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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5592-5596
Copyright © 2004 by The Endocrine Society

Endothelial Dysfunction in Young Women with Polycystic Ovary Syndrome: Relationship with Insulin Resistance and Low-Grade Chronic Inflammation

Ilhan Tarkun, Berrn Ç. Arslan, Zeynep Cantürk, Erdem Türemen, Tayfun Sahn and Can Duman

Departments of Endocrinology and Metabolsim (I.T., B.ÇA., Z.C., E.T.), Cardiology (T.S.), and Biochemistry (C.D.), Kocaeli University, Kocaeli 41110, Turkey

Address all correspondence and requests for reprints to: Dr. Ilhan Tarkun, Endocrinology and Metabolism Department, Sopali-Derince, Kocaeli 41110, Turkey. E-mail: ilhantarkun{at}superonline.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors. Cardiovascular morbidity is elevated even in young women with PCOS. Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP) and endothelial dysfunction have recently been linked to development of atherosclerosis. We compared high-sensitivity (hs)CRP concentrations and endothelium dysfunction in 37 women with PCOS and 25 control subjects matched as a group for age and body mass index (BMI). Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli.

Serum LH, testosterone, androstenedione, and fasting insulin levels were significantly higher in the PCOS group than the control group. The PCOS group was more insulin resistant than age- and BMI-matched control women. CRP concentrations were higher in PCOS women than the healthy control group (0.25 vs. 0.09 mg/dl). hsCRP concentrations were correlated with BMI, insulin sensitivity indices (homeostasis model assessment and quantitative insulin sensitivity check index), and endothelium-dependent vasodilation. The groups were well matched for baseline brachial artery diameter. There was a significant difference in endothelium-dependent (flow- mediated dilation) and endothelium-independent (sublingual nitroglycerin) vascular responses between the women with PCOS and the normal healthy control group (P = 0.002 and P = 0.01, respectively). Endothelium-dependent vasodilation was correlated with hsCRP concentrations and insulin resistance.

In conclusion, this study is the first to demonstrate increased levels of hsCRP, endothelial dysfunction, and the relation with insulin resistance in young and normal-weight women with PCOS. Clinical strategies aimed at reducing insulin resistance may prevent early atherosclerosis in women with PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a reproductive disorder, characterized by chronic anovulation, androgen excess, and insulin resistance, affecting approximately 5–10% of the female population (1). Women with PCOS have a clustering of cardiovascular risk factors, such as obesity, lipid abnormalities, impaired glucose tolerance, and hypertension. Recent data have shown an increased prevalence of cardiovascular disease (CVD) (2, 3, 4) in women with PCOS.

Endothelial dysfunction has been regarded as an early feature of atherosclerosis and plays an important role in the development of atherosclerotic diseases (5, 6). Dysfunction of endothelium cells is probably the earliest event in the process of lesion formation, hence, the concept that assessment of endothelial function may be a useful prognostic tool for coronary artery disease (7). Brachial artery ultrasound is a widely used noninvasive measure of endothelial dysfunction. Assessment of endothelial function by measuring flow-mediated dilation (FMD) of the brachial artery is currently being regarded as a potential tool for predicting coronary heart disease risk (8).

Accumulating evidence suggests that atherosclerosis represents a chronic inflammatory process and inflammatory markers like C-reactive protein (CRP) provide an adjunctive method for global assessment of cardiovascular risk (9). Recent studies also suggest that there is a correlation between endothelium-dependent vasodilation and CRP levels (10). Thus, endothelial dysfunction may be reflected systemically, thereby allowing for a less invasive approach to the assessment of overall endothelial cell biocompatibility.

Because CVD are frequently encountered features of PCOS, it seems logical to hypothesize that early features of atherosclerosis like endothelial dysfunction detected by brachial artery ultrasound or proinflammatory markers like high sensitivity (hs)-CRP could be determined frequently in young women with PCOS as surrogate indicators of future coronary heart diseases. This study was designed to evaluate the relationship among endothelial dysfunction, serum concentrations of a proinflammatory marker like CRP, and some other risk factors like insulin resistance in women with PCOS and the control group.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Thirty-seven women affected by PCOS (mean age 23.45 ± 4.3 yr) were enrolled in our study. The study protocol was approved by Ethics Committee for Human Studies of Kocaeli University Hospital. Informed written consent was obtained from all subjects after explanation of the nature, purpose, and potential risks of the study. PCOS was defined when at least two of the following three features were present after the exclusion of other etiologies (Rotterdam criteria) (11): oligo- or anovulation (fewer than six menstrual periods in the preceding year), clinical (Ferriman-Gallwey score > 8) (12) and/or biochemical signs of hyperandrogenism, and polycystic ovaries. Biochemical criteria included an abnormal LH to FSH ratio (>2) and/or elevated testosterone levels. Ultrasound criteria used for diagnosis of polycystic ovary are the following: presence of 12 or more follicles in each ovary measuring 2–9 mm in diameter and/or increased ovarian volume (>10 ml). Oligomenorrhea or amenorrhea was present in 29 of the 37 patients (mean cycle length: 53.7 ± 10.4 d) All women had normal thyroid, renal, and hepatic functions. Their prolactin levels were within normal limits. Exclusion criteria for all subjects included pregnancy, current or previous use (within 6 months) of oral contraceptives, antiandrogens, antidiabetics, statins, glucocorticoids or other hormonal drugs, cigarette smoking, chronic alcohol consumption, blood pressure of 130/85 mmHg or greater or treated hypertension, known CVD, hypertension, and diabetes mellitus. An overnight dexamethasone suppression test (1 mg) and follicular phase serum 17-hydroxyprogesterone determination were performed to exclude Cushing’s syndrome and late-onset congenital adrenal hyperplasia.

The control group consisted of 25 healthy volunteer doctors and nurses (mean age 24.4 ± 4.07 yr) with regular menses (mean cycle length 29.1 ± 3.8 d) and ultrasonographically normal ovaries. Their clinical, biochemical, and hormonal profiles were within normal limits. The same exclusion criteria as patient group were used for the control group.

All blood samples were obtained in the morning between 0800 and 0900 h after a 3-d, 300-g carbohydrate diet after an overnight fast and during early follicular phase. During the same visit, all subjects underwent anthropometric measurements, oral glucose tolerance test, and transvaginal ultrasonography. The serum concentrations of FSH, LH, testosterone, prolactin, SHBG, and dehydroepiandrosterone sulfate were measured by chemiluminescent enzyme immunoassay (Immulite 2000, Diagnostic Products Corp., Los Angeles, CA) Serum glucose was measured by using glucokinase technique. Lipid analysis in fasting serum was performed for all patients. The lipid profile included measurement of the levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. These parameters were measured by commercial enzymatic methods (Aeroset automated analyzer, Abbott Laboratories, Abbott, IL). LDL cholesterol was calculated by using Friedewald’s formula.

Plasma insulin levels were measured by chemiluminescent enzyme immunoassay (Immulite 1000 Analyzer, Diagnostic Products Corp., Los Angeles, CA) with interassay and intraassay coefficients of variation not exceeding 6.4%. Plasma hsCRP concentrations were measured by chemiluminescent enzyme immunoassay (Immulite 2000, Diagnostic Products) with intraassay coefficient of variation of 8.7% and sensitivity of 0.01 mg/dl. Upper limit of detection was 15 mg/dl.

Insulin resistance (IR) was determined by a number of different methods including fasting insulin, the homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI). The estimate of insulin resistance by HOMA score was calculated with the formula: fasting serum insulin (microunits per milliliter) x fasting plasma glucose (micromoles per liter) / 22.5 (13). QUICKI is derived by calculating the inverse of sum of logarithmically expressed values of fasting insulin and glucose (14).

Using ultrasonography, arterial endothelium and smooth muscle function were measured by examining brachial artery responses to endothelium-dependent (FMD) and endothelium-independent stimuli [sublingual nitroglycerin (NTG)]. Ultrasonographic measurement was carried out according to the method described by Coretti (15). The assessment was performed after an overnight fast in a quiet, air-conditioned room (22–24 C) by one experienced cardiologist who was blinded to diagnosis. The diameter of brachial artery was measured on B-mode ultrasound images, with use of a 7.5-Mhz transducer. Ultrasound measurement was obtained using a high-resolution ultrasound machine (Power Vision 8000, Toshiba Shiomoishigami, Otawara-Shi, Japan). The right brachial artery was scanned in longitudinal sections 2–8 cm above the elbow. After the detection of the right transducer position, the skin surface was marked and the arm kept in the same position during the study. All scans were recorded on videorecorder and analyzed later. Arterial diameters were measured at rest, during reactive hyperemia (FMD), again at rest, and after administration of 0.4 mg sublingual NTG. Reactive hyperemia was induced by inflation of a pneumatic cuff on the upper arm to suprasystolic pressure, followed by cuff deflation after 4.5 min. The diameter of the brachial artery was scanned and recorded after deflation. After 10–15 min rest, the second control scan diameter was recorded. Then sublingual NTG was administered and 3.5–4 min later, a final scan of the diameter was recorded.

The end diastolic arterial diameter was measured from one media-adventitia interface to the other at the clearest section three times: at baseline, every 20 sec after reactive hyperemia, and after administration of NTG. The maximum vessel diameter was defined as the average of the three consecutive maximum diameter measurements after hyperemia and NTG, respectively. Vasodilation by reactive hyperemia or NTG was expressed as the percent change in diameter, compared with baseline values. The intraobserver variation in our clinic was 1.5%.

Statistical analysis

The Statistical Package for the Social Sciences (SPSS version 11.5 for Windows, SPSS Inc., Chicago, IL) was used for statistical analysis. The person doing the data analysis was blinded to diagnosis. Results were expressed as mean ± SD. The characteristics of distribution were tested with Kolmogorov-Smirnof test. Highly skewed variables were analyzed after logarithmic transformation. Spearman rank correlations were used for these variables. The Mann-Whitney U test was used for variables with persisting skewed distribution after log transformation. Differences between means were analyzed by Student’s unpaired t test using two-tailed tests for significance. P < 0.05 was considered statistically significant. Analysis of correlations between parameters was performed by using Pearson’s bivariate correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical and hormonal data of PCOS and control groups are shown in Table 1Go. The patient and control groups were well matched for age, body mass index (BMI), and waist circumference. Serum LH, testosterone, androstenedione levels and LH to FSH ratio were significantly higher, and SHBG levels were significantly lower in the PCOS group. The fasting insulin levels were significantly higher in the PCOS than control women, whereas no difference in fasting glucose concentrations was observed between groups. Insulin sensitivity indices (HOMA and QUICKI) were significantly different between the PCOS and control groups. The mean serum levels of total cholesterol and LDL cholesterol were comparable between the two groups. However, the mean triglyceride concentration was higher and high-density lipoprotein cholesterol concentration was significantly lower in the PCOS group.


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  		TABLE 1. Comparison of anthropomorphic and laboratory data from the PCOS patients and controls

 
Figure 1Go shows CRP concentrations in both groups. The geometric means for the women with PCOS and the control group were 0.25 and 0.09 mg/dl, respectively (P = 0.007). Correlations of various metabolic and hormonal parameters with hsCRP are shown in Table 2Go. CRP was correlated only with BMI, insulin sensitivity indices (HOMA and QUICKI), and FMD.



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  		FIG. 1. hs-CRP concentrations in women with PCOS and controls.

 

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  		TABLE 2. Simple correlations of various metabolic and hormonal parameters with hs-CRP

 
There was a significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the women with PCOS and the normal healthy controls (Table 3Go). The groups were well matched for baseline brachial artery diameter. Correlations of various metabolic and hormonal parameters with FMD are shown in Table 4Go. Endothelium-dependent vasodilation was correlated only with hsCRP and insulin resistance. Endothelium-independent vascular response was not correlated with any of the metabolic or hormonal parameter.


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  		TABLE 3. Brachial artery responses, expressed as percentage of dilation from baseline

 

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  		TABLE 4. Simple correlations of various metabolic and hormonal parameters with FMD

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Women with PCOS have a clustering of cardiovascular risk factors such as obesity, lipid abnormalities, impaired glucose tolerance, and hypertension (16, 17, 18). Recent data have shown not only increased prevalence of CVD (2, 3, 4) but also higher cardiovascular morbidity even in young and thin women with PCOS (20). There is increasing evidence to suggest a role for inflammation in the pathogenesis of CVD (20). Accumulating evidence suggests that atherosclerosis represents a chronic inflammatory process, and hence inflammatory markers like CRP may provide an adjunctive method for global assessment of cardiovascular risk (21, 22). Recent data also suggest that CRP may directly promote endothelial dysfunction by increasing the synthesis of soluble adhesion molecules, increasing monocyte chemoattractant protein secretion, and facilitating macrophage LDL uptake (23). Many studies have shown the higher hsCRP levels in obese women with PCOS than healthy controls (24, 25). We examined hsCRP levels in young women with PCOS who had a normal BMI. This study has shown that CRP concentrations measured using a highly sensitive assay are significantly increased in women with PCOS relative to those age and BMI-matched healthy women. Interestingly, CRP concentrations were correlated with BMI although patients’ mean BMIs were within normal limits. Previous studies have shown the relationship between BMI and CRP levels (26, 27, 28). Moreover, CRP concentrations were correlated with abdominal obesity (29, 30). In this study, although statistically not significant, women with PCOS have increased visceral fat mass relative to the BMI-matched control group because the waist circumference was higher in the PCOS group than the control group (83.16 ± 9.67 vs. 71.87 ± 7.32 cm, respectively). Central fat accumulation may also contribute to high CRP values in PCOS women.

IR is no doubt a key component of PCOS (31). Both lean and obese women with PCOS have peripheral IR and hyperinsulinemia (32, 33). Previous studies also detected a correlation between IR and CRP concentrations (26, 27, 28). In this study we also found that CRP concentrations were correlated with decrease insulin sensitivity in women with PCOS. Decreased insulin sensitivity is known to counteract the physiologic effect of insulin on hepatic acute-phase protein synthesis (34). Therefore, hepatic IR could lead to increased synthesis of acute-phase proteins, such as CRP. Another possible mechanism is that, cytokines, mainly IL-1, IL-6, and TNF{alpha}, may exert stimulating effect on hepatic synthesis of acute-phase proteins (35).

The endothelium is highly active metabolically and plays a key role in vascular homeostasis through the release of variety of autocrine and paracrine substances. The healthy endothelium, particularly endothelium-derived nitric oxide, not only modulates the tone of underlying vascular smooth muscle but also inhibits several proatherogenic processes, including monocyte and platelet adhesion, oxidation of LDLs, synthesis of inflammatory cytokines, smooth muscle proliferation, and migration and platelet aggregation, thus exhibiting important antiatherogenic effects (36). Endothelial cell dysfunction is the initiating event in the development of atherosclerosis (37), and assessment of endothelial function by different methods has emerged as a tool for detection of evidence of preclinical CVD (5, 38). Brachial artery ultrasound is a widely used noninvasive measure of endothelial function.

Studies showing a link between endothelial dysfunction and IR have been reported (39, 40). Endothelial dysfunction might therefore contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects, such as those with PCOS (4, 31). Paradisi (35) documented markedly diminished endothelium-dependent and insulin-mediated flow responses in the femoral artery among obese women with PCOS with a dominant dependence flow response on androgen levels and IR. However, in this study PCOS women were selected on the basis of elevated testosterone, which could bias the outcome. Indeed, an opposite relationship between free testosterone and FMD was suggested in postmenopausal women on hormone replacement therapy who were given a testosterone implant and in whom endothelium-dependent and -independent FMD increased (41). Christopher et al. (42) demonstrated increased vascular stiffness and functional defect in the vascular action of insulin in obese patients. The present study is the first to our knowledge to demonstrate an endothelium-dependent and endothelium-independent dysfunction in young and thin women with PCOS. Mather et al. (19) studied a small group of obese women with PCOS by using brachial artery ultrasound and were unable to demonstrate a defect in endothelium-dependent vascular responses. But this study had various limitations like a small study group, difference in BMI between study groups, and the metabolic profile of the patient group being more normal than expected. In the study endothelium-dependent FMD was correlated with insulin resistance indices. Endothelium dysfunction was not related with any other hormonal parameters including androgen levels. Recent studies also suggest that there is a correlation between endothelium-dependent vasodilation and CRP concentrations (10). We also detected a similar correlation in this study in women with PCOS.

In conclusion, this study provides the first evidence that nonobese women with PCOS had higher hsCRP concentrations than age- and weight-matched healthy women. They had also endothelium-dependent and -independent dysfunction. Endothelium-dependent dysfunction appears to be associated with IR and low-grade chronic inflammation. Clinical strategies aimed at reducing IR may have cardioprotective effects, even in nonobese women with PCOS. Further prospective studies with larger numbers of patients and control groups are necessary to confirm our results.


   Footnotes
 
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; FMD, flow-mediated dilation; HOMA, homeostasis model assessment; hs, high-sensitivity; IR, insulin resistance; LDL, low-density lipoprotein; NTG, nitroglycerin; PCOS, polycystic ovary syndrome; QUICKI, quantitative insulin sensitivity check index.

Received April 26, 2004.

Accepted August 18, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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B. Banaszewska, L. Pawelczyk, R. Z. Spaczynski, J. Dziura, and A. J. Duleba
Effects of Simvastatin and Oral Contraceptive Agent on Polycystic Ovary Syndrome: Prospective, Randomized, Crossover Trial
J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 456 - 461.
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E. DIAMANTI-KANDARAKIS, T. PATERAKIS, and H. A. KANDARAKIS
Indices of Low-Grade Inflammation in Polycystic Ovary Syndrome
Ann. N.Y. Acad. Sci., December 1, 2006; 1092(1): 175 - 186.
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L. J Moran, M. Noakes, P. M Clifton, G. A Wittert, G. Williams, and R. J Norman
Short-term meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome
Am. J. Clinical Nutrition, July 1, 2006; 84(1): 77 - 87.
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E. Diamanti-Kandarakis, T. Paterakis, K. Alexandraki, C. Piperi, A. Aessopos, I. Katsikis, N. Katsilambros, G. Kreatsas, and D. Panidis
Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin
Hum. Reprod., June 1, 2006; 21(6): 1426 - 1431.
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L. Ibanez and F. de Zegher
Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women
Hum. Reprod. Update, May 1, 2006; 12(3): 243 - 252.
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L. Ibanez, C. Valls, and F. de Zegher
Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-{alpha} and the neutrophil/lymphocyte ratio
Hum. Reprod., February 1, 2006; 21(2): 451 - 456.
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J. J. Puder, S. Varga, M. Kraenzlin, C. De Geyter, U. Keller, and B. Muller
Central Fat Excess in Polycystic Ovary Syndrome: Relation to Low-Grade Inflammation and Insulin Resistance
J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6014 - 6021.
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F. Orio Jr., S. Palomba, T. Cascella, B. De Simone, F. Manguso, S. Savastano, T. Russo, A. Tolino, F. Zullo, G. Lombardi, et al.
Improvement in Endothelial Structure and Function after Metformin Treatment in Young Normal-Weight Women with Polycystic Ovary Syndrome: Results of a 6-Month Study
J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6072 - 6076.
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C. Meyer, B. P. McGrath, and H. J. Teede
Overweight Women with Polycystic Ovary Syndrome Have Evidence of Subclinical Cardiovascular Disease
J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5711 - 5716.
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S. Johnsen, S. E. Dolan, K. V. Fitch, K. M. Killilea, J. L. Shifren, and S. K. Grinspoon
Absence of Polycystic Ovary Syndrome Features in Human Immunodeficiency Virus-Infected Women Despite Significant Hyperinsulinemia and Truncal Adiposity
J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5596 - 5604.
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L. W. Cho, V. Jayagopal, E. S. Kilpatrick, and S. L. Atkin
The Biological Variation of C-Reactive Protein in Polycystic Ovarian Syndrome
Clin. Chem., October 1, 2005; 51(10): 1905 - 1907.
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M. Kravariti, K. K. Naka, S. N. Kalantaridou, N. Kazakos, C. S. Katsouras, A. Makrigiannakis, E. A. Paraskevaidis, G. P. Chrousos, A. Tsatsoulis, and L. K. Michalis
Predictors of Endothelial Dysfunction in Young Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5088 - 5095.
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L. Ibanez, A. M. Jaramillo, A. Ferrer, and F. de Zegher
High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception
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B. Vural, E. Caliskan, E. Turkoz, T. Kilic, and A. Demirci
Evaluation of metabolic syndrome frequency and premature carotid atherosclerosis in young women with polycystic ovary syndrome
Hum. Reprod., September 1, 2005; 20(9): 2409 - 2413.
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R. Azziz, C. Marin, L. Hoq, E. Badamgarav, and P. Song
Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4650 - 4658.
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I. Tarkun, B. Cetinarslan, E. Turemen, T. Sahin, Z. Canturk, and B. Komsuoglu
Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome
Eur. J. Endocrinol., July 1, 2005; 153(1): 115 - 121.
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