic of PCOS, therefore suggesting visfatin as a potential biomarker of PCOS.
Apelin
Apelin plays an important role on follicle development, acting on vascular establishment and hormone metabolism in the ovaries, and may regulate glucose and lipid metabolism, modulating insulin secretion . The majority of published data reported higher apelin serum levels in patients with PCOS in relation to control women, with and without correlation with clinical and biochemical PCOS characteristics . Caglayan et al. suggested that vitamin D treatment decreased insulin resistance and apelin values in Turkish women with and without PCOS. In contrast, Altinkaya et al. showed that serum apelin levels were lower in women with PCOS than in controls, even after controlling for BMI.
New adipokines: Chemerin, osteopontin, asprosin, SFRP4
There is increasing evidence that insulin resistance plays a pivotal role in the pathophysiology of PCOS. Several surrogate markers have been proposed to facilitate and improve determination of insulin resistance , as well as to establish whether altered adipose tissue secretion of adipokines is secondary to obesity, hyperandrogenism, and hyperinsulinemia or intrinsic to PCOS . In this sense, some new adipokines have been recently reported in connection with a potential association with PCOS.
Limited data are available on circulating chemerin; significantly increased serum levels have been reported in PCOS cases as compared with age- and BMI-matched control cases, independently of metabolic or androgenic status, in Argentinian women , and associated with serum glucose/insulin levels, and HOMA-IR in Egyptian women with PCOS . While some studies reported similar serum levels of osteopontin in PCOS patients and controls , one report showed significant increased levels of osteopontin in women with PCOS . Published data about asprosin, a new potential metabolic player in PCOS, are still inconclusive; Deniz et al. found significantly higher circulating levels in patients with PCOS compared to controls, while Chang et al. demonstrated that asprosin levels in metabolically altered or overweight PCOS patients were similar to those of corresponding controls. Bicer et al. reported elevated circulating levels of secreted frizzled-related protein 4 (SFRP4) in relation to insulin resistance and androgen excess in women with PCOS. This very new adipokine is related to oocyte maturation and apoptotic processes, as well to glucose and lipid metabolism, being implicated in insulin resistance, type 2 diabetes, and obesity .
Brown adipose tissue in women with PCOS
Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, and found especially in human infants . The BAT is responsive to cold; its primary role is to preserve body temperature, and it can affect whole-body metabolism, improving glucose tolerance, insulin sensitivity, and promoting weight loss. Specifically, brown adipocytes are characterized by high mitochondrial content and expression of uncoupling protein 1 (UCP1), which facilitates heat production via uncoupling of aerobic respiration . A large study involving 3640 consecutive 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomographic and computed tomographic (PET-CT) scans, from 1972 subjects, shows that functional BAT is prevalent in adult humans, with a significant female predominance. Also, the amount of BAT was inversely correlated with BMI, especially in older patients, suggesting a possible role of BAT in protecting against obesity .
Given that insulin resistance (IR) is a common trait in PCOS and is related to higher BMI, waist circumference, and androgen levels, the relationship between PCOS and BAT can potentially provide insight into the pathophysiology and treatment of these women. In a dehydroepiandrosterone (DHEA)-induced, rat model of PCOS, BAT transplantation reversed abnormal estrous cycles, improved systemic insulin sensitivity to a normal level, and activated endogenous BAT, thereby increasing the levels of circulating adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology . Besides, treatment of PCOS rats with rutin (a novel compound for BAT activation) increased BAT activation, thereby improving thermogenesis and systemic insulin sensitivity. Also, the mRNA expression of ovarian steroidogenic enzymes was upregulated, and fertility and birth defects were improved in rutin-treated rats with PCOS . Moreover, rat-to-mouse BAT xenotransplantation did not cause severe rejection reactions, and led to significant recovery of ovarian function, oocyte quality, glucose levels, and insulin sensitivity. Also, transcriptome analysis showed that the recovered PCOS mother following BAT xenotransplantation could also benefit the first generation .
Recent studies in women with PCOS have reported lower BAT activity and smaller BAT mass compared to their non-PCOS counterparts. In turn, the relationship between BAT and BMI in women with PCOS is still not conclusive, with some studies showing an inverse association and others not confirming these findings . Oliveira et al. showed an inverse correlation between BAT activity, waist circumference, and LAP index, an insulin resistance risk marker . Regarding testosterone levels, although data in PCOS are conflicting , a link between androgens and BAT activity cannot be ruled out. Indeed, a study using cultured brown adipocytes found that testosterone inhibits thermogenesis via downregulation of lipolysis and UCP1 mRNA expression and protein transcription .
In the search for possible therapeutic targets related to BAT in PCOS, a recent clinical trial carried out with women with PCOS showed no significant change in BAT activity levels after 60 days of treatment with either metformin or placebo . In another clinical trial, long-term treatment with a combination of spironolactone and two insulin sensitizers (pioglitazone/metformin) in adolescent girls with PCOS, normalized levels of C-X-C motif chemokine ligand-14 (CXCL14) levels, a chemokine recently proposed to be secreted preferentially by BAT, and improved the metabolic profile of participants. These results suggest that the proposed treatment could target BAT to improve the metabolic profile of patients with PCOS, although effects on CXCL14 levels in nonadipose tissues other than adipose tissue cannot be ruled out .
Adipose tissue as an inflammatory environment generator in PCOS
Besides producing adipokines, the adipose tissue also secretes acute-phase proteins and other inflammatory mediators, with impacts on energy balance, glucose metabolism, and proinflammatory or antiinflammatory activities.
Current evidence indicates that women with PCOS have increased serum pro-inflammatory markers when compared to healthy controls, contributing to a chronic low-grade inflammatory state .
In addition, macrophages are part of the innate immune system, and are responsible for maintaining the balance between protective and tissue-damaging cell-mediated immunity in the healing phase of inflammation. In adipose tissue, macrophages are required for recycling of lipids released by adipocytes. The ectopic visceral adipose tissue found in women with PCOS is fully infiltrated by macrophages, at least in part because of increased secretion of fatty acids, which more than double that observed in lean individuals . Insulin resistance, obesity and hyperandrogenism can predispose macrophage polarization to a pro-inflammatory state, known as M1. The M1 phenotype is characterized by enhanced production and release of inflammatory cytokines, such as IL-6 and TNFα, into circulation .
Inflammatory mediators in PCOS
Higher circulating levels of inflammatory markers have been associated with an intrinsic dysfunction of adipose tissue in PCOS. The adipocyte hypertrophy linked to hyperandrogenism in PCOS contributes to chronic low-grade inflammation, which is associated with compression phenomena in the stromal vessels, local hypoperfusion, and disturbed cytokine production, especially in ectopic visceral adipose tissue . In addition, genes involved in inflammation are expressed differentially in the adipose tissue of nonobese women with PCOS, suggesting intrinsic changes in the adipose tissue of women with PCOS independently of obesity by itself . However, intervention studies have also demonstrated that insulin resistance and hyperandrogenism may, at least in part, worsen the inflammatory state, while improving these factors may lead to a healthier, less inflammatory condition. In a 6-month follow-up of 50 nonobese women with PCOS, Orio et al. found that the administration of metformin at a dose of 1700 mg/day decreased WBC counts and CRP levels when compared to baseline . In a recent systematic review and metaanalysis including 27 studies of more than 800 women with PCOS, use of combined oral contraceptives was associated with a reduction of most inflammatory markers. However, most of studies included in this metaanalysis had a short follow-up (3–18 months) and small sample size .
While some new biomarkers of inflammation are being studied, CRP, tumor necrosis factor alpha (TNFα), interleukins 1 and 6 (IL-1, IL-6), and absolute white blood cells (WBCs) count remain the best-studied parameters ( Table 2 ).
| Marker | Source | Effects | Circulating levels in PCOS a |
|---|---|---|---|
| IL-6 | Adipocytes, macrophages, endothelial cells, skeletal muscle, fibroblasts | Insulin resistance | ↑ or ↔ |
| TNF-α | Adipose tissue, macrophages | Insulin resistance, and lipolysis | ↑ or ↔ |
| CRP | Hepatocytes | Pro-inflammatory | ↑ |
| WBCs | Hematopoietic stem cells | Cytokine production, inflammation, insulin resistance | ↑ |
| Other ILs (1β, 7,17,18) | Adipocytes, macrophages, vascular endothelial cells | Insulin signaling, thermogenesis, | ↑ ? |
| MCP-1 | Adipose tissue | Pro-inflammatory, insulin resistance | ↑ ? |
| sE-selectin, sICAM-1, sVCAM-1 | Endothelial cells, macrophages b and lymphocytes b | Pro-inflammatory | ↑ ? |
| ADMA | Peripheral tissues | NOS antagonist | ↑ ? |
| PAI-1 | Adipose tissue, vascular endothelium, smooth muscle cells, hepatocytes | Plasmin and fibrinolysis suppression | ↑ ? |
Interleukin-6, TNFα, and CRP
IL-6 and TNFα are major pro-inflammatory cytokines. Although produced in a variety of cells, both can be derived from dysfunctional adipose tissue in PCOS, especially secreted by resident macrophages. IL-6 stimulates the production of CRP by hepatocytes . PCOS patients exhibit elevated CRP levels, which correlates with obesity and insulin resistance . A metaanalysis including 2359 PCOS women and 1289 controls across 31 studies showed that CRP levels were 96% higher in PCOS patients than in healthy women, independently of obesity . Deshpande et al. found that IL-6 level was associated with ovarian dysfunction in mice .
TNF-α was initially thought to be associated with low-grade chronic inflammation in women with PCOS, independently of obesity . However, more recently, a metaanalysis including 9 studies showed similar serum TNF-α levels in 726 women with PCOS and in 328 controls. The same metaanalysis also found no significant differences in serum IL-6 levels in women with PCOS and controls . However, evidence of publication bias favoring studies underestimating differences in mediator levels between the groups was observed in that metaanalysis .
High TNF-α levels can stimulate the proliferation of theca interna cells via the c-Jun N-terminal kinase (JNK) pathway, and can reduce ovulation by inhibiting the expression of genes involved in the production of progesterone . Finally, both IL-6 and TNF-α also potentially induce insulin resistance, stimulate the production of androgens, and may impair hypothalamic-pituitary-ovarian axis secretion, contributing to PCOS pathophysiology .
White blood cells
In 2005, Orio et al. first found an increase in WBC counts in women with PCOS . WBC count has emerged as one of the most important markers of inflammation in PCOS, and is affected by increases in BMI, fatty acids and insulin resistance . In obesity, not only the total WBC count but also the differential may be affected; even WBC function may be impaired . A Chinese study found that weight loss induced by bariatric surgery may reduce WBC counts in patients with morbid obesity . Increased WBC counts may anticipate the future development of metabolic syndrome in young adults, as demonstrated in one study . WBCs are implicated in the production of cytokines, arterial wall inflammation, and insulin resistance induction, and may be associated with the more severe PCOS phenotypes .
Other cytokines and inflammatory mediators
Many other inflammatory mediators and cytokines are under investigation as markers of adipose tissue dysfunction in PCOS and in the genesis of PCOS manifestations. Their production, as that of the previously mentioned cytokines, occurs mainly in macrophages within adipose tissue. IL-1β and IL-18, besides being markers of insulin resistance and cardiovascular disease, have been associated with ovulatory dysfunction in PCOS. . IL-33, a novel cytokine, is involved in the pathogenesis of PCOS and is related to oxidative stress. It may be involved in follicular dynamics and fertilization, but more studies are necessary to evaluate its true role in other PCOS characteristics.
Other studies have reported increased concentrations of some circulating cytokines, such as: IL-7, and IL-17 ; monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and macrophage migration inhibitory factor (MIF) ; matrix metalloproteinases (MMP)-2 and -9 ; and soluble intercellular adhesion molecule-1 (sICAM-1) and soluble endothelial leukocyte adhesion molecule-1 (sE-selectin) .
Integration between dysfunctional adipose tissue and low-grade inflammation in PCOS
As presented in Fig. 2 , dysfunctional adipose tissue is responsible for the generation of an inflammatory milieu in women with PCOS. Insulin resistance and obesity aggravate and perpetuate this chronic low-grade inflammation. Increased serum and tissue levels of cytokines may also interfere with PCOS manifestation indirectly by inducing derangements of insulin action and adipose tissue function, as well as directly, as mentioned above. Chronic low-grade inflammation increases oxidative stress . An imbalance between oxidant and antioxidant factors in favor of an oxidant environment has been described in PCOS . This pro-oxidative environment and the aforementioned chronic low-grade inflammation may ultimately lead to endothelial damage, as suggested by increased levels of endothelial dysfunction markers, such as endothelin-1, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) asymmetric dimethylarginine (ADMA) and plasminogen activator inhibitor-1 (PAI-1), in women with PCOS . Cytokines and other inflammatory markers, besides signaling inflammation, may also play a role in the genesis of endothelial dysfunction and inflammation. Han et al. demonstrated that elevated CRP blood levels may promote increases in the chemotactic activities of monocytes in response to monocyte chemoattractant protein-1 (MCP-1), leading to atherogenic accumulation of monocytes in the arterial wall . Additionally, increased WBC levels have been associated with atherosclerosis, although a causal effect remains to be demonstrated .
Body fat distribution, insulin resistance, androgen secretion, and adipose tissue dysfunction across PCOS phenotypes
Abdominal adiposity, often present even in nonobese women with PCOS, is a hallmark of insulin resistance. In fact, body fat distribution may be even more important than total adiposity as a driver of developing metabolic complications . The prevalence of metabolic syndrome in women with PCOS as defined by the NIH criteria may be as high as 33%–43%, approximately twice that of the general population. In addition, women with PCOS and metabolic syndrome have greater levels of insulin resistance and a higher prevalence of hyperandrogenemia than those without . One potential mechanism is a greater lipolytic effect of catecholamines in visceral adipocytes, increasing portal free fatty acid delivery to the liver and contributing to insulin resistance. In subcutaneous adipocytes, the lipolytic effect of catecholamines was decreased, possibly enlarging fat cell size . Thus, clinical markers of abdominal adiposity can and should be used to screen women with PCOS for higher metabolic risk, with a view to preventing metabolic comorbidities . In this sense, we have previously shown that waist circumference, an easily measured surrogate marker of body fat distribution, is strongly correlated with truncal fat mass estimated by dual-energy X-ray absorptiometry in obese PCOS and healthy control women with the same BMI . Increased triglycerides, one of the components of metabolic syndrome, have also been regarded as a surrogate marker of cardiovascular risk. Insulin is a proadipogenic hormone, increasing the hepatic uptake of free fatty acids and the synthesis of very-low-density lipoprotein triglycerides, leading to dyslipidemia and ectopic fat deposition . 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 .
Obesity can also exacerbate long-term conditions including metabolic complications, and increase risk of certain types of cancer due to chronic unopposed estrogen exposure. In addition, obese women with PCOS may represent a more severe phenotype of the latter syndrome, with greater degrees of insulin resistance, hyperinsulinemia, metabolic dysfunction, and hyperandrogenism .
The main actions of insulin are to stimulate glucose uptake by insulin-responsive target tissues, such as adipocytes and skeletal and cardiac muscle, and to suppress hepatic glucose production. In adipose tissue, insulin suppresses lipolysis, decreasing circulating free fatty acid levels, which may contribute to the action of insulin on hepatic glucose production. The majority of patients with PCOS present chronic insulin resistance and, possibly, a relative degree of β-cell dysfunction, leading to an increased risk for impaired glucose tolerance and type 2 diabetes mellitus . Despite the common association with excess adiposity, women with PCOS have an imbalance of glucose homeostasis that cannot be explained by general obesity or abdominal adiposity .
Elevated androgen levels are the main biochemical abnormality in women with PCOS. Although these androgens originate predominantly from the ovaries, adrenal androgen excess is also found in 20%–30% of women with PCOS. Clinically, it can lead to hirsutism, acne and androgenetic alopecia . In fact, the role of androgens in PCOS can start as early as the intrauterine environment since gestational hyperandrogenism has been linked to metabolic disturbances in offspring .
Different PCOS phenotypes have been associated with differential metabolic risk. Based on the Rotterdam criteria, the risk of metabolic syndrome is increased in women with phenotypes A and B and decreased for phenotype C, while no increased risk is observed with phenotype D, even in obese women . Moreover, some isolated components of the metabolic syndrome are more prevalent in the classic phenotypes (A and B) than in the ovulatory phenotype and in non-PCOS controls, as previously reported ( Table 3 ).
