Obesity Research & Clinical Practice (2010) 4, e49—e56
ORIGINAL ARTICLE
Endothelial function in young women with polycystic ovary syndrome (PCOS): Implications of body mass index (BMI) and insulin resistance Ghada El-Kannishy a,∗, Shaheer Kamal a, Amany Mousa a, Omayma Saleh a, Adel El Badrawy b, Reham El farahaty c, Tarek Shokeir d a
Department of Internal Medicine, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt b Department of Radiodiagnosis, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt c Department of Clinical Pathology, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt d Department of Obstetrics & Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt Received 8 April 2009 ; received in revised form 26 August 2009; accepted 28 August 2009
KEYWORDS Polycystic ovary syndrome(PCOS); Endothelial dysfunction; BMI; Flow mediated dilatation (FMD); Insulin resistance
∗
Summary Background: Evidence regarding endothelial function in both obese and nonobese women with PCOS is contradictory. It is unknown whether obese women with PCOS carry an increased risk related to body mass index (BMI). Aim: To identify endothelial function and investigate its relationship to body mass index and insulin resistance in young women with PCOS. Subjects and methods: Twenty-two obese women with PCOS (BMI 35.2 ± 3.2) as well as fourteen lean women (BMI 22.8 ± 2.1)with PCOS were included in the study. Fasting serum insulin, blood glucose were estimated and HOMA and Quicki index were calculated. All patients were subjected to ultrasound recording of brachial artery diameter at rest and after reactive hyperemia (FMD) for assessment of endothelial function. Ten age matched healthy females with normal BMI were chosen as a control group. Results: There were higher basal insulin levels with lower Quicki index and higher HOMA index in women with PCOS than normal group, but the differences were significant only between obese PCOS subgroup and control. On the other hand, FMD was significantly and equally decreased in both groups of women with PCOS, compared with control subjects (3.7 ± 3.2% in the nonobese subgroup and 3.5 ± 2.8% in the obese one vs. 10.6 ± 4.1% in control subjects, P, 0.001). FMD was not correlated with BMI nor insulin resistance indices.
Corresponding author. Tel.: +20 502331118. E-mail address: [email protected] (G. El-Kannishy).
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.08.001
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G. El-Kannishy et al. Conclusions: Endothelial dysfunction is already present in young women with PCOS. In this patient group, it cannot be attributed to insulin resistance or obesity. © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Introduction Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting 5—10% of women of reproductive age. PCOS is not only considered a reproductive problem but rather represents a complex endocrine, multifaceted syndrome with important health implications [1]. Several cardiovascular risk factors have been identified in women with PCOS and are present from an early age [2]. These factors often relate to associated metabolic alteration and includes dyslipidemia, hypertension, endothelial dysfunction and low grade chronic inflammation. While insulin resistance appears important [2], the impact of traditional risk factors in subjects with PCOS on long term cadiovascular outcomes remains uncertain. The endothelium is highly active metabolically and plays a key role in vascular homeostasis through the release of variety of autocrine and paracrine substances [3]. The healthy endothelium, particularly endothelium-derived nitric oxide (NO), not only modulates the tone of underlying vascular smooth muscle but also inhibits several proatherogenic processes. These antiatherogenic effects include inhibition of monocyte and platelet adhesion, oxidation of LDLs, synthesis of inflammatory cytokines, smooth muscle proliferation, and migration and platelet aggregation [2—4]. Endothelial dysfunction has been regarded as an early feature of atherosclerosis and plays an important role in the development of atherosclerotic disease. 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 [5,6]. Assessment of endothelial function by different methods has emerged as a tool for detection of evidence of preclinical cardiovascular disease (CVD) [5]. Brachial artery ultrasound is a widely used noninvasive measure of endothelial function [5,6]. In obese women with PCOS, Mather et al. [7] reported normal endothelial function, whereas Paradisi et al. [8] demonstrated endothelial dysfunction and insulin resistance at a vascular level. Studies in younger and nonobese women with PCOS
are lacking. Two recent articles showed impairment of endothelial function and vascular structure in young normal weight women with PCOS [9,10]. In this setting, the aim of this study was to assess endothelial function in women with PCOS using well-validated marker of endothelial function (brachial artery flow-mediated dilation (FMD) and to investigate its relationship to body mass index (BMI) and insulin resistance in young women with PCOS.
Materials and methods Patient population During the period from April 2007 to March 2008, a total of 36 PCOS women attending the outpatient clinic were enrolled in the study. Of these women, 14 were nonobese (BMI < 25) and 22 were obese (BMI > 30). PCOS was defined when at least two of the following three features were present after the exclusion of other etiologies [11]: oligoor anovulation (fewer than six menstrual periods in the preceding year), clinical Ferriman-Gallwey score [12] >8 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). All women had normal thyroid, renal, and hepatic function. Exclusion criteria for all subjects included age over 40 years, pregnancy, current or previous use (within 6 months) of oral contraceptives, antiandrogens, antidiabetics, statins, glucocorticoids or other hormonal drugs, cigarette smoking, blood pressure of 130/85 mmHg or greater or treated hypertension, known CVD, and diabetes mellitus. Other causes of chronic anovulation, including congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, and thyroid disease were also excluded by appropriate tests. Ten healthy age matched females with regular menses and ultrasonographically normal ovaries were selected as a control group. Their clinical,
Endothelial function in young women with PCOS biochemical, and hormonal profiles were within normal limits. The same exclusion criteria as patient group were used for the control group. All subjects gave full informed written consent about the trial. The Institutional Review Board of Mansoura University approved the study.
Brachial ultrasound Vascular reactivity was assessed using brachial artery 2D greyscale ultrasound. A 7.5-MHz linear phased array ultrasound transducer was used to image the dominant arm brachial artery longitudinally just above the antecubital fossa. Studies were performed after a 12-h fast; during this period caffeine-containing drinks were avoided. All patients rested for 10—15 min in a quiet room at room temperature. Diameter of the artery was measured at end diastole then a blood pressure cuff was inflated to 40 mmHg above the systolic pressure on the distal portion of the arm for 4 min and then released. The increased flow in the artery after removal of the blood pressure cuff is termed reactive hyperemia and results in flowmediated dilation (FMD) and is used as a measure of endothelium-dependent vasodilation [13,14]. The brachial artery was scanned continuously for 2 min after cuff deflation, and the vessel diameter at the same point of resting measurement was defined. FMD was determined as the percentage change from baseline to 60 s after ischemia, the point of maximal dilation [15].
Laboratory assays All blood samples were obtained in the morning between 0800 and 0900 h after an overnight fast and during early follicular phase. They were centrifuged immediately and serum was stored at −20 ◦ C until assayed. The samples were assayed within 12 months of their collection. The serum concentrations of testosterone were measured by enzyme
Table 1
2
BMI (kg/m ) Age Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Testosterone (nmol/ml) *
linked immunosorbant assay using Biosourse kit (Biosourse, Europe SA Belgium). Luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured using the LHsp and FSH IRMA kits from Biosource Technologies, Inc., Europe S.A. 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 (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). 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 Biosourse INS-EASIA (Biosource, Europe S.S., Belgium).
Insulin resistance Insulin resistance was estimated by the quantitative insulin sensitivity check index (QUICKI) and HOMA resistance index. QUICKI index was estimated using the following formula [16]: 1/[log(fasting insulin) + log(fasting glucose)]. HOMA index was estimated using the following formula [17]: [fasting glucose × fasting insulin]/22.5.
Statistical analysis Statistical analysis was performed using The Statistical Package for the Social Sciences (SPSS version 13). When data were normally distributed, unpaired t tests were used to compare parameters between groups. For comparison of qualitative data the Chisquare test was used. Pearson’s correlations with r to z significance calculations were performed. Partial correlation and multiple regression analysis were performed to assess the relationship between FMD and the studied parameters. Subsequently, variables whose correlation with the flow mediated
Patient characteristics and hormone studies. Values expressed as means ± SD.
Parameter
**
e51
Obese group (n = 22) 35.2 25.6 165.2 121 44.1 119.8 2.8
P < 0.001 vs. nonobese and control group. P < 0.05 vs. control group.
± ± ± ± ± ± ±
*
3.2 3.4 36.8 109.48** 11.9** 23.5 0.5**
Nonobese group (n = 14) 22.8 25.2 160.1 114.1 46.4 108.4 2.5
± ± ± ± ± ± ±
2.1 3.6 38.9 75.7** 13.05** 25.5 0.8**
Control (n = 10) 21.9 24.4 160.4 88.6 53.6 96.41 1.5
± ± ± ± ± ± ±
2.97 4.07 41.3 36.7 15.4 23.2 1.0
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G. El-Kannishy et al.
Table 2
Glucose metabolism parameters of the patients groups. Values expressed as means ± SD.
Parameter
Obese group (n = 22)
Fasting glucose (mmol/l) Fasting insulin (pmol/l) HOMA QUICKI
5.34 46.2 1.88 0.360
* **
± ± ± ±
Nonobese group (n = 14)
0.59 27.0* 1.26** 0.035**
5.23 43.7 1.71 0.364
± ± ± ±
Control (n = 10)
0.62 25.6 1.04 0.033
5.16 39.1 1.51 0.375
± ± ± ±
0.47 24.4 0.96 0.043
P < 0.05 vs. nonobese and control group. P < 0.05 vs. control group.
Table 3
Brachial artery responses, expressed as percentage dilatation from baseline.
Parameter
Obese group (n = 22)
Nonobese group (n = 14)
Control (n = 10)
Baseline artery diameter (mm) FMD (%)
3.35 ± 0.27 3.5 ± 2.8**
3.34 ± 0.34 3.7 ± 3.2**
3.27 ± 0.33 10.6 ± 4.1
**
P < 0.001 vs. control group.
dilatation achieved statistical significance (P < 0.1) were entered into a stepwise regression model to assess the magnitude of their individual effects on FMD. Statistical significance was defined as a two-sided P < 0.05. All data are expressed as mean ± SD.
There was a normal baseline artery diameter with significant impairment in endotheliumdependent (FMD) vascular responses in PCOS groups (Table 3). FMD was neither correlated with insulin resistance indices nor with BMI in both groups (Pearson’s correlation, P > 0.05), while it was negatively correlated to serum testosterone level (Table 4).
Results
Discussion
Clinical characteristics and hormonal parameters of all women enrolled in the study are shown in Table 1. There was no significant change in total cholesterol, LDL levels between the three studied groups. Serum triglyceride concentrations were increased significantly in both patients groups when compared to the control group while serum HDL concentrations were significantly decreased in the patient groups than the control with insignificant difference between patients groups (P > 0.05). Glucose metabolism parameters of all studied women are shown in Table 2. There was no significant change in fasting serum glucose concentrations among groups. However, fasting insulin concentrations was significantly higher in obese group than the other two groups. Insulin resistance indices (HOMA) were significantly higher in subjects with obesity and tended to be higher (but not statistically significant) in subjects with normal BMI than in the control. The QUICKI was significantly lower in obese group and tended to be lower (but not statistically significant) in nonobese patients group than in the control.
PCOS is associated with an increased lifetime risk of hypertension [18], dyslipidemia [19], type 2 diabetes [20,21], and possibly cardiovascular disease [20,22,23]. The mechanism of the link between
Table 4 Correlations of various metabolic and hormonal parameters with FMD. Correlations of FMD with
r
p
Age BMI (kg/m2 ) Testosterone (nmol/ml) Fasting glucose (mmol/l) Fasting insulin (pmol/l) HOMA QUICKI Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl)
−0.120 0.069 −0.323 0.204 0.331 0.270 −0.271 0.043 −0.230 0.119 0.163
0.34 0.61 * 0.04 0.17 0.08 0.06 0.06 0.69 0.12 0.43 0.29
*
P < 0.05.
Endothelial function in young women with PCOS PCOS and increased cardiovascular risk is not well understood. Controversial data exist regarding the presence of endothelial dysfunction in women with PCOS, certain studies reporting no impairment [7,24—26] and others showing significant impairment [9,10,26—29]. Differences concerning cardiovascular risk factors among the various populations studied might explain these discrepancies. Mather et al. [7] showed no difference in FMD between PCOS patients and controls, despite the hyperandrogenism and insulin resistance of PCOS patients. Similarly, Meyer at al. [25] did not find increased intima-media thickness (IMT) in young overweight PCOS, despite higher HDL and triglycerides levels compared with the control group. On the other hand, Paradisi and co-workers [8] were the first to recognise the presence of endothelial dysfunction in PCOS by the use of invasive leg plethysmography, but differences in HDL and triglycerides plasma levels between PCOS and control women in this study may have accounted for these findings. Kelly et al. [24] found impaired vascular function by the use of an invasive method. In addition, Lakhani et al. [30] evidenced impaired carotid viscoelastic properties in PCOS women, providing additional evidence of vascular dysfunction in women with this syndrome. Finally, Kravariti et al. [27] found altered FMD and nitroglycerine induced dilatation (NID), suggesting a global vascular injury and not only endothelial dysfunction. Our study was designed to evaluate associations of endothelial function with extent of insulin resistance and BMI, but not really to examine other potential bases for endothelial dysfunction. We examined the macrovascular function in lean and obese women with PCOS and in controls using noninvasive methodologies. Our results demonstrated that endothelial function assessed by FMD, was impaired in both PCOS groups. These findings suggest that measurable vascular abnormalities in PCOS women are possibly developed by middle age and that PCOS per se and not simply BMI is responsible for these differences. FMD at the brachial artery was lower in the presence of PCOS, although basal brachial artery diameter was comparable in the three groups. These vascular changes may be the forerunners of more overt cardiovascular abnormalities such as high BP in older women with PCOS. Our data demonstrated that women with PCOS had higher fasting insulin levels and insulin resistance indices than controls, whereas they showed reduced FMD values. Fasting insulin levels and insulin resistance indices were only significantly higher in the obese group. Cibula et al. [31] stated that insulin resistance is a frequent (although not
e53 constant) abnormality in both obese and nonobese women with PCOS. Acien and co-workers [32] stated that insulin resistance is present in 50—80% of women with PCOS and is further worsen by the presence of obesity. Recently, Grimmichová et al. [33] using QUICKI to determine insulin sensitivity in lean PCOS-affected women and healthy controls demonstrated that both groups had the same insulin sensitivity. The association between insulin resistance and endothelial dysfunction has been demonstrated consistently in subjects with type 2 diabetes mellitus [21], obesity [34], the metabolic syndrome [35] and in children of parents with type 2 diabetes [36]. The progression of insulin resistance to diabetes parallels the progression of endothelial dysfunction to atherosclerosis as stated by Hsueh et al. [37]. There are several mechanisms through which insulin resistance can adversely affect the endothelium. Insulin-resistant states are characterized by increased production of free fatty acids and proinflammatory cytokines such as TNF␣ and leptin, which contribute to endothelial dysfunction [26]. There is also evidence to suggest that insulin resistance induces increased oxidant stress, which may have an important pathogenic role [38]. Insulin is also known to have direct effects promoting vascular smooth muscle hyperplasia and collagen synthesis [39], with both factors leading to increased arterial stiffness. In this study, there was no correlation between endothelial dysfunction (assessed by FMD) and insulin resistance indices or BMI in women with PCOS. This finding supports the suggestion that PCOS presence predicted FMD values independently of BMI or insulin resistance indices. Impairment of FMD in lean women with PCOS without significant insulin resistance suggests a crucial role of other cardiovascular risk factors in the development of endothelial dysfunction in women with PCOS. These results match with those of Rajendran et al. [40] who recently reported that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance. Further, the same authors [40] demonstrated significant impairment of vascular endothelial function which was independent of the presence/absence of obesity and associated insulin resistance. On the other hand, Ketel et al. [41] found decreased microvascular and metabolic insulin sensitivity in obese but not normal-weight women independent of PCOS. In general, women with PCOS carry several metabolic aberrations e.g. obesity, insulin
e54 resistance, abnormal lipid profile and hyperandrogenemia [32]. A significant elevation in androgen levels was observed in our PCOS cohort compared to controls. This finding correlated inversely with FMD. Such observation probably suggests an important role for the exposure of androgens in the development of endothelial dysfunction. Previous studies [42—44] have demonstrated the importance of sex hormones in contributing to carotid arterial wall thickness. Hyperandrogenemia in women with PCOS may result in a male pattern of lipoproteins, suggesting an increased atherogenic potential in PCOS patients [45]. The complex correlation between vascular parameters, insulin resistance and hyperandrogenemia suggests that these factors are interrelated and interplay possibly with other unknown factors affecting the vascular bed of a young population of PCOS women who do not carry an increased load of cardiovascular risk factors. Our data support a role of hyperandrogenemia in vascular reactivity in PCOS, but the mode of action of androgens remains unknown. Androgen receptors are known to exist on the vessel wall, and a direct effect of androgens in the vasculature cannot be excluded [46]. Alternatively, androgens may act synergistically with insulin resistance [47] inflammatory cytokines [48] or angioconstrictive peptides [49] on endothelial function. Androgens may promote monocyte adhesion to endothelial cells a proatherogenic effect mediated, at least in part, by an increased endothelial cell-surface expression of VCAM-1 [50] which has been found elevated in PCOS subjects [26]. Different patterns of dyslipidemia can be present, both in lean and obese PCOS. The pattern of dyslipidemia demonstrated in the current study is consistent with previous publications showing abnormal lipid profiles in PCOS [51,52]. These include low HDL-cholesterol, with or without elevated TG. In addition, smaller HDL and LDL particles and elevated postprandial TG responses were also reported [43]. In conclusion our results, although limited, provide additional confirmatory evidence of endothelial dysfunction in women with PCOS which is neither related to BMI nor to insulin resistance. In young women with PCOS, obesity and insulin resistance probably may have an additive role with time.
Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.
G. El-Kannishy et al.
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ORIGINAL ARTICLE
Endothelial function in young women with polycystic ovary syndrome (PCOS): Implications of body mass index (BMI) and insulin resistance Ghada El-Kannishy a,∗, Shaheer Kamal a, Amany Mousa a, Omayma Saleh a, Adel El Badrawy b, Reham El farahaty c, Tarek Shokeir d a
Department of Internal Medicine, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt b Department of Radiodiagnosis, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt c Department of Clinical Pathology, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt d Department of Obstetrics & Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt Received 8 April 2009 ; received in revised form 26 August 2009; accepted 28 August 2009
KEYWORDS Polycystic ovary syndrome(PCOS); Endothelial dysfunction; BMI; Flow mediated dilatation (FMD); Insulin resistance
∗
Summary Background: Evidence regarding endothelial function in both obese and nonobese women with PCOS is contradictory. It is unknown whether obese women with PCOS carry an increased risk related to body mass index (BMI). Aim: To identify endothelial function and investigate its relationship to body mass index and insulin resistance in young women with PCOS. Subjects and methods: Twenty-two obese women with PCOS (BMI 35.2 ± 3.2) as well as fourteen lean women (BMI 22.8 ± 2.1)with PCOS were included in the study. Fasting serum insulin, blood glucose were estimated and HOMA and Quicki index were calculated. All patients were subjected to ultrasound recording of brachial artery diameter at rest and after reactive hyperemia (FMD) for assessment of endothelial function. Ten age matched healthy females with normal BMI were chosen as a control group. Results: There were higher basal insulin levels with lower Quicki index and higher HOMA index in women with PCOS than normal group, but the differences were significant only between obese PCOS subgroup and control. On the other hand, FMD was significantly and equally decreased in both groups of women with PCOS, compared with control subjects (3.7 ± 3.2% in the nonobese subgroup and 3.5 ± 2.8% in the obese one vs. 10.6 ± 4.1% in control subjects, P, 0.001). FMD was not correlated with BMI nor insulin resistance indices.
Corresponding author. Tel.: +20 502331118. E-mail address: [email protected] (G. El-Kannishy).
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.08.001
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G. El-Kannishy et al. Conclusions: Endothelial dysfunction is already present in young women with PCOS. In this patient group, it cannot be attributed to insulin resistance or obesity. © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Introduction Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting 5—10% of women of reproductive age. PCOS is not only considered a reproductive problem but rather represents a complex endocrine, multifaceted syndrome with important health implications [1]. Several cardiovascular risk factors have been identified in women with PCOS and are present from an early age [2]. These factors often relate to associated metabolic alteration and includes dyslipidemia, hypertension, endothelial dysfunction and low grade chronic inflammation. While insulin resistance appears important [2], the impact of traditional risk factors in subjects with PCOS on long term cadiovascular outcomes remains uncertain. The endothelium is highly active metabolically and plays a key role in vascular homeostasis through the release of variety of autocrine and paracrine substances [3]. The healthy endothelium, particularly endothelium-derived nitric oxide (NO), not only modulates the tone of underlying vascular smooth muscle but also inhibits several proatherogenic processes. These antiatherogenic effects include inhibition of monocyte and platelet adhesion, oxidation of LDLs, synthesis of inflammatory cytokines, smooth muscle proliferation, and migration and platelet aggregation [2—4]. Endothelial dysfunction has been regarded as an early feature of atherosclerosis and plays an important role in the development of atherosclerotic disease. 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 [5,6]. Assessment of endothelial function by different methods has emerged as a tool for detection of evidence of preclinical cardiovascular disease (CVD) [5]. Brachial artery ultrasound is a widely used noninvasive measure of endothelial function [5,6]. In obese women with PCOS, Mather et al. [7] reported normal endothelial function, whereas Paradisi et al. [8] demonstrated endothelial dysfunction and insulin resistance at a vascular level. Studies in younger and nonobese women with PCOS
are lacking. Two recent articles showed impairment of endothelial function and vascular structure in young normal weight women with PCOS [9,10]. In this setting, the aim of this study was to assess endothelial function in women with PCOS using well-validated marker of endothelial function (brachial artery flow-mediated dilation (FMD) and to investigate its relationship to body mass index (BMI) and insulin resistance in young women with PCOS.
Materials and methods Patient population During the period from April 2007 to March 2008, a total of 36 PCOS women attending the outpatient clinic were enrolled in the study. Of these women, 14 were nonobese (BMI < 25) and 22 were obese (BMI > 30). PCOS was defined when at least two of the following three features were present after the exclusion of other etiologies [11]: oligoor anovulation (fewer than six menstrual periods in the preceding year), clinical Ferriman-Gallwey score [12] >8 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). All women had normal thyroid, renal, and hepatic function. Exclusion criteria for all subjects included age over 40 years, pregnancy, current or previous use (within 6 months) of oral contraceptives, antiandrogens, antidiabetics, statins, glucocorticoids or other hormonal drugs, cigarette smoking, blood pressure of 130/85 mmHg or greater or treated hypertension, known CVD, and diabetes mellitus. Other causes of chronic anovulation, including congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, and thyroid disease were also excluded by appropriate tests. Ten healthy age matched females with regular menses and ultrasonographically normal ovaries were selected as a control group. Their clinical,
Endothelial function in young women with PCOS biochemical, and hormonal profiles were within normal limits. The same exclusion criteria as patient group were used for the control group. All subjects gave full informed written consent about the trial. The Institutional Review Board of Mansoura University approved the study.
Brachial ultrasound Vascular reactivity was assessed using brachial artery 2D greyscale ultrasound. A 7.5-MHz linear phased array ultrasound transducer was used to image the dominant arm brachial artery longitudinally just above the antecubital fossa. Studies were performed after a 12-h fast; during this period caffeine-containing drinks were avoided. All patients rested for 10—15 min in a quiet room at room temperature. Diameter of the artery was measured at end diastole then a blood pressure cuff was inflated to 40 mmHg above the systolic pressure on the distal portion of the arm for 4 min and then released. The increased flow in the artery after removal of the blood pressure cuff is termed reactive hyperemia and results in flowmediated dilation (FMD) and is used as a measure of endothelium-dependent vasodilation [13,14]. The brachial artery was scanned continuously for 2 min after cuff deflation, and the vessel diameter at the same point of resting measurement was defined. FMD was determined as the percentage change from baseline to 60 s after ischemia, the point of maximal dilation [15].
Laboratory assays All blood samples were obtained in the morning between 0800 and 0900 h after an overnight fast and during early follicular phase. They were centrifuged immediately and serum was stored at −20 ◦ C until assayed. The samples were assayed within 12 months of their collection. The serum concentrations of testosterone were measured by enzyme
Table 1
2
BMI (kg/m ) Age Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Testosterone (nmol/ml) *
linked immunosorbant assay using Biosourse kit (Biosourse, Europe SA Belgium). Luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured using the LHsp and FSH IRMA kits from Biosource Technologies, Inc., Europe S.A. 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 (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). 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 Biosourse INS-EASIA (Biosource, Europe S.S., Belgium).
Insulin resistance Insulin resistance was estimated by the quantitative insulin sensitivity check index (QUICKI) and HOMA resistance index. QUICKI index was estimated using the following formula [16]: 1/[log(fasting insulin) + log(fasting glucose)]. HOMA index was estimated using the following formula [17]: [fasting glucose × fasting insulin]/22.5.
Statistical analysis Statistical analysis was performed using The Statistical Package for the Social Sciences (SPSS version 13). When data were normally distributed, unpaired t tests were used to compare parameters between groups. For comparison of qualitative data the Chisquare test was used. Pearson’s correlations with r to z significance calculations were performed. Partial correlation and multiple regression analysis were performed to assess the relationship between FMD and the studied parameters. Subsequently, variables whose correlation with the flow mediated
Patient characteristics and hormone studies. Values expressed as means ± SD.
Parameter
**
e51
Obese group (n = 22) 35.2 25.6 165.2 121 44.1 119.8 2.8
P < 0.001 vs. nonobese and control group. P < 0.05 vs. control group.
± ± ± ± ± ± ±
*
3.2 3.4 36.8 109.48** 11.9** 23.5 0.5**
Nonobese group (n = 14) 22.8 25.2 160.1 114.1 46.4 108.4 2.5
± ± ± ± ± ± ±
2.1 3.6 38.9 75.7** 13.05** 25.5 0.8**
Control (n = 10) 21.9 24.4 160.4 88.6 53.6 96.41 1.5
± ± ± ± ± ± ±
2.97 4.07 41.3 36.7 15.4 23.2 1.0
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G. El-Kannishy et al.
Table 2
Glucose metabolism parameters of the patients groups. Values expressed as means ± SD.
Parameter
Obese group (n = 22)
Fasting glucose (mmol/l) Fasting insulin (pmol/l) HOMA QUICKI
5.34 46.2 1.88 0.360
* **
± ± ± ±
Nonobese group (n = 14)
0.59 27.0* 1.26** 0.035**
5.23 43.7 1.71 0.364
± ± ± ±
Control (n = 10)
0.62 25.6 1.04 0.033
5.16 39.1 1.51 0.375
± ± ± ±
0.47 24.4 0.96 0.043
P < 0.05 vs. nonobese and control group. P < 0.05 vs. control group.
Table 3
Brachial artery responses, expressed as percentage dilatation from baseline.
Parameter
Obese group (n = 22)
Nonobese group (n = 14)
Control (n = 10)
Baseline artery diameter (mm) FMD (%)
3.35 ± 0.27 3.5 ± 2.8**
3.34 ± 0.34 3.7 ± 3.2**
3.27 ± 0.33 10.6 ± 4.1
**
P < 0.001 vs. control group.
dilatation achieved statistical significance (P < 0.1) were entered into a stepwise regression model to assess the magnitude of their individual effects on FMD. Statistical significance was defined as a two-sided P < 0.05. All data are expressed as mean ± SD.
There was a normal baseline artery diameter with significant impairment in endotheliumdependent (FMD) vascular responses in PCOS groups (Table 3). FMD was neither correlated with insulin resistance indices nor with BMI in both groups (Pearson’s correlation, P > 0.05), while it was negatively correlated to serum testosterone level (Table 4).
Results
Discussion
Clinical characteristics and hormonal parameters of all women enrolled in the study are shown in Table 1. There was no significant change in total cholesterol, LDL levels between the three studied groups. Serum triglyceride concentrations were increased significantly in both patients groups when compared to the control group while serum HDL concentrations were significantly decreased in the patient groups than the control with insignificant difference between patients groups (P > 0.05). Glucose metabolism parameters of all studied women are shown in Table 2. There was no significant change in fasting serum glucose concentrations among groups. However, fasting insulin concentrations was significantly higher in obese group than the other two groups. Insulin resistance indices (HOMA) were significantly higher in subjects with obesity and tended to be higher (but not statistically significant) in subjects with normal BMI than in the control. The QUICKI was significantly lower in obese group and tended to be lower (but not statistically significant) in nonobese patients group than in the control.
PCOS is associated with an increased lifetime risk of hypertension [18], dyslipidemia [19], type 2 diabetes [20,21], and possibly cardiovascular disease [20,22,23]. The mechanism of the link between
Table 4 Correlations of various metabolic and hormonal parameters with FMD. Correlations of FMD with
r
p
Age BMI (kg/m2 ) Testosterone (nmol/ml) Fasting glucose (mmol/l) Fasting insulin (pmol/l) HOMA QUICKI Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl)
−0.120 0.069 −0.323 0.204 0.331 0.270 −0.271 0.043 −0.230 0.119 0.163
0.34 0.61 * 0.04 0.17 0.08 0.06 0.06 0.69 0.12 0.43 0.29
*
P < 0.05.
Endothelial function in young women with PCOS PCOS and increased cardiovascular risk is not well understood. Controversial data exist regarding the presence of endothelial dysfunction in women with PCOS, certain studies reporting no impairment [7,24—26] and others showing significant impairment [9,10,26—29]. Differences concerning cardiovascular risk factors among the various populations studied might explain these discrepancies. Mather et al. [7] showed no difference in FMD between PCOS patients and controls, despite the hyperandrogenism and insulin resistance of PCOS patients. Similarly, Meyer at al. [25] did not find increased intima-media thickness (IMT) in young overweight PCOS, despite higher HDL and triglycerides levels compared with the control group. On the other hand, Paradisi and co-workers [8] were the first to recognise the presence of endothelial dysfunction in PCOS by the use of invasive leg plethysmography, but differences in HDL and triglycerides plasma levels between PCOS and control women in this study may have accounted for these findings. Kelly et al. [24] found impaired vascular function by the use of an invasive method. In addition, Lakhani et al. [30] evidenced impaired carotid viscoelastic properties in PCOS women, providing additional evidence of vascular dysfunction in women with this syndrome. Finally, Kravariti et al. [27] found altered FMD and nitroglycerine induced dilatation (NID), suggesting a global vascular injury and not only endothelial dysfunction. Our study was designed to evaluate associations of endothelial function with extent of insulin resistance and BMI, but not really to examine other potential bases for endothelial dysfunction. We examined the macrovascular function in lean and obese women with PCOS and in controls using noninvasive methodologies. Our results demonstrated that endothelial function assessed by FMD, was impaired in both PCOS groups. These findings suggest that measurable vascular abnormalities in PCOS women are possibly developed by middle age and that PCOS per se and not simply BMI is responsible for these differences. FMD at the brachial artery was lower in the presence of PCOS, although basal brachial artery diameter was comparable in the three groups. These vascular changes may be the forerunners of more overt cardiovascular abnormalities such as high BP in older women with PCOS. Our data demonstrated that women with PCOS had higher fasting insulin levels and insulin resistance indices than controls, whereas they showed reduced FMD values. Fasting insulin levels and insulin resistance indices were only significantly higher in the obese group. Cibula et al. [31] stated that insulin resistance is a frequent (although not
e53 constant) abnormality in both obese and nonobese women with PCOS. Acien and co-workers [32] stated that insulin resistance is present in 50—80% of women with PCOS and is further worsen by the presence of obesity. Recently, Grimmichová et al. [33] using QUICKI to determine insulin sensitivity in lean PCOS-affected women and healthy controls demonstrated that both groups had the same insulin sensitivity. The association between insulin resistance and endothelial dysfunction has been demonstrated consistently in subjects with type 2 diabetes mellitus [21], obesity [34], the metabolic syndrome [35] and in children of parents with type 2 diabetes [36]. The progression of insulin resistance to diabetes parallels the progression of endothelial dysfunction to atherosclerosis as stated by Hsueh et al. [37]. There are several mechanisms through which insulin resistance can adversely affect the endothelium. Insulin-resistant states are characterized by increased production of free fatty acids and proinflammatory cytokines such as TNF␣ and leptin, which contribute to endothelial dysfunction [26]. There is also evidence to suggest that insulin resistance induces increased oxidant stress, which may have an important pathogenic role [38]. Insulin is also known to have direct effects promoting vascular smooth muscle hyperplasia and collagen synthesis [39], with both factors leading to increased arterial stiffness. In this study, there was no correlation between endothelial dysfunction (assessed by FMD) and insulin resistance indices or BMI in women with PCOS. This finding supports the suggestion that PCOS presence predicted FMD values independently of BMI or insulin resistance indices. Impairment of FMD in lean women with PCOS without significant insulin resistance suggests a crucial role of other cardiovascular risk factors in the development of endothelial dysfunction in women with PCOS. These results match with those of Rajendran et al. [40] who recently reported that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance. Further, the same authors [40] demonstrated significant impairment of vascular endothelial function which was independent of the presence/absence of obesity and associated insulin resistance. On the other hand, Ketel et al. [41] found decreased microvascular and metabolic insulin sensitivity in obese but not normal-weight women independent of PCOS. In general, women with PCOS carry several metabolic aberrations e.g. obesity, insulin
e54 resistance, abnormal lipid profile and hyperandrogenemia [32]. A significant elevation in androgen levels was observed in our PCOS cohort compared to controls. This finding correlated inversely with FMD. Such observation probably suggests an important role for the exposure of androgens in the development of endothelial dysfunction. Previous studies [42—44] have demonstrated the importance of sex hormones in contributing to carotid arterial wall thickness. Hyperandrogenemia in women with PCOS may result in a male pattern of lipoproteins, suggesting an increased atherogenic potential in PCOS patients [45]. The complex correlation between vascular parameters, insulin resistance and hyperandrogenemia suggests that these factors are interrelated and interplay possibly with other unknown factors affecting the vascular bed of a young population of PCOS women who do not carry an increased load of cardiovascular risk factors. Our data support a role of hyperandrogenemia in vascular reactivity in PCOS, but the mode of action of androgens remains unknown. Androgen receptors are known to exist on the vessel wall, and a direct effect of androgens in the vasculature cannot be excluded [46]. Alternatively, androgens may act synergistically with insulin resistance [47] inflammatory cytokines [48] or angioconstrictive peptides [49] on endothelial function. Androgens may promote monocyte adhesion to endothelial cells a proatherogenic effect mediated, at least in part, by an increased endothelial cell-surface expression of VCAM-1 [50] which has been found elevated in PCOS subjects [26]. Different patterns of dyslipidemia can be present, both in lean and obese PCOS. The pattern of dyslipidemia demonstrated in the current study is consistent with previous publications showing abnormal lipid profiles in PCOS [51,52]. These include low HDL-cholesterol, with or without elevated TG. In addition, smaller HDL and LDL particles and elevated postprandial TG responses were also reported [43]. In conclusion our results, although limited, provide additional confirmatory evidence of endothelial dysfunction in women with PCOS which is neither related to BMI nor to insulin resistance. In young women with PCOS, obesity and insulin resistance probably may have an additive role with time.
Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.
G. El-Kannishy et al.
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