Mariagrazia Stracquadanio1 and Lilliana Ciotta1
(1)
Obstetrics and Gynecological Pathology, P.O. “S. Bambino”, University of Catania, Catania, Italy
Keywords
PCOS geneticsInsulin resistanceHyperinsulinemiaHyperandrogenismOvarian dysfunction
2.1 Genetics of PCOS
PCOS is a multifactorial polygenic disease (interaction between several genetic and environmental factors), with a heritability of ∼70 %. It is intrinsically difficult to study by a genetic point of view, and most of the current literature (>70 studies based on the candidate gene approach) is inconclusive, with many studies resulting inconsistent, controversial, and without a clear consensus [1].
In the first studies on the genetic basis of PCOS, both maternal and paternal patterns of inheritance are suggested: the incidence of oligomenorrhea and polycystic ovaries was found to be increased in first-degree relatives of PCOS patients compared with controls, and males in those families had increased hairiness according to the questionnaire, suggesting an autosomal dominant pattern of inheritance [2].
Recently, the inheritance was confirmed by some authors who found that PCOS was present in 35 % of the mothers and 40 % of the sisters of PCOS patients [3].
Moreover, increased incidence of insulin resistance in the fathers and brothers of PCOS women [4] has been considered as the “male phenotype” in PCOS families. The genes involved in the pathogenesis of hyperandrogenism are expressed in a variable way depending on the factors predominating in every different ethnic populations; this explains the phenotypic variability of hyperandrogenic disorders. Another theory is that the features of PCOS families result from nongenetic inheritance, and they are related to environmental factors that are present only in the affected families.
Ibanez hypothesized that some insults during pregnancy may induce to intrauterine growth retardation, which probably induces a “thrifty phenotype” in small for gestational age babies. These have a high risk of suffering from insulin resistance, which may result in hypertension, glucose intolerance, adrenal axis hyperactivity with relative cortisol excess, functional hyperandrogenism, and PCOS later in life, especially if they are exposed to environmental factors such as a sedentary lifestyle and a diet rich in saturated fat [5].
These environmental factors may cluster in certain families because exercising and dieting are greatly influenced by parental lifestyle. The metabolic abnormalities of the “thrifty phenotype” can induce additional insult to the pregnancies of these SGA (small for gestational age) and PCOS women, and these defects might be transmitted to another generation without the participation of any genetic abnormality.
On the other hand, if small for gestational age babies have healthy habits, insulin resistance and its consequences might be improved, and theoretically, their fetuses will not be exposed to a hostile metabolic environment during pregnancy, preventing nongenetic inheritance of these conditions. However, intrauterine growth restriction might be influenced by genetic variants as well, and the most likely scenario is represented by an interaction between predisposing genetic abnormalities and unfavorable environmental conditions [6].
Thus, even if several studies conducted in families of women with PCOS have demonstrated the genetic basis of the syndrome, nowadays a genetic pattern certainly involved in PCOS predisposition has not been identified.
Most studies have included different kinds of genes: those related to androgen biosynthesis and action and their regulation, genes involved in insulin resistance and associated disorders, and also genes involved in chronic inflammation and atherosclerosis.
Among the genes involved in androgen biosynthesis, there are:
· CYP17: This gene encodes the P450c17α enzyme, which catalyzes the conversion of pregnenolone and progesterone into, respectively, 17-hydroxypregnenolone and 17-hydroxyprogesterone and of these steroids into dehydroepiandrosterone and androstenedione. In the past, the hyperactivity of this enzyme was correlated to hyperandrogenism [7].
CYP17 is located in chromosome 10q24.3, and its promoter encloses a T/C SNP at 34 bp from the transcription start that might regulate enzyme activity. Some studies hypothesized that this polymorphism was associated with polycystic ovaries morphology on ultrasound [8, 9], and it was found that PCOS patients homozygous for C alleles of this polymorphism showed increased serum testosterone levels [10, 11].
On the contrary, other studies suggested that this is a polymorphism without functional consequences for the development of polycystic ovaries and hyperandrogenism [12–14]. Besides, no significant evidence for linkage or association was found in a family-based genome study [15].
· CYP11A: This gene is located at 15q24 and encodes the cholesterol side chain cleavage enzyme, important for the conversion of cholesterol into progesterone, which is the first step in adrenal and ovarian steroidogenesis. A VNTR polymorphism, consisting in repeats of a (tttta)n pentanucleotide at −528 bp from the ATG start of translation site in the CYP11A promoter, might play a role in the pathogenesis of PCOS [16].
Some studies confirmed its association with polycystic ovaries and hirsute women [16, 17], while other studies did not demonstrate linkage with the CYP11A locus in PCOS patients or association of CYP11A VNTR alleles with hyperandrogenism [18]. Moreover, recent experiments involving a large number of subjects concluded that the existence of associations between CYP11A promoter variation and androgen-related phenotypes had been considerably overestimated in previous studies [19].
· CYP19: This gene encodes aromatase, which converts androgens in estrogens. This enzyme maybe has a decreased activity in granulosa cells and follicles of PCOS women, and the consequent androgen excess might contribute to abnormal follicle development [20, 21]. On the contrary, no evidence for linkage of CYP19 with PCOS was found in other English and American studies [15, 16].
· LH Gene: LH hypersecretion is present in almost 50 % of PCOS women, and two mutations, Trp8Arg and Ile15Thr, could be the cause of an abnormal LH β molecule [22]. The first PCOS GWAS (genome-wide association studies) identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for PCOS: the interaction of LHCGR and its ligand, LH, plays a fundamental role in the folliculogenesis of mammals. A study suggested that LHCGR might participate in the physiopathology of PCOS by deviations in the methylation statuses of its promoter CpG sites, a hypomethylation in particular [23].
· SHBG Genes: Sex hormone-binding globulin (SHBG) controls the admission of testosterone and estradiol to target tissues.
Decreased SHBG is an important feature of hyperandrogenic women, causing increased tissue androgen availability [24].
Recently, an association between a (TAAAA)n polymorphism in the promoter of the SHBG gene and PCOS has been reported. Longer alleles (more than eight repeats) were frequent in Greek PCOS patients, while non-hyperandrogenic women presented with a higher frequency of shorter alleles [25].
The second group of genes includes those involved in insulin resistance and metabolic disorders, which are:
· INSR (Insulin Receptor Gene): Insulin resistance represents the major metabolic aspect of PCOS. INSR contains several polymorphisms, but most of them are silent or are located in intronic regions and are present with similar frequencies in patients with polycystic ovaries and hyperandrogenism and in controls [26].
Polymorphism in exon 17 of the tyrosine kinase domain is the only one found, but it was not associated to insulin resistance [27]. On the other hand, it was found that a C/T SNP at the tyrosine kinase domain of INSR is associated with PCOS, but further studies are needed to confirm it [6].
· INS: Pancreatic β-cell dysfunction in PCOS women seems to have a genetic origin as well. It was found that women with menstrual irregularities and/or hirsutism and polycystic ovaries, who were homozygous for class III alleles, were more frequently anovulatory and had increased BMI and fasting insulin compared with women homozygous for class I alleles. Paternal transmission of class III alleles from heterozygous fathers to anovulatory PCOS patients is more frequent than maternal transmission of the allele [28–30], and in addition, class III alleles predisposed these patients to both PCOS and type 2 diabetes mellitus. However, other studies were not able to prove this [31, 32], and unluckily the INS locus was not associated with PCOS in an American linkage study on PCOS patients [15].
· Insulin Growth Factor System Genes: IGFs, their receptors, binding proteins, and proteases are important for the normal development of the ovary [33].
They are peptide hormones secreted having important functions such as mediation of growth hormone action, stimulation of growth of cultured cells, stimulation of the action of insulin, and involvement in development and growth. IGFs stimulate ovarian cellular mitosis and steroidogenesis, inhibit apoptosis, and might be related to the development of functional hyperandrogenism and PCOS [34].
In particular, IGF-2 stimulates adrenal and ovarian androgen secretion: the increased frequency of homozygosis for these alleles could contribute to hyperandrogenism in PCOS patients [35].
· Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ): They are members of the nuclear receptor superfamily of ligand-activated transcription factors [36]. These genes are involved in adipocyte differentiation, lipid and glucose metabolism, and atherosclerosis [37]. The human PPAR-γ gene is composed of nine exons; recent studies have indicated that the modified Ala12 allele is involved in increased insulin sensitivity by enhanced suppression of lipid oxidation, enabling more efficient glucose disposal [38].
· Calpain-10: It is an enzyme that has an important role in insulin secretion and action [39]. The 112/121 haplotype combination of the University of Chicago single nucleotide polymorphisms (UCSNP)-43, UCSNP-19, and UCSNP-63 in the gene encoding calpain-10, located at 2q37.3, has been reported to increase the risk for diabetes [40]. Some authors found no association between this haplotype and PCOS patients [41, 42], while recently a Spanish study reported an association between PCOS and USCNP-44 [43, 44].
More recently, genes encoding inflammatory cytokines have been identified as target genes for PCOS, as pro-inflammatory genotypes and phenotypes are also associated with obesity, insulin resistance, type 2 diabetes, PCOS, and increased cardiovascular risk.
· Paraoxonase (PON1): The PON1 gene is mainly expressed in the liver and encodes for serum PON1, which is an antioxidant high-density lipoprotein-associated enzyme. Liver PON1 mRNA expression is influenced by genetic and environmental factors, and both androgens and pro-inflammatory mediators decrease liver PON1 expression [45].
Homozygosis for T alleles of the −108C/T polymorphism in PON1 was more frequent in PCOS patients compared with non-hyperandrogenic women. Patients homozygous for −108T alleles of PON1 had increased hirsutism scores, total testosterone, and free testosterone and androstenedione levels related to those carriers of −108C alleles [35]. Nowadays, it is well known that oxidative stress may damage insulin action. Indeed, reduced serum PON1 activity might contribute to the insulin resistance of PCOS patients [46].
· TNF-α: In vitro, this growth factor stimulates proliferation and steroidogenesis in theca cells and helps insulin and IGF-1 to exert their effects on the ovary [47].
Nine polymorphisms in the TNF-α gene were studied (−1196C/T, −1125G/C, −1031T/C, −863C/A, −857C/T, −316G/A, −308G/A, −238G/A, and −163G/A), but no differences between patients and controls were found: only lean hyperandrogenic patients showed increased serum TNF-α levels [48]. This finding might imply that TNF-α gene does not have a major role in PCOS etiology but could be a modifying factor for phenotypic features [6].
· TNFR2 Gene (TNFRSF1B): TNFR2 mediates most of the metabolic effects of TNF-α [49]. The 196Arg allele of the Met196Arg (676T/G) polymorphism in exon 6 of this gene was more frequent in patients with PCOS compared with healthy controls, and it was hypothesized that it was responsible for modulating TNF-α in target tissues [50].
· IL-6: This cytokine seems to be implicated in insulin resistance mechanism, and increased levels were found in peritoneal fluid of anovulatory PCOS patients, suggesting a role in the pathogenesis of hyperandrogenic disorders [51]. Common polymorphisms in both subunits of the IL-6 receptor were studied, and the Arg148 allele of the Gly148Arg polymorphism in the gp130 gene was more frequent in controls compared with hyperandrogenic patients: control women had lower 11-deoxycortisol and 17-hydroxyprogesterone concentrations and a significant decrease in free testosterone levels, suggesting that this polymorphism might have a protective effect against androgen excess [52].
Moreover, there are also other genetic structural variations that regulate gene and phenotype expression, such as telomeres: they are at the ends of eukaryotic chromosomes and are specialized chromatin structures composed of highly conserved tandem hexameric nucleotide repeats—TTAGGG—that extend for several kilobases [53]. Telomeres shorten progressively with each cell division, and their length is largely inherited and modulated by a variety of genetic and environmental factors [54]. Short telomeres can cause chromosomal instability, and this could be the reason of genetic mutations and chromosome abnormalities.
There is a correlation between oxidative stress and PCOS and between oxidative stress and telomere length. For this reason, it has been hypothesized that telomere length plays an important role in the pathophysiology of PCOS.
In a Chinese study, the mean telomere length was measured in a large cohort of PCOS patients and controls, and the association between telomere length and this endocrine–metabolic disease was analyzed. A significant reduction of telomere length was observed in PCOS patients compared with healthy controls. Individuals with the shorter telomere length had significantly higher disease risk than those with the longest telomere length, after adjustment for age. One possible mechanism for the shortened telomeres in PCOS patients is that some etiological factors of PCOS, such as androgen excess, abdominal adiposity, insulin resistance, and obesity, could contribute to raised oxidative stress that leads to telomere shortening. This could represent a negative feedback cycle in which shortened telomeres, in turn, affect endocrine-, metabolic-, or reproductive-related gene expression and worsen the abnormal metabolic phenotypes of the disease [55].
2.2 PCOS Physiopathology
It has been shown that polycystic ovary presents a greater number of small antral follicles (2–9 mm in diameter) than the normal ovary. This morphological scenario could be the consequence of a potential dysregulation of the recruitment mechanism of primordial follicles that, on the contrary, are present in physiological number.
On the other hand, the final pathway of follicular growth, which is gonadotropin dependent, is blocked in the majority of PCOS patients, and it is the basis of anovulation and oligo-/amenorrhea.
In a normal cycle, only the dominant follicle responds to LH action when it reaches 10 mm in diameter. In PCOS patients, the response to LH occurs inappropriately in smaller follicles; a large number of antral follicles reach a terminal differentiation before the appropriate time, producing a larger amount of steroids and inhibin B that have a negative feedback on the production of FSH: the result is the arrest of follicular growth.
As underlined before, the etiology of this syndrome is still partly unknown, but it is likely to be multifactorial. The most significant theories are explained below:
· Exaggerated Adrenarche: It is possible that PCOS might be established and maintained in response to an abnormal adrenal hypersecretion of androgens due to congenital adrenal enzyme deficiency [56].
Yen suggested an etiopathogenetic model, which provides, in response to a stress condition, a transient adrenal androgen hypersecretion, triggering an abnormal pattern of the pituitary gonadotropins’ pulsatility. As puberty progresses, the adrenal cortex is replaced by ovaries in maintaining the hypersecretion of androgens.
Finally, the increase in ovarian androgen level changes adrenal specific enzyme activities involved in the process of steroidogenesis [57].
· Abnormal Secretion of Gonadotropins: The high levels of LH in women with PCOS are due to greater amplitude of the peaks of this hormone and its increased frequency of pulsatility; on the contrary, the average concentration of FSH is mostly decreased. The high levels of LH are not caused by an inability of the hypothalamic-pituitary axis to respond to the negative feedback exerted by estrogen, but it might be caused by the high pituitary sensitivity to LH-RH. The chronically elevated and acyclic levels of estrogens in PCOS patients may, in turn, increase both the basal levels of LH and LH response to GnRH.
Moreover, an elevated endogenous opioid tone might cause an exceeding GnRH release with a following abnormal LH pulsatility, causing increased level of LH-dependent ovarian androgens [58].
· Rosenfield’s Hypothesis: Rosenfield suggested that PCOS results from a hyperactivity of cytochrome P450c17α in the ovarian theca cells. This enzymatic complex binds progesterone and converts it sequentially in 17-hydroxyprogesterone (via a 17α-hydroxylation) and androstenedione (via a C-17,20-lytic activity). The steroidogenetic route particularly involved in the ovary is the Δ-4 pathway.
Moreover, at adrenal level, cytochrome P450c17α forms 17-ketosteroids, especially using the Δ-5 steroidogenetic pathway, and it creates more dehydroepiandrosterone than androstenedione. An abnormal regulation of this enzyme activity, therefore, both at ovarian and adrenal levels, could explain the androgenic hyperfunction of both glands, as occurs in PCOS.
Rosenfield proposed three hypotheses to explain the hyperactivity of this enzymatic complex:
1.
2.
3.
However, according to Rosenfield, the hyperactivity of cytochrome P45017α cannot be the unique cause of PCOS, but it is part of a more complex etiopathogenetic model [59].
· Hyperestronemia: Increased levels of estrone (E1), characteristic of polycystic ovary, are able to modify the normal patterns of gonadotropins’ pulsatility. This high E1 level in PCOS women is generally the result of an increased ovarian production of androstenedione (A) and its conversion into E1 by a specific FSH-dependent enzyme called aromatase.
This enzyme is present in adipose tissue; thus, overweight or obese women have a greater amount of enzyme and, consequently, more estrone compared to normal-weight subjects. Alternatively, estrone levels might be increased in lean women with high production of androstenedione. The part of testosterone converted to estrone is very poor, and probably for this reason, the hypertestosteronemia per se is not able to affect significantly the gonadotropins’ pulsatility [60].
Many women with PCOS are overweight or obese: these conditions are usually associated with low levels of SHBG. This globulin binds both testosterone and estradiol: thus, in conditions in which SHBG is reduced, consequently, estradiol free fraction (the most biologically active) is increased.
This condition causes a negative impact on the release of FSH with consequent alteration of folliculogenesis process and increased release of LH, which is followed by an increased ovarian androgen synthesis.
In addition, the increase of androgen plasma levels contributes to the reduction of hepatic biosynthesis of SHBG.
· Hyperinsulinemia: High level of insulin accelerates the development of granulosa cell LH responsiveness by amplifying the induction of LH receptors, and thus, it induces a block of follicular growth with multiple small follicle formation.
The role of insulin is properly discussed in Sect. 2.3.
2.3 Role of Insulin in the Pathogenesis of PCOS
Insulin controls glucose homeostasis stimulating glucose uptake by tissues that are responsive to insulin (adipocytes, skeletal and cardiac muscle) and by suppressing hepatic glucose production [61, 62]. In addition, insulin decreases free fatty acid levels by suppressing lipolysis [63], and it promotes cell growth and differentiation [64].
“Insulin resistance” is defined as “a decreased ability of insulin to mediate its metabolic actions on glucose uptake, glucose production and lipolysis, requiring increased amounts of insulin to achieve its proper metabolic action.”
In fact, increased circulating insulin levels characterize insulin resistance if pancreatic β-cells are functionally intact [65].
Insulin exerts its function by binding to its cell surface receptor; ligand binding induces auto-phosphorylation of the insulin receptor on specific tyrosine residues, and this actives its intrinsic kinase activity, while serine phosphorylation inhibits it [66, 67].
The tyrosine-phosphorylated insulin receptor phosphorylates, in turn, intracellular substrates, such as IRS 1–4, Shc, and APS to start signal transduction [68–70].
Insulin stimulates glucose uptake by translocating GLUT-4 (the insulin-responsive glucose transporter) from intracellular vesicles to the cell surface [68, 70].
This pathway is mediated by activation of PI3K and Akt/PKB, which also leads to serine phosphorylation of GSK3 (glycogen synthase kinase 3), resulting in inhibition of its kinase activity: this inhibition causes dephosphorylation of glycogen synthase, increasing glycogen synthesis, and also dephosphorylation of eIF2B which increase protein synthesis [64, 70].
Insulin has also an important mitogenic action: it stimulates cell growth and differentiation through the MAPK-ERK pathway [64].
This route is activated by insulin receptor-mediated phosphorylation of Shc or IRS, which stimulates a cascade of serine/threonine kinase resulting in stimulation of MAP kinase and MAPK-ERK 1/2. ERK 1/2 translocates to the nucleus and phosphorylates transcription factors to start cell growth and differentiation.
This mitogenic pathway can be altered without affecting the metabolic actions of insulin and vice versa [64].
Insulin signaling can be terminated by dephosphorylation of the receptor by tyrosine phosphatases; in addition, serine phosphorylation (mediated by serine kinases) of the insulin receptor and its substrates can decrease insulin signaling as well [64, 70].
There is a post-binding defect in insulin signaling in PCOS women, resulting in marked insulin sensitivity decrease. The defect is due to serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases. This causes a decreased activation of PI3K mediated by insulin and resistance to the metabolic actions of insulin too [71].
Moreover, supporting this theory, it was shown that serine kinase inhibitors corrected the phosphorylation defect, underlining the role of a serine kinase extrinsic to the insulin receptor as the cause of decreased receptor auto-phosphorylation. This defect in the first phases of the insulin signaling pathway is present in adipocytes [72, 73] and skeletal muscle [71, 74], which are the most important target tissues for glucose uptake stimulated by insulin.
Even if obesity is the major contributing factor for insulin resistance in PCOS women, dysfunction in post-receptor mechanism action could be a good explanation for insulin-resistant lean/normal-weight PCOS women.
Moreover, ovarian granulosa lutein cells could be considered a selective target tissue too, in which insulin resistance is selective, affecting only the metabolic but not the mitogenic action of insulin.
In addition, it has been taken into consideration the crucial role of serum fetuin-α in the inhibition of insulin receptor tyrosine kinase activity [75].
It is a carrier protein like albumin, and a recent study has shown that fetuin-α serum levels are higher in PCOS women, having probably a role in triggering the processes that lead to insulin resistance and androgen excess in PCOS [76].
Furthermore, it was supposed that hyperinsulinemia might be the result of a decreased insulin clearance or of an increased insulin secretion [77, 78].
Insulin clearance is receptor mediated; thus, insulin-resistant patients are supposed to have a decreased clearance because of intrinsic or acquired decrease in receptor number and/or function [78, 79].
Some authors have shown that fasting hyperinsulinemia in PCOS women is the result of a combination of increased basal insulin secretion and decreased hepatic insulin clearance [80, 81].
Lots of evidence demonstrate a direct insulin action on ovarian steroidogenesis and the importance of the insulin signaling pathway in the control of ovulation. Obviously, insulin receptors are present both in normal and polycystic ovary syndrome women. IGF-1 (insulin growth factor 1) is synthetized by the ovary, and its receptor is a tyrosine kinase with few structural and functional homologies with the insulin receptor [82, 83].
Insulin can bind to the IGF-1 receptor activating it, and IGF-1 can bind to and activate the insulin receptor [84, 85].
The affinity of the IGF-1 receptor for insulin is less than it is for IGF-1 and vice versa; despite this, the two receptors can assemble together to form a hybrid tetramer, which is able to bind insulin and IGF-1 in the same way. Therefore, some insulin action on the ovary may be mediated by IGF-1 or hybrid insulin–IGF-1 receptor [86, 87].
Some studies have shown that insulin action on steroidogenesis in granulosa and theca cells is mediated via insulin receptor, both in normal and PCOS women [88, 89]. Moreover, in PCOS granulosa cells, increased insulin levels might cause premature LH receptor expression in small follicles, leading to premature granulosa terminal differentiation and the arrest of follicular growth, which is the basis for anovulation.
In normal theca cells, insulin and LH activate 17α-hydroxylase activity of P450c17α, a crucial enzyme in the regulation of androgen biosynthesis encoded by CYP17, via PI3K signaling; inhibition of MAPK-ERK1/2 signaling has no effect on 17α-hydroxylase activity [89].
It seems that PCOS theca cells are more responsive to the androgen-stimulating insulin actions rather than normal controls [90].
Physiologically, insulin acts as a “co-gonadotropin” to increase androgen synthesis induced by LH in theca cells [91–93] and to boost FSH-mediated estrogen production and LH-induced luteinization in granulosa cells [94].
Furthermore, human studies have demonstrated that insulin can increase circulating androgen levels in PCOS women: insulin infusion during euglycemic clamp studies increased androgen level without altering gonadotropin secretion, suggesting a direct effect on steroidogenesis [95, 96].
Suppressing insulin levels leads to decreased testosterone levels in women with PCOS, while there is an increase in SHBG levels [97–99]. Thus, low insulinemia is the basis for normal to low androgen production in the ovary and for increasing SHBG levels which leads to low circulating active androgen levels too.
The correlation between PCOS, insulin, hyperandrogenism, and ovarian dysfunction is well exemplified in Fig. 2.1.
Fig. 2.1
Correlation between PCOS, hyperinsulinemia, hyperandrogenism, and ovarian dysfunction
Moreover, insulin action on adrenal androgen production and gonadotropin secretion is not yet well known. Lowering insulin levels with ISD (insulin-sensitizing drugs) resulted in DHEAS decrease in PCOS women [100, 101]; other studies also suggested that insulin resistance and consequent hyperinsulinemia cause a reduced pituitary sensitivity to GnRH, contributing to anovulatory syndrome [102, 103].
According to all these findings, insulin could be defined as a “reproductive hormone” as well.
The central paradox in the pathophysiologic association between hyperinsulinemia and hyperandrogenemia in PCOS is that the ovary remains sensitive to insulin activity and consequent androgen production, despite a systemic insulin resistance: it is the so-called selective insulin resistance theory [104].
On the other hand, androgens can produce insulin resistance by direct effects on the skeletal muscle and adipose tissue insulin action, by altering adipokine secretion, and by increasing visceral adiposity, even if these effects on insulin actions are modest [105].
Additionally, adipose tissue in PCOS women is characterized by hypertrophic adipocytes and impaired lipolysis and insulin action. TNF-α, as well as other adipokines involved in insulin resistance, is altered in these kinds of patients [106].
Adiponectin applies insulin-sensitizing properties by stimulating fatty acid oxidation and reducing hepatic gluconeogenesis: some studies hypothesized that its dysregulation could be implicated in the pathogenesis of insulin resistance [107].
TNF-α is secreted by adipose tissue macrophages and has pro-inflammatory properties: it causes serine phosphorylation of the insulin receptor substrate (IRS-1).
IGFBP3 is secreted by hepatic Kupffer cells and inhibits insulin-stimulated glucose uptake by dephosphorylating insulin receptor.
Both TNF-α and IGFBP3 might inhibit transcription of adiponectin, contributing to insulin resistance [108]: in fact low levels of adiponectin were found in patients with PCOS [109].
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