**5. Obesity and PCOS**

The prevalence of obesity has increased worldwide in the last few decades [52]. Obesity status is defined according to the body mass index (BMI=body weight in kilograms divided by height in meters 2 ) of 30 kg/m2 or more. BMI of 25 to 29.9 kg/m2 is defined as 'over‐ weight', while BMI of less than 25 kg/m2 is considered normal [53]. This had significant impact on the development of chronic diseases such as the metabolic syndrome, coronary heart disease and type 2 diabetes. Also, central obesity can be diagnosed clinically by measuring the waist circumference (WC) larger than 88 cm or waist-to-hip circumference ratio (WHR) greater than 0.85, confer high risk for metabolic complications in obese individuals with BMI between 25.0 and 34.9 kg/m2 .

However, obesity is a common finding in women with PCOS and between 40–80% of women with this condition is reported to be overweight, obese or centrally obese depending on the setting of the study and the ethnical background of the subjects [53-55]. Obesity has a worse additive effect on features of PCOS such as insulin resistance, hyperandrogenism, infertility, hirsutism and pregnancy complications [56].

The relationship between PCOS and obesity is complex, and most likely involves interaction of genetic and environmental factors [57]. Obesity in PCOS is usually of the central variety. It is shown that central obesity is associated with increased risk for diabetes, hyperlipidemia, hypertension, atherosclerosis, and insulin resistance [58]. Fat localized in the upper body is correlated with significantly reduced overall clearance of insulin, which contributes to hyperinsulinemia [59]. The mechanisms underlying obesity causes insulin resistance are not fully understood, the 2 main pathogenetic hypotheses that have been proposed focus on the roles of free fatty acids (FFAs) and tumor necrosis factor-α (TNF-α). FFAs, which are released from adipose tissue triglycerides via lipolysis, as mediators of impaired insulin sensitivity, elevate in PCOS patients. Increased FFA flux into the liver, irrespective of its source, decreases hepatic insulin extraction, increases gluconeogenesis, and produces hyperinsulinemia [60]. Additionally, high circulating FFA concentrations lead to peripheral insulin resistance by reducing glucose uptake by the skeletal muscle [61].

glucose tolerance by a 2-hour oral glucose tolerance test have been suggested and aboratory studies for cardiovascular risk markers such as C-reactive protein and homocysteine are recommend [46, 47]. There were therapeutic overlap between PCOS and MetS. *Weight loss with life-style modification* is the safest and cheapest therapy that has shown benefit both in MetS and

Reduction of insulin resistance is the primary goal for Weight loss in women with PCOS. Lifestyle modification through increased physical activity and reduction in body weight, especially waist circumference, represents the first-line therapy for MetS in PCOS. Successful mainte‐ nance of exercise and weight loss can lower blood pressure, central adiposity, and very low density lipoprotein cholesterol while improving lipid profile and insulin sensitivity [21, 48]. *Medical therapies for insulin resistance* with pharmacological approaches like metformin improve insulin sensitivity, glucose control and even reproductive abnormalities. Also metformin could

However, evidence has demonstrated that a combination of metformin and lifestyle modifi‐ cation improves the metabolic profile in women with PCOS to a greater degree than either

The prevalence of obesity has increased worldwide in the last few decades [52]. Obesity status is defined according to the body mass index (BMI=body weight in kilograms divided

weight', while BMI of less than 25 kg/m2 is considered normal [53]. This had significant impact on the development of chronic diseases such as the metabolic syndrome, coronary heart disease and type 2 diabetes. Also, central obesity can be diagnosed clinically by measuring the waist circumference (WC) larger than 88 cm or waist-to-hip circumference ratio (WHR) greater than 0.85, confer high risk for metabolic complications in obese

However, obesity is a common finding in women with PCOS and between 40–80% of women with this condition is reported to be overweight, obese or centrally obese depending on the setting of the study and the ethnical background of the subjects [53-55]. Obesity has a worse additive effect on features of PCOS such as insulin resistance, hyperandrogenism, infertility,

The relationship between PCOS and obesity is complex, and most likely involves interaction of genetic and environmental factors [57]. Obesity in PCOS is usually of the central variety. It is shown that central obesity is associated with increased risk for diabetes, hyperlipidemia, hypertension, atherosclerosis, and insulin resistance [58]. Fat localized in the upper body is correlated with significantly reduced overall clearance of insulin, which contributes to hyperinsulinemia [59]. The mechanisms underlying obesity causes insulin resistance are not fully understood, the 2 main pathogenetic hypotheses that have been proposed focus on the

) of 30 kg/m2 or more. BMI of 25 to 29.9 kg/m2 is defined as 'over‐

.

decreases weight and BMI, blood pressure and LDL cholesterol [49, 50].

PCOS.

84 Contemporary Gynecologic Practice

measure alone [51].

**5. Obesity and PCOS**

by height in meters 2

individuals with BMI between 25.0 and 34.9 kg/m2

hirsutism and pregnancy complications [56].

TNF-α is produced by adipose tissue has been increasing in hyperandrogenic PCOS women. It leads to insulin resistance by stimulating the phosphorylation of serine residues of the insulin receptor substrate-1. Consequently, tyrosine kinase activity of the insulin receptor β-subunit, the rate-limiting component of the insulin receptor signaling cascade, is inhibited [62].

However, obese and non-obese PCOS patients may have differences in clinical manifestations. The differences in biochemical and clinical features between obese and non-obese PCOS patients allow determining, to some degree, the contributions of obesity to the clinical manifestations of PCOS. Differences in menstrual function have been reported, with obese patients exhibiting a greater prevalence of oligoamenorrhea and anovulation than non-obese women, And the prevalence of infertility has been increasing in obese PCOS patient [63]. Also, it is known that obesity has a direct relationship with the degree of hirsutism in PCOS patients. Obese women with PCOS had a greater prevalence of hirsutism, acanthosis nigricans, than non-obese patients, reflecting a higher prevalence and magnitude of insulin resistance and hyperinsulinemia among obese PCOS patients [64]. Impaired glucose tolerance, type 2 diabetes mellitus and the dyslipidemia has highest risk in obese PCOS patients. Overall, given the prevalence of risk factors for atherosclerosis in women with PCOS, a higher prevalence of cardiovascular events in these patients can be expected [65]. In addition, obese PCOS patients have higher prevalence of endometrial carcinoma than non-obese PCOS women. Anovulation, unopposed estrogen stimulation, and hyperinsulinemia may play a role in the increased risk of this gynecologic carcinoma in PCOS patients [66]. Also, it is reported that obstructive sleep apnea, pregnancy complications such as preeclampsia, gestational induced hypertension and gestational diabetes are more prevalent in obese PCOS patient [67, 68].

However, the impact of obesity on PCOS therapy is very important. Therapeutic modalities directed at the reduction of hyperinsulinemia (weight loss or insulin-sensitizing agents) appear to ameliorate symptoms of PCOS and restore normal ovarian function in obese women with PCOS.

*Weight loss,* especially more than 5% of the baseline weight, is the first-line therapy in treatment of these women. It leads to hormonal, menstrual, and metabolic improvement with increased serum concentrations of SHBG and reduced serum concentrations of free testosterone in obese women with PCOS. The mechanism by which weight loss leads to a reduction of hyperan‐ drogenism appears to involve improved insulin sensitivity with a resultant decline in circu‐ lating insulin levels [69]. *Metformin* can be suggested as a second-line treatment for most obese women with PCOS [70].
