ISSN: 1301-2193 E-ISSN: 1308-9846
  • Turkish Journal of
    Endocrinology and Metabolism

Introduction

Definition of the Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age and also, it is the most common cause of the oligo-anovulation and hyperandrogenism. Its prevalence has been reported as 5%-10% (1). PCOS has been defined for the first time in 1935 by Stein and Leventhal (2,3).
Today, a complete consensus on diagnostic criteria of PCOS has not been achieved yet. Attempts to set universal criteria for the diagnosis of PCOS first emerged in 1990 in a meeting sponsored by the U.S. National Institutes of Health (NIH). Based on the opinions of experienced people on the subject, criteria required for diagnosis were explained at the end of the meeting as the following:

1- Hyperandrogenism (hirsutism, acne, male pattern baldness) and / or hyperandrogenism (elevated serum androgen concentration),
2- Menstrual irregularities due to chronic oligo-anovulation,
3- Elimination of secondary reasonable causes (such as hyperprolactinemia, late-onset adrenal hyperplasia, androgen-secreting tumors and Cushing’s syndrome).
Polycystic ovary image on ultrasound examination has been noted as a possible criterion. According to this conference recommendations, the most important diagnostic criteria of PCOS are considered as hyperandrogenism and / or hyperandrogenemia. Under this definition, however, in some PCOS cases with hyperandrogenemia may not present findings of hyperandrogenism (eg. presence of hirsutism), or hyperandrogenemia may not be seen while signs of hyperandrogenism are present(4).
Universal criteria for diagnosis announced in a meeting held in the city of Rotterdam in the Netherlands in 2003 sponsored by the ESHRE (European Society for Human Reproduction and Embryology) and ASRM (American Society for Reproductive Medicine):
1- Chronic oligo-anovulation,
2- Clinical or laboratory-confirmed Hyperandogenism,
3- Polycystic ovary image on ultrasound examination
Again, together with the elimination of other possible diseases, at least two of these criteria should be present for the diagnosis of PCOS.
At the same meeting diagnostic criteria for polycystic ovary image was determined as follows,
- The presence of 12 or more follicles in each ovary with 2-9 mm in diameter and / or
- Increased ovarian volume (> 10 mL).
It has been suggested that polycystic ovary image on ultrasound examination should not be evaluated as PCOS if oligoamenore or hyperandrogenism is absent (5).
As a result of the ongoing debate on the definition of PCOS, Androgen Excess Society rearranged the diagnostic criteria in 2009. They are:
1- Androgen excess (clinical and/or biochemical hyperandrogenism)
2- Over dysfunction (oligo-anovulation and / or polycystic ovarian morphology)
3- The elimination of other androgen excess and ovulatory disorders.

Androgen Excess Society suggests that these three criteria must coexist for the diagnosis of PCOS. This last criterion added a new phenotype, that is a female with normal ovulation, who has polycystic ovaries on ultrasound examination and hyperandrogenism (clinical or biochemical). Contrary to the Rotterdam criteria, Androgen Excess Society argues that diagnosis of PCOS based on ovulatory dysfunction and polycystic ovary image without hyperandrogenism is not acceptable (6).

Today common features of PCOS include skin symptoms of hyperandrogenism (hirsutism, alopecia, acne, hair loss, hyperhidrosis), menstrual irregularity, findings of insulin resistance (acanthosis nigricans) and obesity. An increase in insulin and insulin resistance are frequent findings in patients with PCOS. Low levels of chronic inflammation (7) and increased cardiovascular risk (CV’s) have also been associated with this condition (8).

Clinical Characteristics

a. Hirsutism

It refers to a male pattern of body hair characterized by excessive sexual hair growth on women (9). In women with hirsutism excessive terminal hair growth is seen in areas sensitive to androgen (upper lip, chin, chest, back, waist, upper abdomen, lower abdomen, upper arm, thighs). The Ferriman-Gallwey method is a quantitative scoring system to evaluate the density of hair in androgen-sensitive areas (10). It is used for evaluating and rating this condition. For a mature female patient, this method use 9 body parts; the upper lip, chin, chest, lower back, upper back, lower and upper abdomen, upper arms and upper parts of legs, to evaluate hirsutism. The hair growth is rated from 0 to 4 in each of the 9 locations and the total score determines the classification of hirsutism: normal: <8; mild hirsutism: 8-15; and mid-advanced hirsutism: > 15

b. Menstrual Irregularities

It is characterized by oligomenorrhea, amenorrhea, a decrease in the ovulation frequency and anovulation. In patients with PCOS, menstrual irregularities begin in peripubertal period. Normal or slightly delayed menarche is followed by irregular menstrual cycles.

c. Metabolic Disorders

1. Obesity

Causes of PCOS accompanying obesity are still unknown but its presence is reported in varying rates from 10 to 75% in different series (11-13). Typically, it is centrally located. In adult women, waist circumference over 88 centimeters is evaluated as abdominal obesity (14). Even in PCOS patients with normal body weight, the body fat content is 50% more than that of normal subjects (15). Increased fat ratio, visceral adiposity in particular, coexists with hyperandrogenism, insulin resistance, glucose intolerance, and dyslipidemia (16). However, not all obese patients have insulin resistance and patients with insulin resistance are not necessarily obese. Nevertheless hyperinsulinemic case caused by insulin resistance and its anabolic effects on lipid metabolism (increased glucose uptake into adipocytes, triglyceride production and hormone-sensitive lipase inhibition) can be effective in the presence of obesity (17).

2. Insulin Resistance

Insulin binds to receptors on the cell membrane and it facilitates glucose uptake into cells by increasing the expression of glucose transporter in many tissues (18). In the events of failure of the insulin binding to its’ receptors, or of the transport mechanism, insulin sensitivity decreases and insulin resistance can be revealed. Studies show that insulin-mediated receptor autophosphorylation is significantly inoperative in about 50% of women with PCOS (19). In addition to these, decrease in insulin sensitivity and secretion disorders in pancreatic beta cells have been reported as well (20,21). Altogether, clinical results show that 30 to 40% of obese women with PCOS have impaired glucose tolerance and about 10% of them are becoming diabetic in their 40s (22,23).

3. Dyslipidemia

Whether or not women with PCOS have a characteristic dyslipidemia is a controversial topic. Yet studies generally report that these women have low HDL cholesterol and high triglyceride levels (24-28). Studies have often shown that they have high TG and LDL coexisting with low HDL levels, which is called atherogenic lipid profile. This condition is associated with insulin resistance and hyperandrogenism observed in these patients. Insulin increases glucose and triglyceride input and stimulates lipogenesis by increasing the production of acetyl-CoA in both arterial and adipose tissue (29).

4. Metabolic Syndrome:

It is a specific symptoms group characterized by insulin resistance, hyperglycemia, hypertension, hyperlipidemia, abdominal obesity and associated with increased cardiovascular risk (30). Metabolic syndrome is observed in 25% of patients with PCOS (31).

d. Cardiovascular Disease Risk

In patients with PCOS, the presence of obesity, insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia and increased visceral adiposity predispose cardiovascular diseases (CVD) (32-34).

The increased risk of CVD observed in women with PCOS is not fully demonstrable but data shows an increased incidence of cardiovascular disease (35,36).

The evidence for increased cardiac morbidity and mortality is also insufficient. Various results are reported in epidemiological studies done in this matter. In early studies among women with PCOS, no significant increase has been observed in nonfatal and fatal CVD frequency (37,38), while an increase has been identified in the incidence of nonfatal cerebrovascular disease (38). In another study, however, a history of menstrual irregularities was found to be associated with an increase in nonfatal and fatal coronary heart disease (39).

In contrast to earlier studies, a recent sub-group study called Women’s Ischemia Evaluation Study (WISE) reported a higher number of cardiovascular events seen in patients with PCOS (40). Moreover, the same study observed a higher incidence of multivessel coronary disease in women with PCOS and a correlation with increased serum testosterone levels. Again in the same study, an increase was reported in frequency of diabetes, obesity and metabolic diseases in patients with PCOS. The frequency of not having a cardiovascular disease in five-year period was 78.9% in patients with PCOS, while this ratio rises up to 88.7% in patients without PCOS characteristics. In this study, the researchers have argued that in postmenopausal women, the recognition of characteristics of PCOS may create an opportunity for the prevention of coronary artery disease and cardiovascular events.

The study by Azeyedo and his colleagues showed that signs of PCOS in the reproductive period were associated with an increase of cardiovascular disease risk (41). In another study, PCOS was associated with premature carotid atherosclerosis and CRP, a marker of inflammation; and the presence of PCOS was found to be related with an increase in carotid intima-media thickness, independent from insulin levels and visceral adipose tissue (42).

Young adult women with PCOS have multiple risk factors for cardiovascular disease such as hyperinsulinemia, dyslipidemia and abdominal obesity, which are results of metabolic syndrome and insulin resistance (36,43,44). In addition, among PCOS patients, higher visceral adiposity was observed even in women of normal weight and higher levels of inflammatory adipocytokines production was monitored as well (45,46).

In the study by Cascella et al., visceral adipose tissue was found to be associated with insulin resistance and it appeared significantly higher in PCOS patients. In linear regression analysis of patients with PCOS, visceral adipose tissue and CRP levels were observed to have positive effects on carotid intima-media thickness (47).

In a research done by Krentz et al. involving 713 non-diabetic female patients with postmenopausal intact ovaries, a gradual correlation has been observed between cardiovascular disease and the presence of PCOS symptoms in patients’ medical history (such as premenopausal menstrual irregularity, hirsutism or existing hyperandrogenism) (48).

1. Endothelial Dysfunction

Endothelial dysfunction is thought to be contributed to the development of atherosclerosis. The presence of endothelial dysfunction in women with PCOS is still controversial. Although some studies (49-52) demonstrate the presence of endothelial dysfunction, there are studies that suggest the opposite (53).
Insulin resistance (49,50), hyperandrogenism (50), high levels of CRP (49), and high total cholesterol (50) were found to be associated with endothelial dysfunction.

2. Subclinical Atherosclerosis

In most of the studies in literature, subclinical atherosclerosis process was shown to be increased in women with PCOS.

a: Evaluation of Coronary Artery Disease by angiography

Angiographic coronary artery disease was observed to be more common in patients with PCOS than normal individuals. In a study angiographically assessing 143 patients under 60 years old, who were followed up due to chest pain or valvular heart disease, ultrasonographic polycystic ovarian morphology has been observed in 42% of patients. In that study, polycystic ovarian morphology was found to be correlated with hirsutism, a decrease in high-density lipoprotein cholesterol (HDL-C) levels, hyperandrogenism and hypertriglyceridemia. Coronary artery disease was observed to be more common in women with polycystic ovarian morphology. In this study, however, no differentiated diagnosis was made between polycystic ovarian morphology and the presence of PCOS. Therefore, it was stated that further studies are needed to determine conclusive results (54).

b: Carotid Intima Media Thickness

In the majority of studies in literature an increased carotid intima-media thickness has been shown in women with PCOS (8,55,56). This condition is a finding in favor of increased atherosclerosis in PCOS.

c: Coronary artery calcium identified by electron-beam computed tomography

This is a non-invasive method of assessing coronary artery calcium as a risk factor for atherosclerosis. 36 premenopausal women of an average age of 38 having PCOS were compared to healthy individuals having similar features in terms of age and weight. Increased coronary artery calcium levels were more commonly observed in women with PCOS (57).

In another study involving 85 healthy subjects and 61 female patients ranging in age from 40 to 61, coronary artery disease and aortic calcification were found to be significantly higher in PCOS group. It is observed that independent from obesity, components of metabolic syndrome (low HDL-C and the presence of insulin resistance) mediates the correlation between PCOS and coronary artery calcification (58).

Coronary artery calcium was assessed in 8 (33%) out of 24 PCOS female patients in the average age of 31, while this number appeared as 2 (8%) out of 24 individuals in healthy control group with similar age and weight criteria (59).

In conclusion, current epidemiological data shows that the frequency of cardiovascular disease is increasing in PCOS, and this increase is thought to be mainly based on increasing overall and abdominal obesity, hyperinsulinemia and hyperandrogenemia. Yet the identification of PCOS features while still in reproductive period and the determination of possible cardiovascular risk and then screening of patients in this respect can provide an opportunity in the prevention of cardiovascular events.

References

1. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet 2007;370:685-97.
2. Stein IL, NL. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181.
3. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. 7th ed. ed. Philadelphia, Pa. ; London: Lippincott Williams & Wilkins; 2005.
4. Dunaif A. Polycystic ovary syndrome. Boston ; Oxford: Blackwell Scientific Publications; 1992.
5. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7.
6. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456-88.
7. Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 2005;26:251-82.
8. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 2003;24:302-12.
9. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:1105-20.
10. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440-7.
11. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992;167:1807-12.
12. Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod 1995;10:2107-11.
13. Azziz R, Ehrmann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 2001;86:1626-32.
14. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006;91:1275-83.
15. Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 2001;16:1255-60.
16. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.
17. Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005;19:471-82.
18. Stephens JM, Pilch PF. The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endocr Rev 1995;16:529-46.
19. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med 1995;98:33S-9S.
20. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96:520-7.
21. Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942-7.
22. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141-6.
23. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165-9.
24. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
25. Robinson S, Henderson AD, Gelding SV, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol (Oxf) 1996;44:277-84.
26. Holte J, Bergh T, Berne C, Lithell H. Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol (Oxf) 1994;41:463-71.
27. Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1985;61:946-51.
28. Legro RS, Blanche P, Krauss RM, Lobo RA. Alterations in low-density lipoprotein and high-density lipoprotein subclasses among Hispanic women with polycystic ovary syndrome: influence of insulin and genetic factors. Fertil Steril 1999;72:990-5.
29. Pekala P, Kawakami M, Vine W, Lane MD, Cerami A. Studies of insulin resistance in adipocytes induced by macrophage mediator. J Exp Med 1983;157:1360-5.
30. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8.
31. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492-7.
32. Lo JC, Feigenbaum SL, Yang J, et al. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1357-63.
33. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011;7:219-31.
34. Setji TL, Holland ND, Sanders LL, et al. Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1741-7.
35. Wild RA. Polycystic ovary syndrome: a risk for coronary artery disease? Am J Obstet Gynecol 2002;186:35-43.
36. Carmina E. Cardiovascular risk and events in polycystic ovary syndrome. Climacteric 2009;12 Suppl 1:22-5.
37. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998;51:581-6.
38. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf) 2000;52:595-600.
39. Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 2002;87:2013-7.
40. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008;93:1276-84.
41. Azevedo GD, Duarte JM, Souza MO, et al. [Menstrual cycle irregularity as a marker of cardiovascular risk factors at postmenopausal years]. Arq Bras Endocrinol Metabol 2006;50:876-83.
42. Talbott EO, Zborowski JV, Boudreaux MY, et al. The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:6061-7.
43. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;37:119-25.
44. Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol 1998;51:415-22.
45. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 2006;91:2100-4.
46. Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:787-96.
47. Cascella T, Palomba S, De Sio I, et al. Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome. Hum Reprod 2008;23:153-9.
48. Krentz AJ, von Muhlen D, Barrett-Connor E. Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease. Menopause 2007;14:284-92.
49. Tarkun I, Arslan BC, Canturk Z, et al. Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J Clin Endocrinol Metab 2004;89:5592-6.
50. Kravariti M, Naka KK, Kalantaridou SN, et al. Predictors of endothelial dysfunction in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:5088-95.
51. Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J Clin Endocrinol Metab 2001;86:4666-73.
52. Carmina E, Orio F, Palomba S, et al. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am J Med 2006;119:356 e1-6.
53. Mather KJ, Verma S, Corenblum B, Anderson TJ. Normal endothelial function despite insulin resistance in healthy women with the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:1851-6.
54. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 1997;126:32-5.
55. Orio F, Palomba S, Colao A. Cardiovascular risk in women with polycystic ovary syndrome. Fertil Steril 2006;86 Suppl 1:S20-1.
56. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000;20:2414-21.
57. Christian RC, Dumesic DA, Behrenbeck T, et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:2562-8.
58. Talbott EO, Zborowski JV, Rager JR, et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:5454-61.
59. Shroff R, Kerchner A, Maifeld M, et al. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab 2007;92:4609-14.