Association of polycystic ovary syndrome with ...

Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

Association of polycystic ovary syndrome with cardiovascular risk factors Tanzeela Akram, Shahid Hasan, Muhammad Imran, Asima Karim & Muhammad Arslan To cite this article: Tanzeela Akram, Shahid Hasan, Muhammad Imran, Asima Karim & Muhammad Arslan (2010) Association of polycystic ovary syndrome with cardiovascular risk factors, Gynecological Endocrinology, 26:1, 47-53, DOI: 10.3109/09513590903159565 To link to this article: http://dx.doi.org/10.3109/09513590903159565

Published online: 11 Dec 2009.

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Date: 15 April 2016, At: 08:11

Gynecological Endocrinology, January 2010; 26(1): 47–53

PCOS

Association of polycystic ovary syndrome with cardiovascular risk factors

TANZEELA AKRAM1, SHAHID HASAN2, MUHAMMAD IMRAN1, ASIMA KARIM1, & MUHAMMAD ARSLAN3

Downloaded by [The University of Edinburgh] at 08:11 15 April 2016

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Department of Physiology and Cell Biology, University of Health Sciences (UHS), Khayaban-e-Jamia Punjab, Lahore, Pakistan, 2Department of Physiology, CMH Lahore Medical College, Lahore, Pakistan, and 3Department of Zoology, University of Punjab, Lahore, Pakistan (Received 16 February 2009; revised 28 April 2009; accepted 22 June 2009)

Abstract Background. Polycystic ovary syndrome (PCOS), also clinically known as Stein-Leventhal syndrome, is an endocrine disorder that affects 5–10% of women. Objective. To evaluate the risk factors for developing early onset of cardiovascular disease (CVD) in young patients with PCOS from our local population. Design. Case-control study. Methods. Fifty women with PCOS selected by history and transvaginal ultrasounds and 30 age-matched healthy women (controls). The case subjects and controls were further divided into two age categories comprising of equal number of subjects, of 20–29 and 30–39 years of age. The subjects underwent a detailed medical history, general physical examination, systolic (SBP) and diastolic blood pressures (DBP). Fasting blood samples were analyzed for glucose, insulin, triacylglycerides (TAG), total cholesterol, high density lipoprotein-C (HDL-C), low density lipoprotein-C (LDL-C), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Results. Women with the PCOS had significantly higher mean arterial pressure (MAP), serum TAG, LDL-C, insulin, and LH levels when compared with the age-matched control subjects. No significant differences were observed between serum cholesterol, glucose, and FSH levels between cases and controls. However, no marked differences were observed in biochemical parameters between the two age groups of PCOS patients. Conclusions. Younger women with PCOS are equally at risk of developing CVD as older women.

Keywords: Insulin resistance, polycystic ovary syndrome, infertility, amenorrhea

Introduction Polycystic ovarian syndrome (PCOS) was first described in 1935 by Stein and Leventhal. This syndrome affects 5–10% of women of reproductive age [1]. Ovarian dysfunction occurs in PCOS because of imbalanced secretion of luteinizing hormone (LH) and insulin [2]. The polycystic ovary is spherical in shape; enlarged with a tough, white outer covering [3]. Ultrasound examination shows eight or more cysts 2–8 mm in diameter arranged in pearl necklace pattern with an increased echogenic stroma [4,5]. The PCOS is defined when two out of three following features are present [6]:

. . .

Oligo-or anovulation. Clinical and /or biochemical signs of hyperandrogenism. Polycystic ovaries.

It is a very common hormonal disorder which occurs among all races and nationalities and also it is a leading cause of infertility [7]. Common symptoms of PCOS are menstrual irregularities, hirsutism, obesity, and insulin resistance [8,9]. Patients with PCOS are at increased risk for type 2 diabetes mellitus, endometrial carcinoma, and spontaneous abortion [10,11] but considerable variation in this syndrome has been observed [12].

Correspondence: Tanzeela Akram, Department of Physiology and Cell Biology, University of Health Sciences (UHS), Khayaban-e-Jamia Punjab, Lahore 54600, Pakistan. E-mail: [email protected] ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd. DOI: 10.3109/09513590903159565


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The factors included in the etiology of PCOS are altered ovarian steroid synthesis, hyperinsulinemia and neuroendocrine abnormalities [13–19]. Genetic factors have also been implicated in the etiology of PCOS [20]. In PCOS, excessive androgens are produced [21] because of increased pulsatile release of gonadotropin releasing hormone. Because of increased secretion of LH, hyperplasia of theca cells occurs leading to increased androgen secretion [22,23]. Decreased follicle-stimulating hormone (FSH) occurs which is associated with hypofunction of granulosa cells resulting in decreased aromatization of androgens to estrogens. PCOS is also associated with insulin resistance and hyperinsulinemia [24,25]. Insulin also acts with LH in a synergistic manner stimulating the production of androgens by ovaries and suppressing sex-hormone binding globulin by the liver [26]. Therefore, there is an increased level of free testosterone and estradiol because of decreased binding. It has been reported that patients with PCOS show cardiovascular risk factors including increased body mass index (BMI), BP, insulin, triacylglycerides (TAG), decreased HDL and increased LDL, and total cholesterol [27,28]. Ethnic background and socioeconomic status also alter the risk factors for cardiovascular disease (CVD) [29]. Previous studies also reported that women with irregular cycles had significantly increased risk for CVD and T2DM [30].

Materials and methods Subjects This case-control study included 50 patients with PCOS and 30 age-matched controls. All subjects were non-obese with a BMI 5 30. They were divided into four groups; Group 1 included 25 women of age 20–29 years with PCOS. Group 2 included 25 women with PCOS of age 30–39 years. Groups 3 and 4 included 15 healthy subjects of corresponding age groups. Informed consent was obtained from each subject by using an appropriately designed form. The protocol of the study was approved by the Ethical Review Committee, University of Health Sciences, Lahore. The following exclusion criteria were used in the selection of patients and controls: age 5 20 years or 4 39 years, BMI 5 18 or 4 30, pregnancy, hypothyroidism, hyperprolactinemia, cushing’s syndrome, nonclassical congenital adrenal hyperplasia, and current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, other hormones, antidiabetic-antiobesity drugs, patients with hyperandrogenism alone, history of any neoplasia or using anti-hypertensives. These factors were ruled out by using an appropriate questionnaire, status record, and physical examination.

A complete physical examination was performed on all subjects which included measurement of height, weight, heart rate, systolic (SBP) and diastolic (DBP) blood pressure (BP) by standard methods. The mean arterial pressure (MAP) was calculated by using the formula DBP þ 1/3 pulse pressure. The BMI was calculated as weight in kg/height in square meters, for all subjects. Five milliliters fasting blood samples were collected by venipuncture and was centrifuged at 3000 rpm for 10–15 minutes to obtain serum. The serum samples were aliquoted and glucose levels were measured immediately. The remaining serum was stored at 7808C until analyzed. Hormone determinations Serum FSH, LH, and insulin levels were determined by ELISA using commercially available kits (Monobind, Lake Forest, CA) with an automated EIA analyzer (CODA, Bio-Rad Laboratories, Hercules, CA). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by the following formula: HOMA-IR ¼ Fasting insulin (mU/ml) 6 Fasting glucose (mmol/l)/22.5 [31]. Lipid profile Serum levels of glucose were determined by GOD/ PAP method and TAG’s by the GPO-PAP method, Cholesterol (Enzyme endpoint method), high density lipoprotein-C (HDL-C), and low density lipoprotein-C (LDL-C) were measured by an automatical chemistry analyzer. Statistical analysis The Data were analyzed using student’s t-test for the significance of differences. P 5 0.05 was considered statistically significant. All calculations were carried out with the SPSS version 12 (SPSS, Chicago, IL). Results Among the 50 study subjects with PCOS, 54% patients had oligo-or amenorrhea, 54% patients presented hirsutism, and 58% of the patients had hyperandrogenism. In addition, 38 of the total patients had primary infertility and 12 had a history of secondary infertility. Acanthosis nigricans was observed only in eight patients (Table I). Physical parameters The mean BMI values of the patients with PCOS and controls were not significantly different in the two

Polycystic ovary Table I. Percentage of various symptoms characterizing PCOS.

Symptoms Polycystic ovaries* Oligo-/amenorrhoea Hirsutism Hyperandrogenemia** Primary infertility Secondary infertility Acanthosis nigricans

Group 1 [n ¼ 25] (20–29 y) (%)

Group II [n ¼ 25] (30–39 y) (%)

Group 1 and II (20–39) y [n ¼ 50] (%)

100 48 52 72 76 24 12

100 60 56 64 76 24 20

100 54 54 58 76 24 16


*As diagnosed by transvaginal ultrasound. **As diagnosed by measuring serum DHEA concentrations.

age matched groups and also when the two age groups were considered together. However, BMI was significantly higher in older control group when compared with the younger control group. The MAP, on the other hand, was significantly higher (P 5 0.001) in subjects with PCOS when compared with their age matched controls in both age groups and was also significantly higher in the older PCOS group when compared with the younger group. Lipid profile PCOS patients had significantly higher (P 5 0.005) TAG levels when compared with their age matched controls in both the age groups and when taken together. The levels of TAG were also significantly higher (P 5 0.05) in older control group compared to the younger control group (Table II) but no significant difference was found between the two PCOS groups. Total serum cholesterol was significantly higher (P 5 0.05) in patients with PCOS only in the 20–29 years group when compared with their age matched controls. However, serum cholesterol was significantly higher (P 5 0.001) in 30–39 age (Table III) controls than to the younger control subjects, but no difference in serum cholesterol was observed between the two PCOS groups or between the patients with PCOS and controls when the two age groups were considered together (Table IV). Patients with PCOS had significantly higher (P 5 0.05) LDL-C levels when compared with controls in both the age groups. The HDL-C levels were significantly lower (P 5 0.05) in the patients with PCOS when compared with the controls only in the younger group. No significant difference was observed in the mean HDL-C levels of patients with PCOS between both age groups and age matched control groups. When values from the two age groups were combined, no significant difference was found in mean HDL-C levels between patients with PCOS and controls.

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Table II. Mean + SEM values of CVD risk factors and endocrinological parameters in subjects with PCOS and controls of 20–29 y age group. Parameters BMI (kg/m2) MAP (mm Hg) Triglyceride (mg/dl) Cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) Fasting glucose (mg/dl) Fasting insulin (mIU/ml) LH (mIU/ml) FSH (mIU/ml) HOMA-IR

Controls

PCOS

21.8 + 1.02 81.6 + 1.6 121 + 8.64 143 + 4.77 45.2 + 2.08 140 + 11.1 94.7 + 3.26 13.01 + 1.1 4.94 + 0.65 6.76 + 1.28 3.0 + 0.3

23.3 + 0.67 92.6 + 1.4* 155 + 8.33* 162 + 8.34* 39.8 + 1.79* 186 + 10.7* 86.7 + 3.25* 32.4 + 5.94* 9.42 + 1.62 6.57 + 0.55 7.26 + 1.45*

*Significantly different from the control group; P 5 0.05 (Student’s t test).

Table III. Mean + SEM levels of CVD risk factors and endocrinological parameters in subjects with PCOS and controls of 30–39 y age group. Parameters BMI (kg/m2) MAP (mm Hg) Triglyceride (mg/dl) Cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) Fasting glucose (mg/dl) Fasting insulin (mIU/ml) LH (mIU/ml) FSH (mIU/ml) HOMA-IR

Controls

PCOS

25.1 + 0.84 92 + 1.64 144 + 7.85 184 + 9.34 47 + 2.72 161 + 14.1 94.8 + 3.46 16.9 + 2.57 5.35 + 0.67 6.15 + 1.22 4.0 + 0.67

23.9 + 0.74 102 + 1.29* 195 + 12.3* 170 + 7.16 45.01 + 2.15 194 + 10.3* 95.7 + 2.44 29.8 + 6.51* 9.88 + 1.22* 7.36 + 0.47 7.28 + 1.62*

*Significantly different from the control group; P 5 0.05 (Student’s t test). Table IV. Mean + SEM levels of CVD risk factors and endocrinological parameters in subjects with PCOS and controls of 20–39 y age group. Parameters 2

BMI (kg/m ) MAP (mm Hg) Triglyceride (mg/dl) Cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) Fasting glucose (mg/dl) Fasting insulin (mIU/ml) LH (mIU/ml) FSH (mIU/ml) HOMA-IR

Controls

PCOS

23.5 + 0.71 1.47 + 1.4 133 + 6.01 164 + 6.29 46.1 + 1.66 150 + 8.91 94.8 + 2.3 14.9 + 1.4 5.15 + 0.45 0.86 + 0.55 3.54 + 0.37

23.6 + 0.50 97 + 1.23* 175 + 7.92* 166 + 5.46 42.4 + 1.43 190 + 7.43* 91.2 + 2.11 31 + 4.5* 9.7 + 1.0* 7 + 0.36 7.27 + 1.08*

*Significantly different from the control group; P 5 0.05 (Student’s t test).

Fasting glucose and insulin levels No significant differences in fasting glucose levels were observed between patients with PCOS and controls. Glucose levels were, however, significantly

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higher (P 5 0.005) in older patients with PCOS when compared with the corresponding younger group but no difference was observed in glucose levels between the two control groups. Patients with PCOS had significantly higher (P 5 0.05) fasting insulin levels when compared with their age matched controls in both the groups and in PCOS and control subjects considering as two groups. HOMA- IR


Insulin resistance as assessed by HOMA-IR was significantly higher in patients with PCOS when compared with respective controls in both the age groups and when the two age groups were combined together. However, no significant difference was noted between younger and older groups. Gonadotropin levels Serum FSH levels between patients and their age matched controls were not significantly different whereas serum LH levels were significantly higher (P 5 0.05) in patients with PCOS when compared with their respective control groups. No significant difference was found in serum FSH or LH levels because of age in controls and patients with PCOS. Discussion Previously, a marked difference has been observed in the predictors of CVD risk factors between the premenopausal and postmenopausal women with PCOS. At age 540 y, PCOS had a significant effect on lipid profile whereas in older patients little difference in predictors of CVD risk factors as observed was found in women with PCOS and controls. In the present study conducted on premenopausal women, we did not find any significant difference in lipid profile and insulin resistance between the younger (530 y) and older (4 30 y) groups but the differences between the patients with PCOS and controls were significantly different, when compared with the age-matched controls. The PCOS subjects and matching controls included in this study were non-obese (BMI 5 30), so as to allow the assessment of cardiovascular risk factors that may not be related to obesity. Recently, it has been demonstrated that Asian women with PCOS were much less likely to be obese and cardiovascular risk may be evident at a lower BMI among the Asians when compared with the European countries [32]. In our study, MAP was higher in women with PCOS of both age groups when compared with their age-matched controls. These findings confirm previous observations which demonstrate similar differences in blood pressure between controls and PCOS

cases [33–35]. In our study, older control subjects and subjects with PCOS had also higher blood pressure than in the younger groups, which could be attributed to the age factor. Serum TAG levels were shown to be significantly higher when compared with their age matched controls in both the groups. Also, the levels of TAG were significantly higher in older control group when compared with the younger control group which may be explained as age related factor. However, mean serum TAG values were higher than normal TAG levels (150 mg/dl) only in the older PCOS group. In some previous studies, presumably, higher TAG levels have been demonstrated only in PCOS cases in the younger groups [36–38]. The mean cholesterol levels were within the normal range (less than 200 mg/dl) in all the four groups. However, a significant increase in cholesterol concentrations was observed between younger PCOS cases and their corresponding controls. Peak estradiol levels during the follicular phase of menstrual cycle, and progesterone during the luteal phase, are lower among the PCOS cases because of oligo-ovulation. If the increase in LDL-C is related to lower estradiol levels across time, the lack of change in ovarian function might possibly explain the slow rate of increase in LDL-C with age among PCOS cases versus controls. The non-significant increase in total cholesterol among controls with increasing age is because of a general decline in ovarian function and is most likely the explanation for the difference in total cholesterol in relation to age among PCOS cases and controls [39]. In the present study, HDL-C levels were significantly lower in the patients with PCOS when compared with the controls only in the younger group. No significant difference was observed in total cholesterol and HDL-C levels between older patients with PCOS and controls. These results are similar to those reported in previous investigations [40]. In one study on non-obese PCOS cases, however, HDL levels were not reduced probably because the full metabolic disturbance is not manifest in the absence of obesity [41]. Women with PCOS in both age groups had higher LDL-C levels when compared with their age-matched controls. If hyperinsulinemia, low HDL-C and high TAG levels noted in the PCOS cases are really a unique profile of risk factors of atherosclerosis and coronary heart disease in women, then women with PCOS should have much more atherosclerosis than control subjects, especially at younger ages. If the risk of atherosclerosis is related to elevated levels of LDL-C, then there is an alternate reason for a higher prevalence of atherosclerosis in patients with PCOS [42]. Higher LDL-C levels in PCOS subjects have also been documented in previous studies carried out elsewhere [32].


Polycystic ovary The PCOS has previously been complicated with insulin resistance that may lead to hyperinsulinemia and T2DM [27,43]. In our study, fasting insulin levels of patients with PCOS in both age groups were significantly and markedly higher than their agematched controls [44]. Previously, based on observation that obese women with PCOS develop greater degree of insulin resistance has been interpreted as because of increase in body mass [45]. This possibility was ruled out in the present study by including non-obese PCOS and their age-matched controls. Hyperinsulinemia stimulates ovarian cytochrome P450c17 a activity in non-obese women with PCOS, thereby increasing serum androgen concentrations [46] and as a consequence, decreasing serum sex hormone-binding globulin (SHBG) concentration [47,48]. Hyperinsulinemia has also been reported to stimulate adrenal P450c17 a activity of some affected women [49]. In this study, fasting glucose levels in patients with PCOS and controls were within the normal range but insulin levels were significantly raised in women with PCOS when compared with the controls. These observations indicate a tendency towards insulin resistance that is compensated by increased secretion of insulin sufficient to keep glucose levels in the normal range in these patients. The present study therefore, supports the view of hyperinsulinemia and insulin sensitivity as salient features of the syndrome even in absence of obesity [50–55]. The PCOS may itself confer insulin resistance and degree of hyperinsulinemia correlates significantly with cardiovascular risk in PCOS, independent of BMI [43]. In our study, mean LH levels were higher in both PCOS groups when compared with their age-matched controls, which is in accordance with a previous study [56], whereas no significant difference was observed between FSH levels. Patients with hyperinsulinemia and excess of LH have been regarded to constitute a distinct subgroup with increased adrenal androgenic activity [57]. Our data demonstrate that PCOS is independently associated with the major cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. These results support and extend previous investigations regarding an association between PCOS and CVD risk factors, that are independent of age and BMI in a selected population of premenopausal women [40,33,58]. In conclusion, patients with PCOS may represent the largest group of young women at high risk for the possible development of early onset of CVD, which can be diagnosed a long time before the onset of clinical symptoms characterizing CVD. The present data warrants further studies on a much larger sample size to determine the precise relationships between PCOS and metabolic dysfunction leading to a

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predisposition to cardiovascular risk and for appropriate health counseling of this section of population. Declaration of interest: The authors report no conflict of interest.

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