3. Insulin and PCOs

According to epidemiological data, there is a wide variation in the prevalence of obese and non-obese PCOs women: in Korean population 20%, in Europe 27–50.5%, and in USA 67% of PCOs woman are obese [7–11]. Regarding to different ethnicity, the prevalence of normal weight and underweight patients with PCOs has been reported 1.5–6.6% [12, 13]. Entirely, by using Rotterdam criteria, the overall prevalence of PCOs is increasing because ovulatory or

Hyperandrogenism hyperandrogenemia Hyperandrogenismhyperandrogenemia Hyperandrogenism

Oligo-ovulation Menstruation abnormality Ovarian dysfunction

Exclusion of other androgen excess conditions is necessary for all of definition: (21-hydroxylase deficient, thyroid dysfunction, nonclassical adrenal hyperplasia, hyper prolactinemia, drug-induced androgen excess, androgenic neoplasm,

Sonographic aspect of poly cystic ovary

/ASRM<sup>2</sup> (Rotterdam) 2003 (two of three) AES 2006 (all of them)

hyperandrogenemia

sonographic aspect

By definition, women with BMI ≤ 25 are non-obese and with BMI > 25 considered obese.

Although at now, we have a few reports about the prevalence of non-obese PCOs patients, but attention toward those patients and their metabolic and health problems are enhanced day by day. The pathophysiology of PCOs is multifactorial and manifests the final effect of genetic, fetal, environmental, and metabolic factors. As a result of weakness or strength of each factor, clinical and subclinical character and their response to therapeutic efforts will be different.

Obvious familial clustering of PCOs and higher prevalence of its sign and symptom, like type 2 diabetes mellitus (T2DM) and hyperandrogenemia in first-degree relatives of women with PCOs, demonstrate its genetic origin [15, 16]. Also, in the Dutch twin study, higher degree of heritability was shown [17]. Initially, autosomal dominant mode of inheritance was suggested [18]; but after a while, researches demonstrate it has more complex inheritance pattern. Despite the progress in genes or loci study, no single gene has been successfully described as the certain responsible gene among all studies [19]. According to microarray analysis results, 14 important genes were recognized: 6 genes were identified as down-regulated genes and 8 genes as up-regulated genes [20]. Another proposed genes are CYP11A, the insulin gene, and a region near the insulin-receptor gene [21]. Also, controlling genes in folliculogenesis and LH receptor and coding genes for TNF-

alpha, IL-6, and IL-6 receptor can be involved in the pathogenesis of this syndrome [22].

non-hyper androgen PCO patients also are considered [14].

NIH Criteria 1990 (all of them) ESHRE<sup>1</sup>

24 Debatable Topics in PCOS Patients

Cushing syndrome, growth hormone excess).

American Society for Reproductive Medicine.

European Society for Human Reproductive Medicine.

Table 1. Different definition of polycystic ovary syndrome.

1

2

2. Genetic and PCOs

For the first time in 1980, the relation between this syndrome and insulin was determinate [23]. Clinically insulin resistance (IR) is specified as inability of a known amount of endogenous or exogenous insulin to enhance glucose uptake and consumption. As a result of a misbelief that IR always accompanies with obesity, in clinical practice, IR is underestimated in non-obese PCO women. IR is a common character between obese and non-obese PCO patients and its overall prevalence is 50–75%. Up to 35% of PCOs women have IGTT and 7–10% are type 2 diabetes mellitus (T2DM) [24].

At now, the most used IR indices are homeostasis-model assessment (HOMA) and insulinemic 2-h area under the curve (AUCi 2 h), both derived from oral glucose tolerance test (OGTT) [25]. The 120-min glucose and insulin evaluation (HOMA-M120) is the best IR index in lean PCOs women according to Morciano et al. study [26]. Meanwhile, there are several earlier studies about IR evaluation in lean PCOs women [27–29]. Although, a study in a large group of European lean PCOs patients displayed that this group had significantly less IR compared with obese PCO women [30]; but, instead of it, there is evidence that in American and Asian PCOs women, IR is independent from BMI [31]. It seems that dietary composition and ethnic background associated with this discrepancy.

Owing to another recent study, the crucial role of insulin in PCO pathogenesis emphasized that IR shall be evaluated even in normal weight and lean PCOs patients [12].

As suggested in the earlier study [32], hyperinsulinemia stimulates ovarian P450c17 alpha activity in non-obese women with PCOs, which means more conversion of progesterone to androstenedione which is changed to testosterone. In granulosa cell, insulin intensifies their response to LH. Therefore, these cells experience premature arrest of follicular growth and abnormal differentiation, and thus anovulation. Also, elevated insulin resistance causes hyperglycemia which leads to hyperinsulinemia and it can increase LH action on theca cells and subsequent elevation in androgen level. Hyperinsulinemia, insulin resistance, and enhancement in androgen production are the famous pathophysiology triads in PCOs. From another side, elevated level of insulin prevents hepatic sex hormone-binding globulin (SHBG) production, which can lead to elevated free androgen and again elevated level of insulin, a positive feedback in an undesirable circle. Thus, IR and hyperinsulinemia are the principal pathological causes of this syndrome, and hyperandrogenemia is their consequence.

As insulin resistance has fundamental role in non-obese PCOs patients, then metformin administration have a beneficial effect on them and regulate their menstruation cycle [33]. As well, there is a new therapeutic option: inositol, a precursor component of second messenger for follicle-stimulating hormone (FSH), thyroid - stimulating hormone (TSH), and insulin receptor. This drug can overcome IR from another way [34]. It is important to mention that only 15% of women with IR are having PCOs criteria; therefore, insulin resistance cannot be the only pathophysiologic pathway [35] and metformin administration may not be effective in all of lean PCOs.
