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CO-MORBIDITIES IN P.C.O.S By: AUTHOR: Co morbidities in women with Polycystic Ovary Syndrome (PCOS)
INTRODUCTION PCOS is a chronic hyperandrogenic state that has many significant short-term and long-term implications for patients such as oligomenorrhea, amenorrhea, infertility, diabetes mellitus, cardiovascular disease, increased risk of endometrial cancer, and excessive body hair (hirsutism). Usually, a woman with PCOS seeks treatment for cycle control, cosmetic problems, or infertility. Nevertheless, such a visit provides the clinician with an opportunity to review the potential long-term health consequences and their preventive measures. DIABETES MELLITUS AND PCOS Insulin resistance and β-cell dysfunction are both known to precede the development of glucose intolerance and type-II DM1. Consequently PCOS women would be predicted to be at an increased risk for type-II DM2. The overall risk of developing type-II diabetes among women with PCOS was found to be increased 3-7 times3. Women with PCOS are at significantly increased risk for glucose intolerance (31·1% IGT) and type-II DM (7·5% undiagnosed diabetes) compared to concurrently studied age, weight and ethnicity-matched controls of the reproductive age. Non-obese PCOS women may also have glucose intolerance (10·3% IGT; 1·5% diabetes). Besides, these women tend to develop diabetes earlier in life, around the third or fourth decade. It is generally recommended, because of the known long-term complications of diabetes, that these young women be tested early in life and followed closely. These women should be screened in early pregnancy, as they have an increased risk of developing gestational diabetes345. Glucose testing: Glucose tolerance testing is important in PCOS. As many as 35% to 45% of PCOS patients will have impaired glucose testing and about 7% to 10% will have type-II diabetes mellitus. A fasting glucose to fasting insulin ratio less than 4.5 is predictive of insulin resistance. Values on the 2HR glucose tolerance test are as follows: 2H < 140 mg/dL (normal); 140-199 mg/dl (impaired glucose); and > 200 mg/dL (type-II diabetes). RELATIONSHIP OF CARDIOVASCULAR DISEASE TO PCOS Women with PCOS would be expected to be at high risk for dyslipidemia due to elevated androgen levels, body fat distribution, and hyperinsulinemic insulin resistance. Several studies have shown that women with PCOS exhibit an abnormal lipoprotein profile characterized by raised concentrations of plasma triglycerides, marginally elevated low-density lipoprotein (LDL) cholesterol, and reduced high-density lipoprotein (HDL) cholesterol6. Higher LDL-cholesterol, lower HDL-cholesterol, elevated triglycerides, elevated C-reactive protein level, hypertension, obesity, and insulin resistance are all known cardiovascular risk factors. Central obesity with a hip ratio of > 0.85 is associated with cardiovascular disease and is a marker for PCOS7. In addition to the lipid abnormalities seen in women with PCOS, these patients are 7 times more likely to have a myocardial infarction8. Because cardiovascular disease is the leading cause of death of among women, prevention is essential. While the association with type-II diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Echocardiography, imaging of coronary and carotid arteries and assessments of both endothelial function and arterial stiffness have recently been employed to address this question. These studies have collectively demonstrated both structural and functional abnormalities of the cardiovascular system in PCOS. These alterations, however, appear to be related to the presence of individual cardiovascular risk factors, particularly insulin resistance, rather than to the presence of PCOS and hyperandrogenemia per se. Overweight women with PCOS have increased cardiovascular risk factors and evidence of early CVD, compared with weight-matched controls, potentially related to IR9. Nevertheless, on examining the cardiovascular risk profiles in women with PCOS compared with healthy age and weight-matched control subjects using novel biochemical and biophysical markers, it was found that there were no differences in surrogate markers of the processes linked to enhanced cardiovascular risk between patients with PCOS and weight-matched controls10. While it is acceptable that women with PCOS have increased levels of cardiovascular risk factors: insulin resistance, obesity, dyslipidemia, hypertension and markers of abnormal vascular function, however, the level of risk for the cardiovascular disease remains uncertain11. Cardiac risk profile It is imperative, that these patients are screened for an abnormal HDL, cholesterol, and triglycerides at 35 years of age. Normal results should be repeated in 3-5 years. Serum TG/HDL-C > 3.2 has high sensitivity and specificity for the detection of metabolic syndrome in women with PCOS. Women with PCOS have an 11-fold increase in the prevalence of metabolic syndrome compared with age-matched controls. The risk of metabolic syndrome is high even at a young age, highlighting the importance of early and regular screening (LEVEL OF EVIDENCE: II-2)12. In addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin-resistant hyperinsulinemic individuals also includes the appearance of smaller and denser low-density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) are associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. This increased activity is found to be independent of obesity13. Evidence is also accumulating that
sympathetic nervous system (SNS) activity is increased in
insulin-resistant, hyperinsulinemic individuals, and, along
with the salt sensitivity associated with insulin
resistance/hyperinsulinemia, increases the likelihood that
these individuals will develop essential hypertension. The
first step in the process of atherogenesis is the binding of
mononuclear cells to the endothelium, and mononuclear cells
isolated from insulin-resistant/hyperinsulinemic individuals
adhere with greater avidity. Adhesion molecules produced by
endothelial cells modulate this process and there is a
significant relationship between the degree of insulin
resistance and the plasma concentration of the several of
these adhesion molecules. Further evidence of the relationship
between insulin resistance and endothelial dysfunction is
the finding that asymmetric dimethylarginine, an endogenous
inhibitor of the enzyme nitric oxide synthase, is increased
in insulin-resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin-resistant subjects. For instance, it has been demonstrated that PCOS women have an increased WBC count14. C- reactive protein (CRP) has been implicated as a vascular disease risk factor. Although CRP was found to be significantly higher in PCOS patients than in controls, PCOS associated with IMT (Intima Media Thickness) independently of CRP and PCOS remained associated with IMT independent of insulin or visceral fat. Thus, it appears that CRP does not appreciably mediate the effect of PCOS on IMT. Obesity partially explained the influence of PCOS and CRP on IMT15. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes PCOS is not a simple task 6. Endothelial Dysfunction, Obesity and Adipose Hormones In recent years, it has been shown that adipocytes are secretory cells that produce a variety of proteins with hormonal-type functions, which collectively have been called adipocytokines. The first adipose hormone discovered was leptin a protein which acts mostly as a signaling factor from adipose tissue to the central nervous system thus regulating food intake and energy expenditure, its circulating levels are strictly correlated to adipose mass and are higher in obese humans16. Adiponectin is produced exclusively by adipose cells and may have a role in preventing or counteracting the development of insulin resistance 17. In contrast to leptin, the production of adiponectin is decreased in obese subjects 18. Finally, a third protein produced by adipocytes, resistin, was synthesized and was thought to be related to the development of insulin resistance 19. It has been reported that circulating levels of resistin are increased in obesity 20. It has been reported that leptin is mostly produced by subcutaneous adipose tissue. Adiponectin was believed to correlate with visceral fat production but not with subcutaneous fat. This has been recently challenged and is found that reduction in both distribution of fat reduces adiponectin 21. In PCOS, leptin levels were similar to those of matched controls and in general were strongly correlated with body weight (expressed as BMI) and less well with insulin and insulin sensitivity (expressed as QUICKI). There was little difference between controls and women with PCOS and the correlations of leptin with insulin and insulin resistance were strictly dependent on changes in body weight. Adiponectin was clearly lower in PCOS. For the entire group, resistin levels were also higher in PCOS, although this difference was less obvious with BMI stratification. A decrease of adiponectin and an increase of resistin have been linked to the development of insulin resistance. While in normal women both adiponectin and resistin, although in opposite ways, correlated with insulin and QUICKI, these correlations were not found in PCOS. It has been suggested that differences in adipose tissue distribution may influence the secretion of the different adipocytokines. Therefore, women with PCOS who are having a normal weight may have, in reality, an increase in total visceral adipose tissue that may contribute to the development of cardiovascular risk in these patients. A study was designed to determine if abnormal carotid IMT and brachial flow-mediated dilation (FMD) in young women with PCOS may be explained by insulin resistance and elevated adipocytokines. These data suggest that young women with PCOS have evidence for altered endothelial function. Adverse endothelial parameters were correlated with insulin resistance and lower adiponectin. Both insulin resistance and adiponectin appeared to be important parameters 22. Cardiovascular Risks in PCOS in Young Adults Polycystic ovary syndrome (PCOS) is associated with premature carotid atherosclerosis. PCOS affects femoral and carotid wall mechanics leading to premature sub-clinical atherosclerosis in young women with PCOS 23. Adolescence may be a more appropriate time to intervene for PCOS patients, as many cardiovascular risks are already present during early adulthood. Significant vascular abnormalities range from endothelial dysfunction and low-grade or sub-clinical inflammation to evident atherosclerosis. Among many cardiovascular risk factors evaluated, the diagnosis of PCOS, increased body mass index and decreased sex hormone-binding globulin were significant independent predictors of increased IMT. PCOS women had higher left atrium size and left ventricular mass index, lower left ventricular ejection fraction and early to late mitral flow velocity ratio than controls. The differences between PCOS women and controls were maintained in overweight and obese women. In normal-weight PCOS women also, a significant increase in the left ventricular mass index and a decrease in the diastolic filling were observed. This shows that PCOS can have a detrimental effect on the cardiovascular system even in young women asymptomatic for cardiac disease 11. Middle-aged women with PCOS are at increased risk of the metabolic cardiovascular syndrome and have been demonstrated to increase the incidence of coronary artery calcification and aortic calcification as compared with controls. Components of metabolic cardiovascular syndrome mediate the association between PCOS and coronary artery calcification, independently of obesity 24. PCOS AND HYPERTENSION Although a positive relationship between insulin and blood pressure has been demonstrated in many populations, it is possible that this association does not exist in PCOS. Women with PCOS do not appear to be hypertensive compared to control subjects matched for body composition, even if they have significant insulin resistance11. One study confirmed the advantages and the importance of 24-hour monitoring as a diagnostic and predictive method for assessment of blood pressure alterations even in the absence of overt hypertension. PCOS is characterized by a higher incidence of unstable blood pressure that is an additional risk factor for further development of cardiovascular diseases in this relatively young age group25. PCOS AND FIBROCYSTIC BREAST DISEASE Two studies show paradoxical results as regards the association between the fibrocystic disease of the breast and PCOS. While one shows that there is a positive correlation between PCOS and occurrence of fibrocystic disease of the breast, another study shows that there is a protective effect of PCOS 26 27. As a result in clinical practice, it will be best to wait for further studies to get a clear picture. PCOS AND ENDOMETRIAL CANCER While the majority of women with endometrial cancer are postmenopausal, when endometrial carcinoma does develop before age 40, it is usually foreshadowed by chronic obesity and/ or anovulation 28. The chronic anovulatory or oligo-ovulatory state of PCOS is characterized by high estrogen (and insulin) but little or no progestogen activity, with resultant endometrial hyperplasia. Tonically elevated insulin up-regulates estrogen-producing aromatase enzyme systems in both, endometrial glands as well as in the stroma51. This yields additive and deleterious results for the woman who is both hyperinsulinemic and anovulatory. Once present, endometrial hyperplasia advances to frank endometrial carcinoma in as many as 30% of cases 29. Indeed, endometrial cancer cell lines demonstrate an accelerated growth rate in the presence of insulin 30. PCOS AND OTHER GYNECOLOGICAL MALIGNANCIES Ovarian cancer risk was found to increase 2.5-fold among women with PCOS 31. This association is found to be stronger among women who never used oral contraceptives. The data suggest that the hormonal status of women with PCOS featuring abnormal patterns of gonadotropin secretion (enhanced levels of LH) in lean women may be a mitigating factor for the observed association between PCOS and ovarian cancer. Although the proportion of women with a positive family history of breast cancer was significantly greater in women with PCOS compared with controls 32. The risk of breast cancer risk is not clearly increased with PCOS. CONCLUSION The fundamental flaw in PCOS remains unknown and is an area of perpetually continuing study. There is now a reasonable agreement to the fact that the key features in PCOS include insulin resistance, androgen excess, and abnormal gonadotropin dynamics. There are clear associations between PCOS and endometrial cancer, obesity, cardiovascular disease and diabetes mellitus with both short and long term consequences. 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