Open access peer-reviewed chapter

Clinical Impact of Insulin Resistance in Women with Polycystic Ovary Syndrome

Written By

Maria Mitkova Orbetzova

Submitted: August 29th, 2019 Reviewed: December 3rd, 2019 Published: January 10th, 2020

DOI: 10.5772/intechopen.90749

Chapter metrics overview

1,309 Chapter Downloads

View Full Metrics


Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder characterized by multiple hormonal imbalances, reflecting on the clinical presentation. Among them, the insulin resistance (IR), defined as a metabolic state characterized by a decrease in cellular ability to respond to insulin signaling, is a key feature of PCOS independently of obesity. Thus, IR occurs in more than 70% of obese PCOS women and in 30–50% of lean ones. Compensatory high insulin levels are both a symptom and an underlying physiopathological driver of PCOS. Insulin appears to disrupt all components of the hypothalamic-pituitary-ovarian axis, and ovarian tissue IR results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia. The latter is the main culprit of the clinical picture in PCOS. Testing for IR can be helpful to rule out other conditions that are commonly misdiagnosed as PCOS and to recommend an appropriate treatment for the different PCOS phenotypes.


  • polycystic ovary syndrome
  • insulin resistance
  • obesity
  • adipose tissue
  • adipocytokines

1. Introduction

Polycystic ovary syndrome (PCOS) is emerging as one of the most common endocrine disorders, affecting about 5–14% of the women of reproductive age and a leading cause of infertility [1, 2, 3]. In recent decades, there has been a wealth of evidence that the disease is a typical example of a female sex specific metabolic syndrome (MetS) due to IR, with obesity having an additional aggravating effect [4, 5, 6]. The interest in PCOS, from its first description in 1935 by Stein and Leventhal as a combination of bilaterally enlarged polycystic ovaries with manifest hirsutism, obesity, amenorrhea/oligomenorrhea, and infertility in a group of women [7], is an ever increasing one, becoming interdisciplinary, as affected girls and young women are at increased risk of cardiovascular disease (CVD) compared to age-matched healthy women [8, 9, 10]. This opinion is based mainly on the metabolic disorders established in PCOS (Table 1).

Overweight/obesity (android type)
Insulin resistance/hyperinsulinemia
Impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)/
Diabetes mellitus (DM) type 2
Gestational diabetes mellitus
Dyslipidemia (↓HDL-cholesterol; ↑ triglycerides)
Arterial hypertension/Arterial hypertension during pregnancy

Table 1.

Metabolic disorders in PCOS.

PCOS is a complex disorder that results from the interaction of diverse genetic and environmental factors. Heritable factors include polycystic ovarian morphology due to functional ovarian steroidogenic defects, hyperandrogenemia, IR, and insulin secretory defects. Acquired obesity is a major postnatal unfavorable factor [11] (Figure 1).

Figure 1.

Mechanisms by which obesity may determine the obese PCOS phenotype (adаpted according to [11]).

The major atherogenic risk factor is IR, since excluding all other pathological abnormalities, weight included, the hyperinsulinemic women with PCOS have a 5-fold higher incidence of CVD risk factors than the normoinsulinaemic ones. But the latter, in turn, remain at a significantly higher CVD risk than their age-and BMI-matched healthy controls [12]. This fact supports the main impact of the disease itself. The role of hyperandrogenemia as an independent determinant of CVD risk in PCOS is controversial—there are studies supporting [13] and rejecting [14] the direct link; moreover, elevated androgen levels are interpreted by most authors as being secondary to an underlying IR [15, 16, 17].

Not only does the presence of hyperandrogenemia and IR/compensatory hyperinsulinemia in PCOS elucidate such important pathogenetic mechanisms of the disease, but some clinical observations show that, in fact, the late metabolic complications are more deleterious than the reproductive dysfunction itself. Moreover, recent data from a long-term prospective study indicate that hyperinsulinemia and IR tend to deepen spontaneously in PCOS women, even without worsening of the hyperandrogenism [18]. PCOS is a markedly heterogeneous disease that is why the results of numerous studies on CVD risk assessment in the PCOS women are controversial. This is due to some differences in research trial designs and the characteristics of PCOS women cohorts in terms of weight and anthropometric variables, presence or absence of IR, and other metabolic disorders [19].


2. Carbohydrate disturbances and insulin resistance in PCOS

Glucose tolerance in women with PCOS was systematically investigated for the first time by Dunaif et al. in 1987 [20]. A number of studies involving large populations of PCOS women reported incidence of carbohydrate disturbanceshigher than 40% (30–35%: IGT and 8–12%: overt DM type 2) [20, 21], which is considerably higher than the one observed in population studies of age-matched women. Overweight is a prerequisite for the development of carbohydrate disturbances, but Legro et al. [22] demonstrated that even lean PCOS women were exposed to a higher risk—31.1% had IGT and 7.5% were newly diagnosed with DM. In an Italian study, the incidence of carbohydrate disturbances was found to be lower—DM 2.5% and IGT 15.5% [23]. The Australian study of Dabadghao et al. reported incidence of overt DM 4% and IGT 15.6%, the latter correlating with age, family history, abdominal obesity, and the presence of MetS [24].

In general, the incidence of a newly diagnosed DMin targeted studies in PCOS women reaches 10%, the greater part of the affected women being in the third or fourth decade of life. Even the lower DM incidence in certain populations of PCOS women has proved to be significantly higher, as compared to the age-matched populations. For instance, in a study conducted at the University of Pittsburgh, DM type 2 was observed in 12.6% of PCOS women of an average age 42 years, against 1.4% observed in the corresponding healthy population [25]. In the Netherlands, DM was found in 2.3% of the normal-weight PCOS women, aged 45–54, but this incidence was four times higher, as compared to the control population [26]. Two studies of ours in Bulgaria [27, 28] found DM incidence of 1.4% in a group of 142 PCOS women and 1.1% in another group of 94 patients, which is a comparatively low figure. However, we must take into consideration that DM in PCOS women is manifested relatively later, at an age between 30 and 40, and the predominant part of our patients were of a younger age (average age 22 years). That is why special attention should be paid to the risk groups—the women with IFG and IGT (in our studies they were 4.9 and 7.4%, respectively) and especially those who are overweight or obese as well (5.8 and 6.4%, respectively) [27, 28].

The PCOS women are more predisposed to development of gestational DMas well [29]. On the other hand, women with gestational DM have a higher incidence of PCOS, diagnosed postpartum [30, 31], and this is associated with persistent carbohydrate disturbances occurring afterward [32], in contrast to the usual returning to the norm. A study involving diabetic PCOS women found that 55% of them had gestational DM during pregnancy [33].

Following the initial evidence of Burghen et al. concerning the presence of hyperinsulinemia in PCOS [34], many other investigators obtained similar results demonstrating that both lean and obese PCOS women are characterized by IR and hyperinsulinemia [35, 36]. It has been proved that PCOS women have a more marked IR as compared to age- and BMI-matched healthy women, the difference becoming greater with the increase in BMI [33, 34, 35, 36, 37]. The use of insulin sensitizers significantly improved the characteristic metabolic and endocrine features of PCOS, ovulatory function, menstrual cyclicity, and fertility [19, 38, 39, 40, 41].

It is generally accepted that obese PCOS women are insulin-resistant. The obese PCOS women have higher insulin levels and/or more marked IR, as compared to obese controls and normal-weight PCOS women [42]. Still debatable is the issue whether IR in PCOS depends on weight and/or the android redistribution of adipose tissue, or it is intrinsic to the disease, since there is evidence in both directions [35, 43, 44, 45, 46]. Studies differing in design have obtained similar results, showing that both obese and lean PCOS women have IR and hyperinsulinemia. Some of these differences are due mainly to nonstandardized criteria for diagnosing both PCOS and IR. Family history of DM type 2 is not always taken into account. In addition, there are certain racial and ethnic peculiarities, which become more and more distinct regarding not only the individual characteristics of PCOS, but also the insulin sensitivity and the MetS itself [47, 48, 49].

It is important to know that irrespective of the occurrence of multiple risk factors, DM develops only in the presence of impaired β-cell function. In addition to the reduced insulin sensitivity, secretory dysfunction in pancreatic β-cells has been found in PCOS [50, 51]. This β-cell defect—increased fasting and reduced postprandial insulin secretion—results in inability of the available insulin to compensate for the degree of resistance to its action. The reduced postprandial response to insulin in PCOS women resembles the defect typical of DM type 2 and is much more marked in those who have first-degree relatives with DM type 2. Weight reduction results in significant improvement in IR, but the β-cell defect persists [38], which presupposes that it may prove to be a primary abnormality in PCOS. This is supported by the fact that the β-cell is unable to compensate for the peripheral IR that occurs early in the course of PCOS. Thus, a reduced first phase of insulin secretion has been established in adolescent girls with PCOS, as well as reduced index of glucose disposal and increased liver glucose production [52].

As it was stated above, the PCOS women have an increased basal insulin secretion, although the insulin secretory response to glucose loading as a whole is inadequate, as compared to that of healthy women [43, 53]. On tissue level, IR develops in the liver, adipose tissue, and muscles of PCOS women. Hyperinsulinemia in PCOS is considered to be secondary to IR. The latter involves a new mechanism of marked defects in insulin-dependent glucose transport, with significant alterations in receptor dynamics [54]. Marked reduction in insulin sensitivity has been found in biopsy-obtained adipocytes of PCOS women, as well as a milder but also significant decrease in the maximum rate of insulin-stimulated glucose transport, secondary to the reduced expression of GLUT-4 glucose transporters [55]. Such defects are observed in DM type 2 and obesity, but in PCOS they are found even in the absence of carbohydrate disturbances, overweight, and alteration in the waist-to-hip ratio (WHR). Moreover, they do not correlate with sex hormone levels, which suggest that the impairment of insulin action is most likely primary [56].

With a view to further elucidate post-receptor defects, a reduction in insulin-dependent receptor tyrosine autophosphorylation has been found in isolated fibroblasts of about 50% of PCOS women, as well as an increase in noninsulin dependent receptor serine phosphorylation, i.e., receptor tyrosine kinase activity is inhibited. A factor extrinsic to the insulin receptor, probably serine/threonine kinase, induces serine phosphorylation of the insulin receptor, which results in signal inhibition [5758]. This defect leads to IR in the early stages of insulin-receptor-mediated signal transduction. This unique PCOS characteristic distinguishes it from the other clinical conditions with IR [57]. The resultant hyperinsulinemia, arising as it seems upon triggering of puberty, may involve the system of ovarian insulin-like growth factors (IGFs), influence the liver production of the IGF binding protein-1(IGFBP-1), and is probably a pathogenetic factor in the development of the disease [59].

Serine phosphorylation seems to modulate the activity of the key regulatory enzyme of androgen biosynthesis—Р450с17, present in both ovarian and adrenal steroidogenic tissue. In this way, serine phosphorylation enhances enzymatic activity and increases androgen synthesis [60]. It is interesting to note that serine phosphorylation of insulin receptor substrate-1 (IRS-1) is also the mechanism of the TNF-α-mediated IR in obesity [61]. Thus, one and the same defect—serine phosphorylation—is likely to result in both IR and hyperandrogenism. This is a very tempting hypothesis explaining the syndrome pathogenesis; unfortunately, it is valid for only a part (about 50%) of the population of PCOS women.

With view to establishing a defect in insulin action after binding to the receptor, Book and Dunaif [62] investigated the metabolic and mitogenic effects of insulin and IGF-1 in a culture of skin fibroblasts from PCOS women and healthy controls. The authors found that in PCOS, a selective defect was present involving insulin metabolic but not mitogenic signaling pathways; a similar defect was found in the action of IGF-1 (this fact shows that insulin and IGF-1 stimulate glycogen synthetase by one and the same post-receptor pathways) [62]. Poretsky et al. demonstrated that the inhibition of PI-3-kinase activity did not alter insulin-induced stimulation of progesterone production in cultures of human ovarian cells [63]. On the other hand, insulin-stimulated PI-3-kinase activity in skeletal muscles of PCOS women was damaged [64]. The results suggest that the insulin regulation of steroidogenesis and glucose metabolism uses different signaling pathways, the first one remaining functionally active and probably even overstimulated by the increased insulin levels in women with IR [4] (Figure 2).

Figure 2.

Role of insulin in the pathogenesis of PCOS.

The hypothesis of presence of a post-receptor defect in insulin action in PCOS is consistent with the results of investigations performed on a molecular level, which have not found structural anomalies in the insulin receptor [65, 66, 67]. What exactly the defect is remains to be elucidated. An evidence provided by Ek et al. [68] suggests a selective impairment in the function of the protein kinase A-dependent hormone-sensitive enzyme lipase, which regulates the lipolytic response to catecholamines in visceral adipose tissue in lean PCOS women with mild IR. An abnormal post-receptor sensitivity to catecholamines has been observed while the antilipolytic sensitivity to insulin is preserved [68]. This anomaly differs from the impaired balance occurring in the MetS between the lipolytic β3- and the antilipolytic α2-adrenoreceptors [69]. It is still unclear whether this unique defect found in PCOS is primary or secondary to other factors, such as increased serum androgen levels.

Thus, the logical question arises—if IR and hyperinsulinemia play a major pathogenetic role in PCOS, why all women with hyperinsulinemia (e.g., with DM type 2) are not hyperandrogenic as well? IR and reproductive disturbances are probably indicative of single genetic defects and IR unmasks the syndrome in genetically predisposed individuals. Because of the fact that PCOS-related IR is a selective one and involves the metabolic but not the mitogenic and signaling pathways, we can explain the paradox of a persistent biological insulin action on reproductive processes on the background of systemic IR [70]. In general, studies have shown that predominantly PCOS women with both hyperandrogenism and chronic anovulation seem to be insulin-resistant. Women with only hyperandrogenism or a morphological finding of polycystic ovaries who have normal ovulation are less likely to develop IR [20, 71].

To sum up, insulin and LH act synergetically on the theca-cells of the polycystic ovary(hyperplasia of these cells is usually present) and activate Р450с17α1; thus, enhancing the biosynthesis of ovarian androgens and testosterone [72, 73, 74, 75]. A further adverse action of hyperinsulinemia on the ovaries of PCOS women includes arresting the development of the ovarian follicle up to 5–10 mm in size and preventing ovulation [71, 75]. Outside the ovary, insulin can act directly as a co-gonadotropin enhancing LH activity by stimulating the ovarian receptors for insulin and IGF, or indirectly by increasing the amplitude of LH serum pulses, enhancing the sensitivity to GnRH stimulation (Figure 3).

Figure 3.

Schematic representation of the factors regulating ovarian steroidogenesis.

The possible mechanism of insulin-induced enhanced ovarian steroidogenesis is supported by the higher incidence of PCOS in women with DM type 1—the ovaries of the affected women are exposed to hyperinsulinemia resulting from the availability of exogenously administered insulin in the systemic circulation [76].

In approximately 40% of the women diagnosed with PCOS in conformity with the NIH (National Institute of Health) criteria, an IGT or DM type 2 developed as sequelae of IR in the fourth decade of life, the age and weight gain having an unfavorable effect on glycemic control [27, 77, 78, 79, 80]. In addition, a study based on the Rotterdam diagnostic criteria, 2003 reported IR in 71.54% of the studied PCOS women [81].

The incidence of IR, however, differed considerably among the various phenotypes—80.4% in the “classical” one (phenotypes А and В), 65% in the women with normal ovulation (phenotype С) and 38.1% in the group with normoandrogenemia (phenotype D). The classical phenotype and to a lesser degree the phenotype without ovulatory dysfunction were independently associated with IR, whereas in the normoandrogenic phenotype no IR was found [81]. This was confirmed by another study, showing that the number of women with PCOS and a HOMA-index >3.8 is considerably higher in the hyperandrogenic phenotypes, as compared to the normoandrogenic one [82]. That is why the nature and course of carbohydrate disturbances in women with different phenotypic presentations of PCOS require establishing a precise and timely diagnosis, as well as proper behavior by changing one’s lifestyle and dietary regimen, weight reduction whenever needed, with view to reducing the risk of developing DM and/or its complications.

The risk factors for developing carbohydrate disturbances in PCOS are presented in Table 2.

Abdominal deposition of adipose tissue
Insulin resistance
β-cell dysfunction
Family history of DM type 2
Chronic anovulation
Dyslipidemia (hypertriglyceridemia)
Ethnicity (certain risk populations)

Table 2.

Risk factors for developing carbohydrate disturbances in PCOS.

Having in mind the incidence of carbohydrate disturbances in the general population of women aged 20–44 (7.8% for IGT and 1.0% for newly diagnosed DM type 2) and the average prevalence of PCOS (about 5%), it can be extrapolated that PCOS-associated IR contributes approximately to 20% of IGT and 40% of DM type 2 in women of reproductive age, which gives prominence to the social importance of this syndrome. In the light of this evidence in 2006, the Аmerican Association of Clinical Endocrinologists (ААСЕ) [83] recommended screening for presence of DM in all PCOS women after the age of 30, irrespective of weight—normal or overweight. Under certain risk circumstances, screening has been recommended before that age as well [83]. Considering the fact that DM type 2 can develop with age progression, the women who have had initially a negative result should be followed-up periodically.

The methods for evaluation of insulin sensitivity are presented in Table 3.

Euglycemic insulin clamp technique
Minimal model—multiple determination from i.v. GTT
Sensitivity insulin infusion tests
  • insulin tolerance test

  • insulin suppression test

Insulin parameters in oral glucose tolerance test (oGTT)
  • sum of insulin values

  • area under the insulin curve

  • maximal insulin/peak of insulin

Baseline insulin and derivative indexes, according to baseline blood sugar
  • glucose-to-insulin ratio,

  • НОМА-index (Homeostasis Model Assessment):

fasting insulin (μIU/ml) × fasting blood sugar (mmol/l) / 22.5
  • QUICKI (Quantitative Insulin Sensitivity Check Index):

1/(log (fasting insulin μU/mL) + log (fasting blood sugar mg/dL))

Table 3.

Methods for evaluation of insulin sensitivity.

In the routine clinical practice a measurement of basal and during oGTT glucose and insulin levels is most frequently used.


3. Obesity and insulin resistance in PCOS

The association between PCOS and obesity is complex. In the USA, it was reported that obesity affects from 30 to 75% of PCOS women [41, 84], which is higher than the percentage found in Europe [85, 86]. In a systematic review and meta-analysis of the literature, Lim et al. concluded that in PCOS women, as compared to the age-matched controls, a higher incidence of overweight and obesity was found [87]. In addition, the carriers of the syndrome of the Caucasian origin were found to be more overweight than their counterparts from the Asian origin [87]. These results are compromised to a certain extent by the fact that in most of the published studies, the patients have been selected from clinical practices on the basis of a subjective evaluation and local diagnostic methods. In general, overweight women are more often referred to a specialist for searching PCOS. However, in independent population samples, the incidence of obesity in PCOS does not seem as high as the one found in clinically targeted populations [27, 88]. Furthermore, PCOS incidence, based on the diagnostic criteria of NIH, is relatively stable throughout the world, irrespectively of the variable incidence of obesity in different populations [89].

In one of our studies, we found obesity in 51% and overweight of 22% in an unselected Bulgarian population of 142 women with PCOS [27]. Obesity incidence in our patients was higher than 38% found in women with PCOS from the island of Lesbos, Greece [90], and closer to the one found in England, where around 60% of the studied PCOS women were obese [71]. According to many studies including ours, PCOS women have higher ratio of central to peripheral redistribution of adipose tissue in comparison to controls [27, 91, 92, 93, 94]. Obesity, of visceral type mainly, plays a key role in developing and maintaining the syndrome [95, 96] and influences significantly its severity as well as metabolic and CVD risk, since it is a well-known risk factor for IGT and DM type 2, IR and dyslipidemia [91, 97, 98]. In this respect, insulin sensitizers may exert complex positive effects on both metabolic consequences and clinical manifestations of hyperandrogenism in women with PCOS [19, 47, 48, 83, 91] (Figure 4).

Figure 4.

Role of insulin sensitizers in the treatment of PCOS.

Obesity may promote the onset and exacerbate other long-term sequalae of PCOS, including metabolic disorders, the occurrence of some types of carcinoma, potentiated by chronic unopposed estrogen secretion, and leads to further impairing of the quality of life (QOL), low self-esteem, and worsened social adaptation, which may even potentiate occurrence of mental disorders. Obese PCOS women have a more severe clinical picture with higher incidence of IR, hyperinsulinemia, carbohydrate and lipid disturbances, and hyperandrogenism. Many studies, including ours, have shown that overweight PCOS women possess a higher degree of IR in comparison to the lean ones [27, 91, 92, 93, 94].

Data exist that even normal-weight carriers of the syndrome show unfavorable abdominal redistribution of adipose tissue and IR [99]. In a study of young normal-weight PCOS women (mean age 15.9 ± 1.8 years, mean BMI 22.7 ± 2.3 kg/m2) Cree-Green et al. found reduced insulin sensitivity and mitochondrial dysfunction in the muscles, relative postprandial hyperinsulinemia, abnormal glucose disposal, and increased hepatic fat in comparison to healthy controls [100].

PCOS women frequently have decreased sex hormone-binding globulin(SHBG) levels, which may decrease further with obesity development [101]. In turn, SHBGwas found to correlate positively with HDL-cholesterol and physical activity and negatively with obesity, central distribution of adipose tissue, triglycerides, IR parameters, and presence of DM type 2 [102].

In conclusion, the concomitant obesity, especially of an android type, is associated with an increase in the long-term metabolic risk in women with PCOS.


4. Visceral adipose tissue, adipocytokines, and insulin resistance in PCOS

In the last decades, visceral adipose tissue is perceived as a source of biologically active substances—adipocytokines [103]. Commonly, PCOS women have increased amount of visceral adipose tissue and associated metabolic disorders. The influence of adipose tissue hormones on IR processes, carbohydrate, lipid, and atherogenic disorders in PCOS women is a subject of increased research interest [104].

4.1 Leptin

Leptinis known to act as a chief “adipostat”—it suppresses the intake of food and water and leads to activation of catabolic metabolic pathways related to an increased production of energy. It improves the peripheral (liver and musculoskeletal) insulin sensitivity and affects β-cell function. It has been found that there is a positive correlation between plasma leptin levels and the amount of adipose tissue in the body. Leptin levels decrease rapidly during fasting and increase after food intake. Leptin is important not only for energy balance regulation and food intake but it also performs a function of metabolic and neuroendocrine hormone; participates in glucose metabolism, reproductive processes, interacts with the hypothalamic-pituitary-adrenal axis; influences thyroid hormone and growth hormone secretion; and even interferes with hematopoiesis and the immune system function. There are data for a strong association of circulating leptin and immunoreactive insulin (IRI) values and fasting plasma glucose, HOMA index, dyslipidemia, arterial hypertension that is independent or only partially dependent on obesity[103, 104].

A close relationship between IR and hyperleptinemia in PCOS women was found irrespective of their weight [105, 106] but the results are mostly controversial due to the differences in the studies designs and the lack of data on the independent effect of obesity, as well as the presence of various phenotype expressions of PCOS. In one of our studies [107], we found higher leptin levels with borderline significance in PCOS women in comparison to age-, weight-, waist circumference-, and WHR-matched healthy controls. Significant correlation of leptin was found with BMI, waist circumference, WHR, percentage of adipose tissue, as well as with basal insulin and HOMA-index in the PCOS group [107]. These findings were confirmed and complemented by our more recent studies of women with IR syndromes, including PCOS [108, 109]. Thus, leptin exhibited significantly positive correlation with BMI, WHR, percentage of adipose tissue, basal glucose and insulin, HOMA-index, total cholesterol, triglycerides, plasma atherogenic index, Castelli I, and Castelli II indexes. A significant negative correlation was found of leptin with Matsuda index, QUICKI-index, and adiponectin [108, 109].

Mohiti-Ardekani et al. [110] also found a positive correlation between free and total leptin levels and HOMA-index in PCOS women (r = 0.78, Р < 0.001; r = 0.84, Р = 0.003, respectively), as well as in healthy controls (r = 0.86, Р < 0.001; r = 0.69, Р < 0.001, respectively). Similar results were reported by authors from Australia [111], Brazil [112], Canada [113], Finland [114], Italy [115], Sweden [116], Turkey [117] and the USA [118, 119]. In a more recent study of PCOS women (mean age 34.30 ± 2.08 years, mean BMI 34.84 ± 4.77 kg/m2) and normally ovulating controls with comparable BMI (mean age 28.10 ± 4.61 years, mean BMI 33.59 ± 1.23 kg/m2) Nomair et al. [120] found higher leptin concentrations in PCOS women in comparison to controls (P = 0.005), significant differences being found in intergroup comparative analysis between the insulin-resistant and non-insulin-resistant PCOS women as well (P = 0.044). In women with PCOS a positive correlation between leptin and BMI (P = 0.049) was found. Authors also consider BMI and IR the two chief factors associated with leptin levels [120].

Our results, as well as those from the above-mentioned studies, are indisputable proof for the role of leptin in the pathogenesis of IR in PCOS.

4.2 Adiponectin

Adiponectin is a model of an anti-inflammatory adipocytokine. A negative correlation was found between its serum levels and the degree of obesity, IR, IGT, dyslipidemia, and atherosclerosis [121, 122, 123]. The increased amount of visceral adipose tissue results in hypoadiponectinemia due to reduced expression of adiponectin genes. This leads to suppression of the insulin activity in the liver, muscles, and other peripheral tissues. Conversely, the high adiponectin levels are an independent factor for an increased insulin sensitivity and reduced risk for DM type 2. On the basis of the effects on insulin sensitivity and its anti-inflammatory properties, adiponectin is perceived as an antiatherogenic factor. The decreased adiponectin is also combined with increased production of pro-inflammatory proteins IL-6, С-reactive protein (CRP). A positive correlation between the reduced levels of the hormone and the development of ischemic heart disease has been registered [124]. It was established that adiponectin production is suppressed in conditions of IR—DM type 2 and obesity [125]. Low adiponectin levels in obesity are probably due to the process of “down”-regulation mediated by the increased amount of adipose tissue. In a study of a large population in Japan [126] and American Pima Indians [127], adiponectin levels were found to be in negative correlation with the indexes of IR even if the factors age and BMI were excluded.

Initial studies of the levels of this antiatherogenic adipocytokine in women with PCOS were conducted by Orio et al. [128] and Panidis et al. [129]. Orio et al. [128] determined serum adiponectin levels in 60 PCOS women (30 normal-weight and 30 overweight) and in 60 age- and BMI-matched healthy women. Adiponectin levels were significantly lower in obese women in comparison to normal-weight women in the PCOS group, as well as in the control group. A significant difference in adiponectin levels between PCOS women and healthy women was not found, its levels in both groups correlated negatively with BMI and HOMA-index. The authors concluded that adiponectin concentrations vary depending on the quantity of the adipose tissue and that insulin sensitivity does not play a key role in controlling adiponectin levels in PCOS women [128]. Although in other IR conditions adiponectin was found to be decreased, both cited studies reported that in normal-weight PCOS women with IR and hyperinsulinemia its levels did not differ from those in the controls [128, 129].

However, in PCOS women with severe IR, Sepilan et al. found that it was the insulin sensitivity but not the weight that was the chief determinant for adiponectin levels [130]. This fact was confirmed by one of our more recent studies [131], which revealed higher adiponectin levels in non-insulin resistant PCOS women in comparison to insulin resistant ones. In addition, insulin levels and HOMA-index proved to be higher in the group of obese PCOS women in comparison to BMI-matched controls while adiponectin levels were similar in both obese groups. On the other hand, adiponectin concentrations were significantly higher in PCOS women with normal BMI in comparison to those with obesity. In PCOS women a negative correlation between adiponectin and body weight, BMI, waist circumference, hip circumference, WHR, blood glucose at 60 and 120 min, IRI at 0, 60, and 120 min of oGTT, HOMA-index, triglycerides, triglycerides/HDL-cholesterol ratio, plasma atherogenic index, and leptin was found. We observed also a positive correlation of adiponectin with Matsuda and QUICKI indexes [109, 131]. Most probably the relation between adiponectin and IR is confined to the ability of this adipokine to stimulate glucose utilization and to reduce glucose production by the liver [71114]. The established significant correlation of adiponectin and androstenedione in PCOS which presupposes some interrelation between this hormone and ovarian steroidogenesis is very interesting and needs further elucidation [11, 131].

It is believed that the leptin/adiponectin ratio (L/A)correlates better with the degree of IR in comparison to leptin and adiponectin values taken separately. L/A is a powerful independent predictor of CVD, its values being strongly associated with the intima-media thickness and correlating positively with a number of other anthropometric, metabolic and clinical parameters [132]. In our studies we found significantly higher L/A values in PCOS women with IR in comparison to those without IR [109, 131]. This is yet another proof that insulin resistant PCOS women are with a higher CVD risk.

4.3 Resistin

Resistin, described for the first time in 2001, is a protein rich in cystein, secreted by adipocytes, and it is suspected to carry out the relationship between obesity and DM. Due to its association with obesity, inflammatory process and IR, resistin is thought to be a potential biomarker for the MetS. Thus, the higher resistin levels found in patients with overt MetS in comparison to clinically healthy individuals support this theory [133]. However, data concerning the presence of significant dependencies between resistin levels and parameters of weight and insulin sensitivity in basal conditions and following weight reduction are controversial. Some authors found significantly higher resistin levels in obese individuals in comparison to individuals with normal weight [134], while others, including us [135], did not find significant differences [136, 137].

There is controversial data in studies among PCOS women concerning resistin levels in terms of a lack of association with the syndrome [138, 139], or an increase in PCOS [140]. Thus, Panidis et al. [139] did not confirm an active role of resistin in the pathogenesis of PCOS. The authors compared anovulatory PCOS women (obese and non-obese) and healthy controls with normal weight. Resistin was significantly higher only in the obese PCOS women in comparison to the other two groups irrespectively of the differences in insulin levels and the glucose/insulin ratio. Resistin did not correlate with any hormonal or metabolite index in our Bulgarian population of PCOS women with overweight [135]. Pangaribuan et al. [141] also did not find significant difference in serum resistin levels between PCOS women and controls. Meanwhile, the authors did not find significant correlation between resistin, BMI and HOMA-index [141]. Similar serum resistin levels in normal-weight women with or without PCOS were found by Seow et al. [142]. But resistin iRNA expression in adipocytes was twice as high in PCOS women. Probably, the overexpression of the resistin gene plays a role as a local factor [142].

Olszanecka-Glinianowicz et al. [143] studied the association of adiponectin and resistin with the process of IR in PCOS women and controls. All study participants were divided into two subgroups—obese and normal-weight. Comparable serum resistin concentrations between the two subgroups of PCOS women and controls were observed. No correlations between the adipokines, HOMA-index and androgen levels were found [143]. Lewandowski et al. published similar data [144]. The authors did not find a correlation between adiponectin and resistin with the parameters of IR (basal IRI, HOMA-index, QUICKI) [144]. Yilmaz et al. obtained different results—higher resistin in PCOS women in comparison to controls, however, they observed that resistin levels remained independent of the degree of IR and BMI [145] which supports the data of some of the above-mentioned studies.

The results from our studies in adipocytokines in PCOS [47, 48, 104, 107, 108, 109, 146] showed similar resistin levels in PCOS women and metabolically healthy obese women, higher resistin levels in insulin-resistant PCOS women in comparison to non-insulin resistant ones, lack of significant difference among the different subgroups of PCOS women, divided according to BMI. Resistin correlated positively with IRI at 0 and 120 min during oGTT, HOMA-index and negatively with Matsuda and QUICKI indexes [109, 146]. Wang et al. [147] registered significantly higher resistin levels in PCOS women (obese and normal-weight) in comparison to clinically healthy women. In similarity with our data, the authors reported a positive correlation of resistin with HOMA-index and a negative one with adiponectin [147]. Resistin in our study showed a positive correlation with IL-6 [109, 146]. Our data is peculiar in this aspect since it is considered that IL-6 is the main adipocytokine which regulates resistin levels. An in-vitrostudy showed that IL-6 production, as well as the one of other cytokines (IL-1 and TNFα), increased resistin expression in mononuclear cells [148].

A number of studies on the relation of resistin with obesity, IR, MetS, CVD risk in different age populations have been conducted so far, which, though being controversial in some respects, lead to further clarification of the role of resistin in the processes of atherogenesis [149, 150]. It was found that with the increase in the number of MetS components, serum levels of resistin and other pro-inflammatory markers increase as well [150]. These and a number of other results fully support the hypothesis on the relation between circulating resistin levels and the degree of IR. Having in mind that PCOS is considered a prototype of female specific MetS in young age populations, the role of resistin has to be clarified.

4.4 Visfatin

Visfatin—a protein derived from adipose tissue that is considered to have antidiabetic properties. Visfatin is isolated in the form of a cytokine which stimulates β-cell precursor maturation, therefore it was called pre-β cell colony-enhancing factor (PBEF)[151]. Visfatin stimulates glucose utilization from the adipocytes and myocytes and suppresses glucose release from liver cells, exhibiting the ability to bind to the insulin receptor and to activate it through inducing tyrosine phosphorylation. Acting as an insulin mimetic, visfatin can partially reduce IR, although it is found in much lower concentration in the circulation that insulin [152]. Visfatin participates in the process of adipocytes formation. A positive correlation between visfatin and the presence of obesity, increased visceral tissue, DM type 2 was found, and it was also elevated in patients with MetS [109, 131]. Taking in consideration these findings, the research interest in the changes in visfatin levels in PCOS is completely justified.

A meta-analysis [153] encompassing a study among 1341 women (695 with PCOS and 646 controls) showed higher visfatin levels in PCOS women without a significant correlation between it and BMI, HOMA-index, and testosterone. The authors concluded that high circulating visfatin can be perceived as a specific characteristic of PCOS, which even presupposes a role for this adipokine as a potential diagnostic biomarker for PCOS [153]. Kowalska et al. [154] found higher visfatin levels and a reduced insulin sensitivity in both normal-weight and obese PCOS women in comparison to healthy controls. Visfatin correlated negatively with parameters of IR, this correlation being well-expressed in normal-weight PCOS women, but missing in obese ones. It must be noted that in some circumstances visfatin does not succeed in exhibiting its beneficial effects on carbohydrate metabolism [154]. A hypothesis that the increase in serum visfatin levels is a secondary process aiming to prevent IR exists. On the other hand, insulin possesses the property to inhibit visfatin expression from the adipocytes so that the observed interrelationship could be explained as an inability of insulin to inhibit visfatin production in an already developed insensitivity to its action [155]. In this context, in the study of Kowalska et al. a positive correlation of visfatin with total testosterone and free androgen index (FAI) in the lean PCOS women was established [154]. The study of Tan et al. [156] also confirmed higher visfatin levels in PCOS women in comparison to age- and weight-matched healthy women. The researchers found a stimulated process of expression of visfatin mRNA and of the protein precursor of visfatin both in subcutaneous and visceral adipose tissue in PCOS women. Plasma visfatin levels were in a positive correlation with basal IRI (Р < 0.01), HOMA-index (Р < 0.01), testosterone (Р = 0.03), and estradiol (Р = 0.046). After performing a multiple regression analysis, the researchers found that the HOMA-index was the only predictive factor for visfatin levels. In contrast to plasma visfatin levels, the expressed visfatin mRNA in subcutaneous and visceral adipose tissue correlated positively with BMI and WHR [156].

In our Bulgarian studies [109, 131], we found higher serum visfatin levels in insulin-resistant PCOS women in comparison to non-insulin resistant ones. Visfatin levels in the PCOS women with obesity/overweight and in the BMI-matched metabolically healthy controls did not differ significantly. In our PCOS women, a negative correlation of visfatin with HDL-cholesterol and Matsuda index was found as well as a positive one with diastolic arterial pressure [109, 131]. In similarity to our results, Kowalska et al. reported a negative correlation between visfatin and HDL-cholesterol (r = −0.27, Р = 0.004) [154]. Such negative correlation (r = −0.349, Р = 0.013) was confirmed also by El-Said et al. [157] in insulin resistant PCOS women. In addition, the authors reported a positive correlation of visfatin with BMI, waist circumference, HOMA-index, FAI and a negative one with LH, total testosterone and sex hormone-binding globulin (SHBG). In this study, as well, visfatin was significantly higher in the PCOS women in comparison to the healthy women (72.94 ± 33.3 vs54.69 ± 31.5 ng/mL, Р = 0.039) [157]. In contrast to our results and the ones mentioned so far, Gen et al. reported a positive correlation between visfatin and HDL-cholesterol in normal-weight PCOS women [158].

It appears that there is controversy with respect to the relation of visfatin with insulin sensitivity indexes in women with IR and namely with PCOS and MetS. The main action of visfatin is intended at prevention of IR development as it was already pointed out, and this can explain its increase in PCOS women. The negative correlation of visfatin with IRI and HOMA-index and respectively the positive one with atherogenic indexes QUICKI and Matsuda in women with overt MetS registered in our studies is in support of this suggestion. Visfatin secretion control is a subject of increased research interest that arises much debate. Up till now, the conducted clinical studies comprising insulin resistant individuals with obesity and MetS, exhibit controversial results. The changes in this adipocytokine in PCOS women with different phenotypes are still to be clarified in targeted studies.

4.5 Tumor necrosis factor α (TNF-α) and Interleukin-6 (IL-6)

Adipose tissue is an important source of factors of low-grade inflammation not only due to the production of various cytokines by the adipocytes themselves, but also because of tissue infiltration with pro-inflammatory macrophages. The adipose tissue macrophages are responsible for the production of almost the entire amount of TNF-αand a significant portion of IL-6[159].

TNF-αis a cytokine, which interferes with the regulation of the amount of adipose tissue (inhibits the conversion of young immature fat cells into mature ones), the insulin action (disrupts the insulin receptor signal in peripheral cells) that causes post-receptor defect with subsequent development of IR [160]. The data regarding its relationship with IR are not consistent—some authors do not find any [161], but according to others insulin sensitivity is changing in parallel with the change in this cytokine levels [162, 163]. We also did not find a significant correlation of TNF-α and some parameters of IR in patients with various obesity morphotypes [135]. Basically, in our study, TNF-α levels were very similar in normal-weight women and in obese women, which corresponds to the data of Pincelli et al. [164]. It seems that the TNF-α levels, which we measure in the circulation, cannot reflect the degree of IR in obesity. It should be taken into account that this cytokine can have predominantly autocrine or paracrine action and can induce IR at a tissue level, since its concentrations in situ, at the level of adipose tissue, are much higher in comparison to the circulatory ones [165].

Elevated levels of TNF-α have been observed in PCOS women, which correlated positively with BMI and negatively with insulin sensitivity [166]. Gonzalez et al. [167] found elevated levels of TNF-α in normal-weight PCOS women as compared to controls. However, in all obese women in this study, despite the absence/presence of PCOS, TNF-α levels were similar. Direct correlation of TNF-α was detected with BMI, but with insulin such a correlation was found only in the healthy women. Apparently, factors other than obesity were the cause of TNF-α increase in normal-weight PCOS women. On the other hand, this cytokine did not correlate with testosterone, LH, and DHEA-S in the PCOS women [167].

We found significantly higher TNF-α concentrations in PCOS women compared to BMI-matched controls [109, 131]. In our studies, we did not establish a significant difference when comparing serum levels of TNF-α between insulin-resistant and non-insulin-resistant PCOS women. Higher levels of TNF-α were registered in obese PCOS women as compared to overweight PCOS women, but not to normal weight PCOS women. No correlations between TNF-α and the parameters of IR were established in the PCOS women [109, 131]. Contrary to our results are those of Soares et al., who did not detect a significant difference in the TNF-α levels between PCOS women and BMI-matched controls [168].

Data are controversial regarding the role of IL-6in the development of IR. In general, it is considered that circulating levels of IL-6 are elevated in patients with obesity and IR. It is assumed, that persistent high levels of IL-6 in chronic inflammatory conditions (obesity and DM type 2) can cause disturbances in insulin sensitivity, while only periodically elevated IL-6 levels are associated with normal carbohydrate homeostasis [162, 169]. Lin et al. suggested that IL-6 may serve as an early chronic low-grade-inflammation marker in PCOS [170]. This hypothesis, also described by other authors [171, 172], launches the idea of an association of PCOS with increased CVD risk, and the strategies affecting the chronic low-grade inflammatory conditions, can be useful for coping with PCOS and related metabolic and atherogenic disorders [173].

Mohlig et al. [174] studied IL-6 and CRP in PCOS women and in age-matched controls, analyzing the influence of C-174G-IL-6 gene polymorphism on the IL-6 and androgens levels, and on the degree of obesity. The authors did not find elevated CRP and IL-6 levels in PCOS women (both lean and obese) compared to the controls. In PCOS women the anthropometric variables (BMI, WHR, amount of adipose tissue) and the parameters of IR, but not the markers of hyperandrogenic condition, showed significant correlation with IL-6 and CRP. In addition, a 6-month metformin treatment resulted in a significant decrease in the body weight, the amount of adipose tissue and total testosterone levels, but did not affect the levels of IL-6 and CRP. Using multivariate linear regression analysis, it was established that in PCOS women BMI but not HOMA-index constituted a dominant factor explaining 18% and 24% of the variations in IL-6 and CRP levels, respectively [174].

This fact was also confirmed by another study conducted in pre-menopausal women [175]. In the study of Mohlig et al. [174], no link between the C-genotype and the IL-6 and BMI levels was found. However, the heterogeneous GC genotype was associated with lower levels of androstenedione [174]. The C-174G polymorphisms of the IL-6 gene promoter could be expected to modify its activity in certain in vitroconditions [176]. In some studies, C-174G polymorphism was associated with higher levels of IL-6, with more pronounced IR, with a higher degree of obesity and with hyperandrogenism [177, 178].

Our studies [107, 108, 109, 131] showed similar levels of IL-6 between the groups of PCOS women—insulin-resistant vsnon-insulin-resistant; normal weight vsoverweight and obese. We did not establish a significant difference in IL-6 between PCOS women and controls. Our data are in conformity with those of Villuendas et al. in women with ovarian hyperandrogenism [179], but are in confliction with the results of another study of Kelly et al. in PCOS women [180].

In a study of Tarkun et al. [181] in PCOS women and age- and weight-matched healthy women, a comparative analysis of TNF-α and IL-6 was made, with an assessment of their role in IR pathogenesis. Higher concentrations of TNF-α and IL-6 were found in PCOS women compared to controls. A positive correlation was observed between TNF-α and BMI, waist circumference, triglycerides, basal insulin and HOMA-index (P < 0.001). IL-6 correlated positively with basal glucose and degree of IR (P < 0.05). The authors concluded that TNF-α and IL-6 have a pathogenetic role in the development of IR in PCOS [181].

In another study consisting of obese PCOS women, weight-matched healthy women and normal weight controls Vgontzas et al. [182] determined basal cytokine concentrations and conducted an 8-h nocturnal polysomnography searching for obstructive sleep apnea syndrome. Higher IL-6 plasma concentrations were observed in PCOS women as compared to obese and normal-weight controls (4.75 ± 0.5; 3.65 ± 0.4; 1.84 ± 0.3 pg/mL, respectively, P < 0.01). TNF-α levels were somewhat higher in the obese PCOS and control women compared to the normal-weight women, but the differences did not reach statistical significance (4.05 ± 0.3; 3.79 ± 0.2; 3.14 ± 0.2 pg/mL, respectively, P = 0.103). IL-6 and TNFα correlated positively with BMI (P < 0.01) in the obese healthy women, but not in the obese PCOS women. In addition, a stronger correlation of IL-6 and TNF-α levels with IR indexes (HOMA and QUICKI) was established in the PCOS women than in the obese controls. The authors came to the conclusion that IL-6 may be elevated in PCOS women, irrespectively of obesity and presence of obstructive sleep apnea, and may have a role in the process of IR in this syndrome [182].

Grimaldi Barcellos et al. [183] investigated the impact of PCOS and obesity on the levels of TNFα, IL-6 and CRP in young PCOS women and age- and BMI-matched women with a normal menstrual cycle without CVD risk factors (DM, dyslipidemia, arterial hypertension). The authors did not establish a significant difference in the levels of TNF-α, IL-6 and CRP between the PCOS women and the controls (2.1 vs1.9 pg/mL, P = 0.397; 3.8 vs5.7 pg/mL, P = 0.805, and 0.9 vs0.5 ng/mL, P = 0.361). The TNF-α levels were similar between obese and normal-weight women. IL-6 and CRP were significantly higher in women with overweight/obesity than in normal-weight women (8.7 vs2.0 pg/mL, P < 0.001, and 1.4 vs0.2 ng/mL, P < 0.001). The authors concluded that obesity, but not PCOS itself, affects the levels of circulating markers of a chronic low-grade inflammation in young carriers of the syndrome without major CVD risk factors [183].

The pathogenesis of an inflammatory process development in MetS, and in particular in PCOS, has not yet been fully clarified. In scientific terms, the most logical and most widespread is the explanation that the higher amount of adipose tissue in case of obesity leads to increased excretion of IL-6 and TNF-α in the circulation, which in turn causes increased production of CRP by the liver. There is another hypothesis highlighting IR as the primary cause of the higher production of cytokines [184].


5. Conclusion

Women with PCOS, combining IR and hyperandrogenism are carriers of an unfavorable cardiovascular risk profile. However, data concerning the long-term risk of cardiovascular morbidity and mortality are scarce, controversial and this issue has not yet been addressed appropriately in targeted large prospective studies. However, since there is compelling evidence of the presence of MetS components and early stages of atherosclerotic processes in young PCOS women that are still reversible, it is essential that they must be diagnosed on the basis of the current knowledge in order to administer adequate complex treatment to prevent late consequences of IR.


  1. 1. Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): Arguably the most common endocrinopathy is associated with significant morbidity in women. The Journal of Clinical Endocrinology and Metabolism. 1999;84(6):1897-1899
  2. 2. Strauss JF III. Thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Annals of the New York Academy of Sciences. 2003;997:42-48
  3. 3. Solomon CG. The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinology and Metabolism Clinics of North America. 1999;28(2):247-263
  4. 4. Moghetti P. Insulin resistance: What is its role in the polycystic ovary syndrome? Current Opinion in Endocrinology & Diabetes. 2002;9(6):444-450
  5. 5. Nestler JE. Insulin resistance and the polycystic ovary syndrome: Recent advances. Current Opinion in Endocrinology and Diabetes. 2000;7:345-349
  6. 6. Cho LW, Randeva HS, Atkin SL. Cardiometabolic aspects of polycystic ovarian syndrome. Vascular Health and Risk Management. 2007;3(1):55-63
  7. 7. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. American Journal of Obstetrics and Gynecology. 1935;29:181-186
  8. 8. Amowitz LL, Sobel BE. Cardiovascular consequences of polycystic ovary syndrome. Endocrinology and Metabolism Clinics of North America. 1999;28:439-458
  9. 9. Dahlgren E, Janson PO, Johansson JS, et al. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstetricia et Gynecologica Scandinavica. 1992;71:599-604
  10. 10. Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15(7):821-826
  11. 11. Gambineri A, Pelusi C, Vicennati V, et al. Obesity and the polycystic ovary syndrome. International Journal of Obesity. 2002;26:883-896
  12. 12. Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertility and Sterility. 2000;73:150-156
  13. 13. Graf MJ, Richards CJ, Brown V, et al. The independent effects of hyperandrogenaemia, hyperinsulinaemia, and obesity on lipid and lipoprotein profiles in women. Clinical Endocrinology. 1990;33:119-131
  14. 14. Toscano V, Bianchi P, Balducci R, et al. Lack of linear relationship between hyperinsulinaemia and hyperandrogenism. Clinical Endocrinology. 1992;36:197-202
  15. 15. Ciampelli M, Fulghesu AM, Cucinelli F, et al. Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome. Metabolism. 1999;48:167-172
  16. 16. Vidal-Puig A, Munoz-Torres M,Jodar-Gimeno E, et al. Hyperinsulinaemia in polycystic ovary syndrome: Relationship to clinical and hormonal factors. The Clinical Investigator. 1994;72:853-857
  17. 17. Wild RA. Obesity, lipids, cardiovascular risk, and androgen excess [review]. The American Journal of Medicine. 1995;98:27S-32S
  18. 18. Pasquali R, Gambineri A, Anconetani B, et al. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clinical Endocrinology. 1999;50(4):517-527
  19. 19. Orbetzova M. Cardiovascular risk, subclinical and clinically overt cardiovascular diseases in polycystic ovary syndrome.InPrevention, Diagnosis, Treatment – Current Problems, 2018; еds. М. Vlaskovska, М. Оrbetzova, B. Georgiev, G. Momekov, L. Кirov. Sofia Havitis; pp.445-485 . ISBN: 978-954-92936-0-9 (In Bulgarian)
  20. 20. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. The Journal of Clinical Endocrinology & Metabolism. 1987;65:499-507
  21. 21. Legro RS. Diabetes prevalence and risk factors in polycystic ovary syndrome. Current Opinion in Endocrinology & Diabetes. 2002;9(6):451-458
  22. 22. Legro RS, Kunselman AR, Dodson WC, et al. 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. The Journal of Clinical Endocrinology and Metabolism. 1999;84:165-169
  23. 23. Gambineri A, Pelusi C, Manicardi E, et al. Glucose intolerance in a large cohort of Mediterranean women with polycystic ovary syndrome: phenotype and associated factors. Diabetes. 2004;53:2353-2358
  24. 24. Dabadaghao P, Roberts BJ, Wang J, et al. Glucose tolerance abnormalities in Australian women with polycystic ovary syndrome. Medical Journal of Australia. 2007;187(6):328-331
  25. 25. Talbott EO, Zborovski JV, Bourdreaux MY. Do women with polycystic ovary syndrome have an increased risk of cardiovascular disease? Review of the evidence. Minerva Ginecologica. 2004;57:27-39
  26. 26. Elting MW, Korsen TJ, Bezemer PD, et al. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Human Reproduction. 2001;16:556-560
  27. 27. Orbetzova M, Kamenov Z, Kolarov G, et al. Metabolic disturbances in women with polycystic ovary syndrome. Folia Medica. 2003;3:12-20
  28. 28. Orbetzova M, Orbetzova V, Kamenov Z, et al. Comparison of the diagnostic indices for evaluation of disorders in carbohydrate metabolism in women with polycystic ovary syndrome (PCOS). Akusherstvo i Ginekologia. 2003;42(4):10-15 (in Bulgarian)
  29. 29. Lanzone A, Caruso A, Di Simone N, et al. Polycystic ovary disease. A risk factor for gestational diabetes? The Journal of Reproductive Medicine. 1995;40:312-316
  30. 30. Kousta E, Cela E, Lawrence N, et al. The prevalence of polycystic ovaries in women with a history of gestational diabetes. Clinical Endocrinology. 2000;53:501-507
  31. 31. Anttila L, Karjala K, Penttila RA, et al. Polycystic ovaries in women with gestational diabetes. Obstetrics and Gynecology. 1998;92:13-16
  32. 32. Koivunen RM, Juutinen J, Vauhkonen I, et al. Metabolic and steroidogenic alterations related to increased frequency of polycystic ovaries in women with a history of ges tational diabetes. Journal of Clinical Endocrinology & Metabolism. 2001;86:2591-2599
  33. 33. Conn J, Jacobs HS, Conway GS. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clinical Endocrinology. 2000;52:81-86
  34. 34. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. The Journal of Clinical Endocrinology and Metabolism. 1980;50:113-116
  35. 35. Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174
  36. 36. Grulet H, Hecart AC, Delemer B, et al. Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome. Clinical Endocrinology. 1993;38:621-626
  37. 37. Chae SJ, Kim JJ, Choi YM, et al. Clinical and biochemical characteristics of polycystic ovary syndrome in Korean women. Human Reproduction. 2008;23(8):1924-1931
  38. 38. Holte J, Bergh T, Berne C, et al. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1995;80(9):2586-2593
  39. 39. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clinical Endocrinology. 1992;36:105-111
  40. 40. Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism. 2000;85:2767-2774
  41. 41. Azziz R, Ehrmann E, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: A multicenter, double blind, placebo-controlled trial. Journal of Clinical Endocrinology & Metabolism. 2001;86:1626-1632
  42. 42. Shoupe D, Kumar DD, Lobo RA. Insulin resistance in polycystic ovary syndrome. American Journal of Obstetrics and Gynecology. 1983;147:588-592
  43. 43. Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992;41:1257-1266
  44. 44. Holte J, Bergh T, Berne C, et al. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. The Journal of Clinical Endocrinology & Metabolism. 1994;78:1052-1058
  45. 45. Holte J, Gennarelli G, Berne C, et al. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: A sign of a pre-hypertensive state? Human Reproduction. 1996;11(1):23-28
  46. 46. Morales AJ, Laughlin GA, Butzow T, et al. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: Common and distinct features. The Journal of Clinical Endocrinology and Metabolism. 1996;81:2854-2864
  47. 47. Kolarov G, Orbetzova M. Polycystic Ovary Syndrome. Sofia: Viara; 2004. ISBN 954-9409-01-5; 232 pp. (in Bulgarian)
  48. 48. Kamenov Z, Оrbetzova М, Gateva А. Polycystic Ovary Syndrome. Sofia: ZIP Ltd.; 2010 258 p. ISBN 978-954-9369-17-5 (in Bulgarian)
  49. 49. Orbetzova M. Polycystic ovary syndrome (PCOS). Epidemiology, pathophysiology, clinical course, complications. Nauka Endokrinologia. 2007;1:7-10 (in Bulgarian)
  50. 50. Dunaif A. DT Finegood. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1996;81:942-947
  51. 51. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. The Journal of Clinical Investigation. 1995;96:520-527
  52. 52. Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome:Roles of insulin resistance and [beta]-cell dysfunction and risk of cardiovascular disease. The Journal of Clinical Endocrinology and Metabolism. 2001;86:66-71
  53. 53. Paterakis TS, Diamanti-Kandarakis E. Aspects of cardiometabolic risk in women with polycystic ovary syndrome. Current Obesity Reports. 2014;3:377-386
  54. 54. Ciaraldi TP, El-Roeiy A, Madar Z, et al. Cellular mechanism of insulin resistance in polycystic ovarian syndrome. The Journal of Clinical Endocrinology and Metabolism. 1992;75:577-583
  55. 55. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: Decreased expression of GLUT-4 glucose transporters in adipocytes. The American Journal of Physiology. 1993;264:E197-E202
  56. 56. El Mkadem SA, Lautier C, Macari F, et al. Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. Diabetes. 2001;50:2164-2168
  57. 57. Eldar-Geva T, Spitz IM, Groome NP, et al. Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome. Human Reproduction. 2001;16:2552-2556
  58. 58. El-Roeiy A, Chen X, Roberts VJ, et al. Expression of insulin-like growth factor I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. The Journal of Clinical Endocrinology and Metabolism. 1993;77:1411-1518
  59. 59. Suikkari AM, Koivisto VA, Koistinen R, et al. Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin. The Journal of Clinical Endocrinology and Metabolism. 1989;68:135-140
  60. 60. Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: Implications for adrenarche and the polycystic ovary syndrome. Proceedings of the National Academy of Sciences of the United States of America. 1995;92:10619-10623
  61. 61. Rosen ED, Spiegelman BM. Tumor necrosis factor-a as a mediator of insulin resistance of obesity. Current Opinion in Endocrinology & Diabetes. 1999;6:170-176
  62. 62. Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1999;84:3110-3116
  63. 63. Poretsky L, Seto-Young D, Shrestha A, et al. Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. The Journal of Clinical Endocrinology and Metabolism. 2001;86:3115-3119
  64. 64. Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annual Review of Medicine. 2001;52:401-419
  65. 65. Conway G, Avey C, Rumsby G. The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. Human Reproduction. 1994;9:1681-1683
  66. 66. Sorbara LR, Tang Z, Cama A, et al. Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome. Metabolism, Clinical and Experimental. 1994;43:1568-1574
  67. 67. Talbott JA, Bicknell EJ, Rajkhowa M, et al. Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. The Journal of Clinical Endocrinology and Metabolism. 1996;81:1979-1983
  68. 68. Ek I, Arner P, Ryden M, et al. A unique defect in the regulation of visceral fat cell lypolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes. 2002;51:484-492
  69. 69. Hoffstedt J, Wahrenberg H, Thorne A, et al. The metabolic syndrome is related to beta-adrenoreceptor sensitivity in visceral adipose tissue. Diabetologia. 1996;39:838-844
  70. 70. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nature Reviews Disease Primers. 2016;2:16057
  71. 71. Robinson S, Kiddy D, Gelding SV, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clinical Endocrinology. 1993;39:351-355
  72. 72. Nestler JE, Strauss JE III. Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinology and Metabolism Clinics of North America. 1991;20:807-823
  73. 73. Franks S, Mason H, White D, Willis D. Mechanisms of anovulation in polycystic ovary syndrome. In: Flicori M, Flamigni C, editors. The Ovary: Regulation, Dysfunction and Treatment. Amsterdam: Elsevier; 1991. pp. 183-186
  74. 74. White D, Leigh A, Wilson C, Donaldson A, Franks S. Gonadotropin and gonadal steroid response to a single dose of a long-acting agonist of gonadotropin-releasing hormone in ovulatory and anovulatory women with polycystic ovary syndrome. Clinical Endocrinology. 1995;42:475-481
  75. 75. Willis DS, Watson H, Mason HD, et al. Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: Relevance to mechanism of anovulation. The Journal of Clinical Endocrinology and Metabolism. 1998;83:3984-3991
  76. 76. Escobar-Morreale HF, Roldan B, Barrio R, et al. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism. 2000;85:4182-4187
  77. 77. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: A controlled study. The Journal of Clinical Endocrinology and Metabolism. 2005;90:3236-3242
  78. 78. Norman RJ, Masters L, Milner CR, et al. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Human Reproduction. 2001;16:1995-1998
  79. 79. Boudreaux MY, Talbott EO, Kip KE, et al. Risk of T2DM and impaired fasting glucose among PCOS subjects: Results of an 8-year follow-up. Current Diabetes Reports. 2006;6:77-83
  80. 80. Livadas S, Kollias A, Panidis D, Diamanti-Kandarakis E. Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: Evidence from 1345 women with the syndrome. European Journal of Endocrinology. 2014;171:301-309
  81. 81. Moghetti P, Tosi F, Bonin C, et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2013;98:E628-Е637
  82. 82. Bil E, Dilbaz B, Cirik DA, et al. Metabolic syndrome and metabolic risk profile according to polycystic ovary syndrome phenotype. The Journal of Obstetrics and Gynaecology Research. 2016;42:837-843
  83. 83. AACE - American Association of Clinical Endocrinologists. Position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocrine practice. 2005;11(2):125-134
  84. 84. Ehrmann DA. Polycystic ovary syndrome. The New England Journal of Medicine. 2005;352(12):1223-1236
  85. 85. Carmina E, Koyama T, Chang L, et al. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? American Journal of Obstetrics and Gynecology. 1992;167(06):1807-1812
  86. 86. Carmina E, Legro RS, Stamets K, et al. Difference in body weight between American and Italian women with polycystic ovary syndrome: Influence of the diet. Human Reproduction. 2003;18(11):2289-2293
  87. 87. Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: A systematic review and meta-analysis. Human Reproduction Update. 2012;18(06):618-637
  88. 88. Lizneva D, Kirubakaran R, Mykhalchenko K, et al. Phenotypes and body mass in women with polycystic ovary syndrome identified in referral versus unselected populations: Systematic review and meta-analysis. Fertility and Sterility. 2016;106(06):1510-1520
  89. 89. Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertility and Sterility. 2016;106(01):6-15
  90. 90. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: Hormonal and metabolic profile. The Journal of Clinical Endocrinology and Metabolism. 1999;84:4006-4011
  91. 91. Orbetzova M. Polycystic ovary syndrome. In: Vlaskovska M, Tankova T, Popova D, Georgiev B, editors. Prophylaxis, Diagnostics, Therapy - Current Problems 2012. Sofia: Havitis; 2012. pp. 407-434. ISBN: 978-954-92936-1-6 (in Bulgarian)
  92. 92. Godoy-Matos AF, Vaisman F, Pedrosa AP, et al. Central-to-peripheral fat ratio, but not peripheral body fat, is related to insulin resistance and androgen markers in polycystic ovary syndrome. Gynecological Endocrinology. 2009;25:793-798
  93. 93. Strowitzki T, Halser B, Demant T. Body fat distribution, insulin sensitivity, ovarian dysfunction and serum lipoproteins in patients with polycystic ovary syndrome. Gynecological Endocrinology. 2002;16:45-51
  94. 94. Cosar E, Üçok K, Akgün L, et al. Body fat composition and distribution in women with polycystic ovary syndrome. Gynecological Endocrinology. 2008;24:428-432
  95. 95. Liou T-H, Yang J-H, Hsieh C-H, et al. Clinical and biochemical presentations of polycystic ovary syndrome among obese and nonobese women. Fertility and Sterility. 2009;92:1960-1965
  96. 96. Kiddy DS, Sharp PS, White DM, et al. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: An analysis of 263 consecutive cases. Clinical Endocrinology. 1990;32:213-220
  97. 97. Karabulut A, Yaylali GF, Demirlenk S, et al. Evaluation of body fat distribution in PCOS and its association with carotid atherosclerosis and insulin resistance. Gynecological Endocrinology. 2012;28:111-114
  98. 98. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clinical Endocrinology. 1992;37:119-125
  99. 99. Svendsen PF, Nilas L, Norgaard K, et al. Obesity, body composition and metabolic disturbances in polycystic ovary syndrome. Human Reproduction. 2008;23:2113-2121
  100. 100. Cree-Green M, Rahat H, Newcomer B, Bergman B. Insulin resistance, hyperinsulinemia and mitochondria dysfunction in non-obese girls with polycystic ovary syndrome. Journal of the Endocrine Society. 2017;1:931-944
  101. 101. Thaler MA, Seifert-Klauss V, Luppa PB. The biomarker sex hormone-binding globulin – From established applications to emerging trends in clinical medicine. Best Practice & Research Clinical Endocrinology & Metabolism. 2015;29:749-760
  102. 102. Sutton-Tyrrell K, Wildman RP, Matthews KA, et al. Sex hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the study of women across the nation (SWAN). Circulation. 2005;111:1242-1249
  103. 103. Milcheva B, Orbetzova M. Adipose tissue – endocrine organ. Endocrinologia. 2004;9(2):64-72 (in Bulgarian)
  104. 104. Orbetzova M. Adipose-tissue hormones at women with polycystic ovary syndrome. Literature review with own data. Nauka Endokrinologia. 2009;6:258-261 (in Bulgarian)
  105. 105. Calvar CE, Intebi AD, Bengolea SV, et al. Leptin in patients with polycystic ovary syndrome. Direct correlation with insulin resistance. Medicina B Aires. 2003;63:704-710
  106. 106. Morin-Papunen L, Koivunen R, Tomas C, et al. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1998;83:2566-2568
  107. 107. Orbetzova M, Pehlivanov B, Mitkov M, et al. Effect of short-term standard therapeutic regimens on neuropeptide Y and adipose tissue hormones in overweight Insulinresistant women with polycystic ovary syndrome. Folia Medica. 2011;53(3):15-24
  108. 108. Koleva DI, Orbetzova MM, Atanassova PK. Adipose tissue hormones and appetite and body weight regulators in insulin resistance. Folia Medica. 2013;55(1):25-32
  109. 109. Koleva DI. Adipose tissue hormones, appetite and body weight regulators, and endothelial function in women with insulin resistance. Abstract of a doctoral thesis for the award of educational and scientific degree “PhD”. Plovdiv; 2017 (in Bulgarian)
  110. 110. Mohiti-Ardekani J, Tarof N, Aflatonian A. Relationships between free leptin and insulin resistance in women with polycystic ovary syndrome. Iranian Journal of Reproductive Medicine. 2009;7(2):53-58
  111. 111. Chapman IM, Wittert GA, Norman RJ. Circulating leptin concentrations in polycystic ovary syndrome: Relation to anthropometric and metabolic parameters. Clinical Endocrinology. 1997;46:175-181
  112. 112. Spritzer PM, Poy M, Wiltgen D, et al. Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: Influence on LH and relationship with hormonal, metabolic, and anthropometric measurements. Human Reproduction. 2001;16:1340-1346
  113. 113. Pirwany IR, Fleming R, Sattar N, et al. Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. European Journal of Endocrinology. 2001;145:289-294
  114. 114. Rouru J, Anttila L, Koskinen P, et al. Serum leptin concentrations in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1997;82:1697-1700
  115. 115. Carmina E, Ferin M, Gonzalez F, et al. Evidence that insulin and androgens may participate in the regulation of serum leptin levels in women. Fertility and Sterility. 1999;72:926-931
  116. 116. Gennarelli G, Holte J, Wide L, et al. Is there a role for leptin in the endocrine and metabolic aberrations of polycystic ovary syndrome? Human Reproduction. 1998;13:535-541
  117. 117. Telli MH, Yildirim M, Noyan V. Serum leptin levels in patients with polycystic ovary syndrome. Fertility and Sterility. 2002;77:932-935
  118. 118. Mantzorous CS, Dunaif A, Fiiler S. Leptin concentration in the polysistic ovary syndroume. The Journal of Clinical Endocrinology and Metabolism. 1997;82:1697-1700
  119. 119. Laughlin GA, Morales AJ, Yen SS. Serum leptin levels in women with polycystic ovary syndrome: The role of insulin resistance/hyperinsulinemia. The Journal of Clinical Endocrinology and Metabolism. 1997;82:1692-1696
  120. 120. Nomair AM, Aref NK, Rizwan F, et al. Serum leptin level in obese women with polycystic ovary syndrome, and its relation to insulin resistance. Asian Pacific Journal of Reproduction. 2014;3(4):288-294
  121. 121. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. The Journal of Clinical Endocrinology and Metabolism. 2004;89(2):447-452
  122. 122. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocrine Reviews. 2005;26(3):439-451
  123. 123. Orbetzova M, Atanasova I, Milcheva B, et al. Adiponectin and its relation to certain clinical, hormonal and metabolic characteristics at women with android obesity. Endocrinologia. 2007;1:4-17 (in Bulgarian)
  124. 124. Reinhart RA, Gani K, Arndt MR, et al. Apolipoproteins AI and B as predictors of angiographically defined coronary artery disease. Archives of Internal Medicine. 1990;150(8):1629-1633
  125. 125. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. The Journal of Biological Chemistry. 1996;271:10697-10703
  126. 126. Yamamoto Y, Hirose H, Saito I, et al. Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clinical Science. 2002;103:137-142
  127. 127. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia. The Journal of Clinical Endocrinology and Metabolism. 2001;86:1930-1935
  128. 128. Orio F, Palomba S, Kascella T, et al. Adiponectin levels in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2003;88:2619-2623
  129. 129. Panidis D, Kourtis A, Farmakiotis D, et al. Serum adiponectin levels in women with polycystic ovary syndrome. Human Reproduction. 2003;18(9):1790-1796
  130. 130. Sepilan V, Nagamani M. Adiponectin levels in women with polycystic ovary syndrome and severe insulin resistance. Journal of the Society for Gynecologic Investigation. 2005;12(2):129-134
  131. 131. Koleva DI, Orbetzova MM, Nyagolova PV, Mitkov MD. Adipokines, metabolic and atherogenic parameters in insulin resistant and non-insulin resistant women with polycystic ovary syndrome. Giornale Italiano di Ostetricia e Ginecologia. 2016;38(1):114-118
  132. 132. Norata GD, Raselli S, Grigore L, et al. Leptin: Adiponectin ratio is an independent predictor of intima media thickness of the common carotid artery. Stroke. 2007;38:2844-2846
  133. 133. Filippidis G, Liakopoulos V, Mertens PR, et al. Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purification. 2005;23:421-428
  134. 134. Azuma K, Katsukawa F, Oguchi S, et al. Correlation between serum resistin level and adiposity in obese individuals. Obesity Research. 2003;11(8):997-1001
  135. 135. Orbetzova М, Atanassova I, Milcheva B, et al. Adipose tissue hormones in women with different morphotypes of overweight. Endocrinologia. 2004;9(4):214-224 (In Bulgarian)
  136. 136. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: Cross-sectional and interventional studies in normal, insulinresistant, and diabetic subjects. The Journal of Clinical Endocrinology and Metabolism. 2003;88(10):4848-4856
  137. 137. Silha JV, Krsek M, Skrha JV. Plasma resistin, adiponectin and leptin levels in lean and o bese subjects: Correlations with insulin resistance. European Journal of Endocrinology. 2003;149(4):331-335
  138. 138. Carmina E, Orio F, Palomba S, et al. Endothelial dysfunction in PCOS: Role of obesity and adipose hormones. The American Journal of Medicine. 2006;119:356-366
  139. 139. Panidis D, Koliakos G, Kourtis A, et al. Serum resistin levels in women with polycystic ovary syndrome. Fertility and Sterility. 2004;81(2):361-366
  140. 140. Munir I, Yen HW, Baruth T, et al. Resistin stimulation of 17 alpha hydroxylase activity in ovarian theca cells in vitro: Relevance to polycystic ovary synd Rome. The Journal of Clinical Endocrinology and Metabolism. 2005;90:4852-4857
  141. 141. Pangaribuan B, Yusuf I, Mansyur M, et al. Serum adiponectin and resistin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Therapeutic Advances in Endocrinology and Metabolism. 2011;2(6):235-245
  142. 142. Seow KM, Juan CC, Wu LY, et al. Serum and adipocyte resistin in polycystic ovary syndrome with insulin resistance. Human Reproduction. 2004;19(1):48-53
  143. 143. Olszanecka-Glinianowicz M, Kuglin D, Dąbkowska-Huć A, et al. Serum adiponectin and resistin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2011;154(1):51-56
  144. 144. Lewandowski KC, Szosland K, O’Callaghan C, et al. Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: A significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices. Molecular Genetics and Metabolism. 2005;85:61-69
  145. 145. Yilmaz M, Bukan N, Demirci H, et al. Serum resistin and adiponectin levels in women with polycystic ovary syndrome. Gynecological Endocrinology. 2009;25(4):246-252
  146. 146. Koleva DI, Оrbetzova ММ, Nyagolova PV, et al. Resistin and insulin resistance in women with polycystic ovary syndrome. Endocrinologia. 2016;XXI(4):211-222
  147. 147. Wang Y, Xie X, Zhu W. 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. 2010;30(5):638-642
  148. 148. Kaser S, Kaser A, Sandhofer A, et al. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochemical and Biophysical Research Communications. 2003;309:286-290
  149. 149. Malo E, Ukkola O, Jokela M, et al. Resistin is an indicator of the metabolic syndrome according to five different definitions in the Finnish health 2000 survey. Metabolic Syndrome and Related Disorders. 2011;9:203-210
  150. 150. Makni E, Moalla W, Benezzeddine-Boussaidi L, et al. Correlation of resistin with inflammatory and cardiometabolic markers in obese adolescents with and without metabolic syndrome. Obesity Facts. 2013;6:393-404
  151. 151. Rabe K, Lehrke M, Parhofer KG, et al. Adipokines and insulin resistance. Molecular Medicine. 2008;14(11-12):7417-7451
  152. 152. Fukuhara A, Matsuda M, Nishizawa M, et al. A protein secreted by visceral fat that mimics the effects of insulin. Science. 2005;307:426-430
  153. 153. Sun Y, Wu Z, Wei L, et al. High visfatin levels in women with polycystic ovary syndrome: Evidence from a meta-analysis. Gynecological Endocrinology. 2015;31(10):808-814
  154. 154. Kowalska I, Straczkowski M, Nikolajuk A, et al. Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Human Reproduction. 2007;22(7):1824-1829
  155. 155. Haider DG, Schaller G, Kapiotis S, et al. The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia. 2006;49:1909-1914
  156. 156. Tan B, Chen J, Digby J, et al. Icreased 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. 2006;91(12):5022-5028
  157. 157. El-Said MH, El-Said NH, Mohamad NAE-G. Plasma Visfatin concentrations in polycystic ovary syndrome: Relationships with indices of insulin resistance and hyperandrogenism. Medical Journal Cairo University. 2009;77(3):1-7
  158. 158. Gen R, Akbay E, Muşlu N, et al. Plasma visfatin level in lean women with PCOS: Relation to proinflammatory markers and insulin resistance. Gynecological Endocrinology. 2009;25(4):241-245
  159. 159. Fernaґndez-Real JM, Pickup JC. Innate immunity, insulin resistance and type 2 diabetes. Trends in Endocrinology and Metabolism. 2008;19:10-16
  160. 160. Moller DE. Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends in Endocrinology and Metabolism. 2000;11:212-217
  161. 161. Hube F, Birgel M, Hauner H, et al. Expression pattern of tumor necrosis factor receptors im subcutaneous and omental human adipose tissue: Role of obesity and non-insulin dependent diabetes mellitus. European Journal of Clinical Investigation. 1999;29:672-678
  162. 162. Kern P, Ranganathan S, Li C. Adipose tissue tumor necrosis factor and interleukin 6 expression in human obesity and insulin resistance. The American Journal of Physiology - Endocrinology and Metabolism. 2001;280:E745-E751
  163. 163. Lofgren P, van Harmelen V, Reynisdottir S. Secretion of tumor necrosis factor D shows a strong relationship to insulin stimulated glucose transport in human adipose tissue. Diabetes. 2000;49:688-692
  164. 164. Pincelli AI, Brunani A, Scacchi M, et al. The serum concentration of tumor necrosis factor alpha is not an index of growthhormone- or obesity-induced insulin resistance. Hormone Research. 2001;55(2):57-64
  165. 165. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. European Cytokine Network. 2006;17:4-12
  166. 166. Araya AV, Aguirre A, Romero C, et al. Evaluation of tumor necrosis factor alpha production in ex vivo short term cultured whole blood from women with polycystic ovary syndrome. European Cytokine Network. 2002;13(4):419-424
  167. 167. Gonzalez F, Thusu K, Abdel-Rahman E, et al. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism, Clinical and Experimental. 1999;48(4):437-441
  168. 168. Soares GM, Vieira CS, Martins WP, et al. Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: One more characteristic inherent to the syndrome? Clinical Endocrinology. 2009;71:406-411
  169. 169. Mooney RA. Counterpoint: Interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. Journal of Applied Physiology. 2007;102:816-818
  170. 170. Lin YS, Tsai SJ, Lin MW, et al. Interleukin-6 as an early chronic inflammatory marker in polycystic ovary syndrome with insulin receptor substrate-2 polymorphism. American Journal of Reproductive Immunology. 2011;66:527-533
  171. 171. Ibanez L, Valls C, Marcos MV, et al. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: Effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. The Journal of Clinical Endocrinology and Metabolism. 2004;89:4331-4337
  172. 172. Tumu VR, Govatati S, Guruvaiah P, et al. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. Journal of Assisted Reproduction and Genetics. 2013;30:1541-1546
  173. 173. Ojeda-Ojeda M, Murri M, Insenser M, et al. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Current Pharmaceutical Design. 2013;19:5775-5791
  174. 174. Mohlig M, Spranger J, Osterhoff M, et al. The polycystic ovary syndrome per se is not associated with increased chronic inflammation. European Journal of Endocrinology. 2004;150:525-532
  175. 175. Escobar-Morreale HF, Villuendas G, Botella-Carretero JI, et al. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women. Diabetologia. 2003;46:625-633
  176. 176. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. The Journal of Clinical Investigation. 1998;102:1369-1376
  177. 177. Hulkkonen J, Pertovaara M, Antonen J, et al. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL-6 gene in primary Sjogren’s syndrome and correlate with the clinical manifestations of the disease. Rheumatology. 2001;40:656-661
  178. 178. Jones KG, Brull DJ, Brown LC, et al. Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation. 2001;103:2260-2265
  179. 179. Villuendas G, Millan JLS, Sancho J, Escobar-Morreale HF. The 597 G A and 174 G C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. The Journal of Clinical Endocrinology & Metabolism. 2002;87:1134-1141
  180. 180. Kelly CC, Lyall H, Petrie JR, et al. Low grade chronic inflammation in women with polycystic ovarian syndrome. The Journal of Clinical Endocrinology and Metabolism. 2001;86:2453-2455
  181. 181. Tarkun I, Çetinarslan B, Türemen E, et al. Association between circulating tumor necrosis factor-α, interleukin-6, and insulin resistance in normal-weight women with polycystic ovary syndrome. Metabolic Syndrome and Related Disorders. 2006;4(2):122-128
  182. 182. Vgontzas AN, Trakada G, Bixler EO, et al. Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea. Metabolism. 2006;55(8):1076-1082
  183. 183. Grimaldi Barcellos CR, Rocha MP, Hayashida SAY, et al. Obesity, but not polycystic ovary syndrome, affects circulating markers of low-grade inflammation in young women without major cardiovascular risk factors. Hormones. 2015;14(2):251-257
  184. 184. Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005;111:1448-1454

Written By

Maria Mitkova Orbetzova

Submitted: August 29th, 2019 Reviewed: December 3rd, 2019 Published: January 10th, 2020