1. The Metabolic Syndrome in PCOS

3. An international consensus group of the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM)4 recently established that PCOS is diagnosed by the presence of at least 2 of the following: oligo-ovulation or anovulation, clinical or laboratory evidence of hyperandrogenism, and polycystic ovaries as defined by ultrasonography

4. Ultrasound criteria: ---increased ovarian area/volume ---10-15 microcyst(<10 mm diameter) organized in a peripheral rosary pattern. ---increased echogenicity of ovarian stroma.

6. In addition, the definition requires the exclusion of other medical conditions that cause irregular menses and androgen excess

8. Pathogenesis of the Metabolic Syndrome in PCOS Possible theories regarding the association include: (1) insulin resistance underlies the pathogenesis of both the metabolic syndrome and PCOS;

9. (2) obesity and related adipose tissue factors, independently of insulin resistance, are the major pathogenic contributors to both conditions

10. (3) vascular and coagulation abnormalities are the primary pathogenic contributors to both conditions

11. Aberrant Gonadotropin Secretion Women with PCOS have increased LH pulse frequency and amplitude. This is secondary to increased pulse frequency of gonadotropin-releasing hormone, which selectively increases LH release, resulting in an elevation of the absolute level of circulating LH compared to that of control subjects

12. Androgen production by ovarian thecal cells is LH-dependent, and the elevated LH likely contributes to the excess androgens. Lowering LH levels using oral contraceptives or gonadotropinreleasing hormone agonists decreases androgen levels

13. In contrast to LH, follicle stimulating hormonelevels chronically remain in the midfollicular range,which is an insufficient level for adequately aromatizing androgens into estrogens within the ovarian follicles. Follicle growth and development is arrested and anovulation results

14. Hyperandrogenism In addition to altered gonadotropin dynamics contributing to increased androgen production, there isalso evidence that the thecal cells from the ovaries of PCOS patients are innately different from control thecal cells. Both in vivo and in vitro studies show that thecal cells derived from PCOS ovaries are more efficient at converting androgen precursors to testosterone than thecal cells from control ovaries

15. Adrenal androgen production (and not ACTH) is also increased in many PCOS patients, suggesting that there may be a common defect in ovarian and adrenal biosynthesis

16. Insulin Resistance Many PCOS women, both obese and nonobese, are insulin resistant and insulin resistance is believed to play a prominent role in the pathophysiology of the syndrome

17. Insulin resistance may contribute to hyperandrogenic, anovulatory dysfunction through multiple ways: in vitro and in vivo studies suggest that insulin via its own receptor or via type1 insulin-like growth factor receptors synergizes with LH to promote androgen production by thecal cells; insulin inhibits hepatic synthesis of sex hormone binding globulin, thereby increasing the free pool of androgens

19. Insulin may affect the pituitary by favoring the secretion of luteinizing hormone; and insulin increases adrenal androgen production by enhancing adrenal sensitivity to ACTH. Additionally, insulin may stimulate cytochrome P450- c17 enzyme activity as suggested by the reduction of enzyme activity when insulin-sensitizing agents are used or weight loss is achieved

20. Nevertheless, it is likely that a combination of various factors interacts with or results from insulin resistance to manifest the metabolic abnormalities of the metabolic syndrome and PCOS

21. In addition, genetic susceptibilities and genetic polymorphisms or mutations likely contribute to the expression of these manifestations

23. Metabolic Syndrome in Women With PCOS Of the metabolic abnormalities diagnostic of the metabolic syndrome, low high-density lipoprotein cholesterol (HDL-C) occurred most frequently (68%), followed closely by elevated body mass index (BMI) and waist circumference (67%), high blood pressure (45%), hypertriglyceridemia (35%), and elevated fasting glucose (4%)

24. Compared to women with PCOS who did not meet the diagnostic criteria of the metabolic syndrome, women with PCOS and the metabolic syndrome more frequently demonstrated the phenotypic feature of acanthosis nigricans, a marker of insulin resistance

26. Apridonidze et al also reported that PCOS women with the metabolic syndrome had more hyperandrogenemia than PCOS women without the metabolic syndrome

27. Several factors have been shown to predict the risk of metabolic syndrome among women with PCOS Fasting insulin — although not used to diagnose metabolic syndrome or PCOS — has been reported to be twice as high in women who meet the criteria for both PCOS and metabolic syndrome compared with women diagnosed with PCOS alone

28. In addition, this same group of investigators reported that obesity, a key determinant of insulin concentrations, has an independent effect on the risk for metabolic syndrome in women with PCOS. Among their cohort of 394 women with PCOS, women in the highest quartile for BMI had a 14-fold increased chance of having the metabolic syndrome

29. Further, they found that women with PCOS who have a family history of diabetes meet a greater number of individual diagnostic criteria for the metabolic syndrome than women with a negative family history

30. Risk for Type 2 Diabetes Mellitus in Women With PCOS Insulin resistance and compensatory hyperinsulinemia are well-recognized pathogenic factors in both metabolic syndrome and PCOS

31. Among women with PCOS, 30% to 40% have impaired glucose tolerance and 7.5% to 10% have type 2 diabetes by their fourth decade

32. Legro et al14 recently reported an annual conversion rate of 16% from normal to impaired glucose tolerance among women with PCOS

33. Data from the US and Australia suggest the conversion rate from impaired glucose tolerance to frank diabetes is 5- to 10-fold higher among women with PCOS

34. Converse to evidence that women with PCOS have a high risk of type 2 diabetes, studies have also revealed that a higher prevalence of PCOS is present among premenopausal women with type 2 diabetes

35. Not surprisingly, the American Association of Clinical Endocrinologists recommends routine screening for diabetes with an oral glucose tolerance test by the age of 30 for all women with PCOS

36. Risk for Cardiovascular Disease in Women With PCOS In comparison with normally cycling women of similar age, women with PCOS have been reported to have an increased prevalence of several cardiovascular risk factors, including hypertension, dyslipidemia, and surrogate markers for early atherosclerosis

37. In addition, PCOS has been associated with evidence of endothelial dysfunction and subclinical cardiovascular disease

38. Furthermore, overweight adolescents with PCOS already demonstrate at an early age abnormalities in nocturnal blood pressure regulation. With increasing age, the incidence of hypertension in PCOS rises. Postmenopausal women with PCOS have a 2-fold increased prevalence of hypertension compared with aged-matched controls

39. Dyslipidemia has been reported to occur frequently in women with PCOS, with the abnormal lipoprotein profile characterized by reduced HDL-C levels, elevated triglyceride levels, elevated low density lipoprotein cholesterol (LDL-C) levels, and higher LDL-to-HDL ratios

40. Both obese and lean women with PCOS have dyslipidemia, with lean women more often presenting with reduced levels of HDL-C and an HDL-subfraction known as HDL-2. Of note, a low-HDL-C level is an especially strong predictor of cardiovascular disease in women

41. In addition to hypertension and dyslipidemia, women with PCOS display several surrogate markers for early atherosclerosis and cardiovascular disease, including increased C-reactive protein concentrations, plasminogenactivator inhibitor type 1, endothelin-1, leukocytes, and reduced fibrinolysis

42. Several studies have documented an increased risk of subclinical cardiovascular disease in women with PCOS. In 1990, Wild et al64 evaluated 102 women presenting for coronary artery catheterization for past symptoms and signs of hyperandrogenism and reported that a history of significant hirsutism and acne as well as an elevated waist-to-hip ratio were more common in women with confirmed coronary artery disease

43. Christian et al68 evaluated 36 premenopausal women with PCOS and 71 ovulatory women between ages 30 and 45 for coronary artery calcifications. They reported that coronary artery calcifications were more prevalent in PCOS women (39%) than in BMI matched controls (21%; odds ratio, 2.4; P=0.05) or nonobese women of similar age (9.9%; odds ratio, 5.9; P<0.001)

44. Clinical Evaluation of Metabolic Syndrome in PCOS The association of PCOS with insulin resistance and the consequent increase in the risk for type 2 diabetes and cardiovascular disease indicates that PCOS is not only a reproductive problem but also a general health problem

45. When evaluating women with PCOS, including younger adolescents, physicians should assess for the presence of components of metabolic syndrome. Therefore, clinical evaluation should include assessments of blood pressure, waist circumference and/or BMI, fasting lipid profile, and glucose tolerance by a 2-hour oral glucose tolerance test

46. Therefore, the measurement of fasting serum glucose is not an effective screening tool to exclude impaired glucose tolerance and diabetes in women with PCOS, and that an oral glucose tolerance test should be performed, particularly in obese women or adolescents with PCOS and those with a family history of type 2 diabetes

47. Summary One-third to nearly half of all women diagnosed with PCOS meet criteria for the metabolic syndrome and over 90% of all women with PCOS have at least one adverse cardiovascular risk factor, suggesting an increased risk of cardiovascular disease in the syndrome

48. Furthermore, these metabolic abnormalities may be already present in adolescence. The insulin resistance associated with PCOS increases the risk of glucose intolerance, diabetes, and dyslipidemia, and treatment improving insulin sensitivity with weight loss and/or pharmacotherapy has proven beneficial

49. Early screening for glucose intolerance is essential in all women with PCOS, even those who are young adolescents