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:

The second group of genes includes those involved in insulin resistance and metabolic disorders, which are:

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.

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].

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:

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.