(BMI) and Insulin Resistance

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Obesity Research & Clinical Practice (2010) 4, e49e56

ORIGINAL ARTICLE

Endothelial function in young women withpolycystic ovary syndrome (PCOS): Implications ofbody 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, Egyptb Department of Radiodiagnosis, Mansoura University Hospital, Mansoura Faculty of Medicine, Egyptc Department of Clinical Pathology, Mansoura University Hospital, Mansoura Faculty of Medicine, Egyptd 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 PCOScarry an increased risk related to body mass index (BMI).

Aim: To identify endothelial function and investigate its relationship to body massindex and insulin resistance in young women with PCOS.Subjects and methods: Twenty-two obese women with PCOS (BMI 35.2 3.2) as wellas fourteen lean women (BMI 22.82.1)with PCOS were included in the study. Fast-ing serum insulin, blood glucose were estimated and HOMA and Quicki index werecalculated. All patients were subjected to ultrasound recording of brachial arterydiameter at rest and after reactive hyperemia (FMD) for assessment of endothelialfunction. Ten age matched healthy females with normal BMI were chosen as a controlgroup.Results: There were higher basal insulin levels with lower Quicki index and higherHOMA index in women with PCOS than normal group, but the differences were sig-

nificant only between obese PCOS subgroup and control. On the other hand, FMDwas significantly and equally decreased in both groups of women with PCOS, com-pared with control subjects (3.73.2% in the nonobese subgroup and 3.52.8% inthe obese one vs. 10.64.1% in control subjects, P, 0.001). FMD was not correlatedwith 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
mailto:[email protected]://dx.doi.org/10.1016/j.orcp.2009.08.001http://dx.doi.org/10.1016/j.orcp.2009.08.001mailto:[email protected]


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e50 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 com-mon endocrinopathy in women, affecting 510%of women of reproductive age. PCOS is not onlyconsidered a reproductive problem but ratherrepresents a complex endocrine, multifaceted syn-drome with important health implications [1].Several cardiovascular risk factors have been iden-tified in women with PCOS and are present froman early age [2]. These factors often relate toassociated metabolic alteration and includes dys-

lipidemia, hypertension, endothelial dysfunctionand low grade chronic inflammation. While insulinresistance appears important [2], the impact oftraditional risk factors in subjects with PCOS onlong term cadiovascular outcomes remains uncer-tain.

The endothelium is highly active metabolicallyand plays a key role in vascular homeostasis throughthe release of variety of autocrine and paracrinesubstances [3]. The healthy endothelium, partic-ularly endothelium-derived nitric oxide (NO), notonly modulates the tone of underlying vascularsmooth muscle but also inhibits several proathero-genic processes. These antiatherogenic effectsinclude inhibition of monocyte and platelet adhe-sion, oxidation of LDLs, synthesis of inflammatorycytokines, smooth muscle proliferation, and migra-tion and platelet aggregation [24].

Endothelial dysfunction has been regarded asan early feature of atherosclerosis and plays animportant role in the development of atheroscle-rotic disease. Dysfunction of endothelium cells isprobably the earliest event in the process of lesionformation, hence, the concept that assessment ofendothelial 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 evi-dence of preclinical cardiovascular disease (CVD)[5]. Brachial artery ultrasound is a widely used non-invasive measure of endothelial function [5,6].

In obese women with PCOS, Mather et al.[7] reported normal endothelial function, whereasParadisi et al. [8] demonstrated endothelial dys-function and insulin resistance at a vascular level.Studies in younger and nonobese women with PCOS

are lacking. Two recent articles showed impairmentof endothelial function and vascular structure inyoung normal weight women with PCOS [9,10].

In this setting, the aim of this study was toassess endothelial function in women with PCOSusing well-validated marker of endothelial function(brachial artery flow-mediated dilation (FMD) andto investigate its relationship to body mass index(BMI) and insulin resistance in young women withPCOS.

Materials and methods

Patient population

During the period from April 2007 to March 2008,a total of 36 PCOS women attending the outpa-tient clinic were enrolled in the study. Of thesewomen, 14 were nonobese (BMI < 25) and 22 wereobese (BMI > 30). PCOS was defined when at leasttwo of the following three features were presentafter the exclusion of other etiologies [11]: oligo-or anovulation (fewer than six menstrual periods

in the preceding year), clinical Ferriman-Gallweyscore [12] >8 and/or biochemical signs of hyper-androgenism, and polycystic ovaries. Biochemicalcriteria included an abnormal LH to FSH ratio (>2)and/or elevated testosterone levels. Ultrasoundcriteria used for diagnosis of polycystic ovary arethe following: presence of 12 or more follicles ineach ovary measuring 29 mm in diameter and/orincreased ovarian volume (>10 ml).

All women had normal thyroid, renal, and hep-atic function. Exclusion criteria for all subjectsincluded age over 40 years, pregnancy, currentor previous use (within 6 months) of oral con-

traceptives, antiandrogens, antidiabetics, statins,glucocorticoids or other hormonal drugs, cigarettesmoking, blood pressure of 130/85 mmHg or greateror treated hypertension, known CVD, and diabetesmellitus. Other causes of chronic anovulation,including congenital adrenal hyperplasia, Cushingssyndrome, hyperprolactinemia, and thyroid diseasewere also excluded by appropriate tests.

Ten healthy age matched females with regu-lar menses and ultrasonographically normal ovarieswere selected as a control group. Their clinical,


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Endothelial function in young women with PCOS e51

biochemical, and hormonal profiles were withinnormal limits. The same exclusion criteria aspatient group were used for the control group. Allsubjects gave full informed written consent aboutthe trial. The Institutional Review Board of Man-soura University approved the study.

Brachial ultrasound

Vascular reactivity was assessed using brachialartery 2D greyscale ultrasound. A 7.5-MHz linearphased array ultrasound transducer was used toimage the dominant arm brachial artery longitu-dinally just above the antecubital fossa. Studieswere performed after a 12-h fast; during thisperiod caffeine-containing drinks were avoided. Allpatients rested for 1015 min in a quiet room atroom temperature. Diameter of the artery wasmeasured at end diastole then a blood pressurecuff was inflated to 40 mmHg above the systolic

pressure on the distal portion of the arm for4 min and then released. The increased flow in theartery after removal of the blood pressure cuffis termed reactive hyperemia and results in flow-mediated dilation (FMD) and is used as a measure ofendothelium-dependent vasodilation [13,14]. Thebrachial artery was scanned continuously for 2 minafter cuff deflation, and the vessel diameter at thesame point of resting measurement was defined.FMD was determined as the percentage change frombaseline to 60s after ischemia, the point of maximaldilation [15].

Laboratory assays

All blood samples were obtained in the morningbetween 0800 and 0900 h after an overnight fast andduring early follicular phase. They were centrifugedimmediately and serum was stored at 20 C untilassayed. The samples were assayed within 12months of their collection. The serum concentra-tions of testosterone were measured by enzyme

linked immunosorbant assay using Biosourse kit(Biosourse, Europe SA Belgium). Luteinizing hor-mone (LH) and follicle stimulating hormone (FSH)were measured using the LHsp and FSH IRMA kitsfrom Biosource Technologies, Inc., Europe S.A.Serum glucose was measured by using glucokinasetechnique.

Lipid analysis in fasting serum was performedfor all patients. The lipid profile included measure-ment of the levels of total cholesterol, high-densitylipoprotein (HDL) cholesterol, low-density lipopro-tein (LDL) cholesterol, and triglycerides (TG).These parameters were measured by commercialenzymatic methods (Aeroset automated analyzer,Abbott Laboratories, Abbott, IL). LDL cholesterolwas calculated by using Friedewalds formula.Plasma insulin levels were measured by BiosourseINS-EASIA (Biosource, Europe S.S., Belgium).

Insulin resistance

Insulin resistance was estimated by the quantita-tive insulin sensitivity check index (QUICKI) andHOMA resistance index. QUICKI index was estimatedusing the following formula [16]: 1/[log(fastinginsulin)+ log(fasting glucose)]. HOMA index wasestimated using the following formula [17]: [fastingglucose fasting insulin]/22.5.

Statistical analysis

Statistical analysis was performed using The Statis-

tical Package for the Social Sciences (SPSS version13). When data were normally distributed, unpairedt tests were used to compare parameters betweengroups. For comparison of qualitative data the Chi-square test was used. Pearsons correlations withr to z significance calculations were performed.Partial correlation and multiple regression analysiswere performed to assess the relationship betweenFMD and the studied parameters. Subsequently,variables whose correlation with the flow mediated

Table 1 Patient characteristics and hormone studies. Values expressed as means SD.

Parameter Obese group (n = 22) Nonobese group (n = 14) Control (n =10)

BMI (kg/m2) 35.2 3.2* 22.8 2.1 21.9 2.97Age 25.6 3.4 25.2 3.6 24.4 4.07Total cholesterol (mg/dl) 165.2 36.8 160.1 38.9 160.4 41.3Triglyceride (mg/dl) 121 109.48** 114.1 75.7** 88.6 36.7HDL-cholesterol (mg/dl) 44.1 11.9** 46.4 13.05** 53.6 15.4LDL-cholesterol (mg/dl) 119.8 23.5 108.4 25.5 96.41 23.2Testosterone (nmol/ml) 2.8 0.5** 2.5 0.8** 1.5 1.0

* P< 0.001 vs. nonobese and control group.** P


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Table 2 Glucose metabolism parameters of the patients groups. Values expressed as means SD.

Parameter Obese group (n = 22) Nonobese group (n = 14) Control (n =10)

Fasting glucose (mmol/l) 5.34 0.59 5.23 0.62 5.16 0.47Fasting insulin (pmol/l) 46.2 27.0* 43.7 25.6 39.1 24.4HOMA 1.88 1.26** 1.71 1.04 1.51 0.96QUICKI 0.360 0.035** 0.364 0.033 0.375 0.043

*

P


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PCOS and increased cardiovascular risk is not wellunderstood.

Controversial data exist regarding the pres-ence of endothelial dysfunction in women withPCOS, certain studies reporting no impairment[7,2426] and others showing significant impair-ment [9,10,2629]. Differences concerning cardio-

vascular risk factors among the various populationsstudied might explain these discrepancies. Matheret al. [7] showed no difference in FMD betweenPCOS patients and controls, despite the hyperan-drogenism and insulin resistance of PCOS patients.Similarly, Meyer at al. [25] did not find increasedintima-media thickness (IMT) in young overweightPCOS, despite higher HDL and triglycerides levelscompared with the control group. On the otherhand, Paradisi and co-workers [8] were the first torecognise the presence of endothelial dysfunctionin PCOS by the use of invasive leg plethysmography,but differences in HDL and triglycerides plasma lev-

els between PCOS and control women in this studymay have accounted for these findings. Kelly et al.[24] found impaired vascular function by the use ofan invasive method. In addition, Lakhani et al. [30]evidenced impaired carotid viscoelastic propertiesin PCOS women, providing additional evidence ofvascular dysfunction in women with this syndrome.Finally, Kravariti et al. [27] found altered FMD andnitroglycerine induced dilatation (NID), suggestinga global vascular injury and not only endothelialdysfunction.

Our study was designed to evaluate associations

of endothelial function with extent of insulin resis-tance and BMI, but not really to examine otherpotential bases for endothelial dysfunction. Weexamined the macrovascular function in lean andobese women with PCOS and in controls using non-invasive methodologies. Our results demonstratedthat endothelial function assessed by FMD, wasimpaired in both PCOS groups. These findings sug-gest that measurable vascular abnormalities inPCOS women are possibly developed by middle ageand that PCOS per se and not simply BMI is responsi-ble for these differences. FMD at the brachial arterywas lower in the presence of PCOS, although basal

brachial artery diameter was comparable in thethree groups. These vascular changes may be theforerunners of more overt cardiovascular abnormal-ities such as high BP in older women with PCOS.

Our data demonstrated that women with PCOShad higher fasting insulin levels and insulin resis-tance indices than controls, whereas they showedreduced FMD values. Fasting insulin levels andinsulin resistance indices were only significantlyhigher in the obese group. Cibula et al. [31] statedthat insulin resistance is a frequent (although not

constant) abnormality in both obese and nonobesewomen with PCOS. Acien and co-workers [32] statedthat insulin resistance is present in 5080% ofwomen with PCOS and is further worsen by thepresence of obesity. Recently, Grimmichov et al.[33] using QUICKI to determine insulin sensitivityin lean PCOS-affected women and healthy controls

demonstrated that both groups had the same insulinsensitivity.The association between insulin resistance and

endothelial dysfunction has been demonstratedconsistently in subjects with type 2 diabetes melli-tus [21], obesity [34], the metabolic syndrome [35]and in children of parents with type 2 diabetes [36].The progression of insulin resistance to diabetesparallels the progression of endothelial dysfunctionto atherosclerosis as stated by Hsueh et al. [37].

There are several mechanisms through whichinsulin resistance can adversely affect the endothe-lium. Insulin-resistant states are characterized by

increased production of free fatty acids and proin-flammatory cytokines such as TNF and leptin,which contribute to endothelial dysfunction [26].There is also evidence to suggest that insulin resis-tance induces increased oxidant stress, which mayhave an important pathogenic role [38]. Insulinis also known to have direct effects promotingvascular smooth muscle hyperplasia and colla-gen synthesis [39], with both factors leading toincreased arterial stiffness.

In this study, there was no correlation betweenendothelial dysfunction (assessed by FMD) and

insulin resistance indices or BMI in women withPCOS. This finding supports the suggestion thatPCOS presence predicted FMD values independentlyof BMI or insulin resistance indices. Impairmentof FMD in lean women with PCOS without signif-icant insulin resistance suggests a crucial role ofother cardiovascular risk factors in the develop-ment of endothelial dysfunction in women withPCOS. These results match with those of Rajen-dran et al. [40] who recently reported that inPCOS subjects, independent of obesity and associ-ated insulin resistance, profound and reproducibleimpairment of platelet responsiveness to NO is

an additional component of cardiovascular home-ostatic disturbance. Further, the same authors [40]demonstrated significant impairment of vascularendothelial function which was independent ofthe presence/absence of obesity and associatedinsulin resistance. On the other hand, Ketel et al.[41] found decreased microvascular and metabolicinsulin sensitivity in obese but not normal-weightwomen independent of PCOS.

In general, women with PCOS carry sev-eral metabolic aberrations e.g. obesity, insulin


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resistance, abnormal lipid profile and hyperandro-genemia [32]. A significant elevation in androgenlevels was observed in our PCOS cohort com-pared to controls. This finding correlated inverselywith FMD. Such observation probably suggests animportant role for the exposure of androgensin the development of endothelial dysfunction.

Previous studies [4244] have demonstrated theimportance of sex hormones in contributing tocarotid arterial wall thickness. Hyperandrogenemiain women with PCOS may result in a male patternof lipoproteins, suggesting an increased athero-genic potential in PCOS patients [45]. The complexcorrelation between vascular parameters, insulinresistance and hyperandrogenemia suggests thatthese factors are interrelated and interplay possiblywith other unknown factors affecting the vascularbed of a young population of PCOS women who donot carry an increased load of cardiovascular riskfactors.

Our data support a role of hyperandrogenemia invascular reactivity in PCOS, but the mode of actionof androgens remains unknown. Androgen recep-tors are known to exist on the vessel wall, and adirect effect of androgens in the vasculature cannotbe excluded [46]. Alternatively, androgens may actsynergistically with insulin resistance [47] inflam-matory cytokines [48] or angioconstrictive peptides[49] on endothelial function. Androgens may pro-mote monocyte adhesion to endothelial cells aproatherogenic effect mediated, at least in part,by an increased endothelial cell-surface expression

of VCAM-1 [50] which has been found elevated inPCOS subjects [26].Different patterns of dyslipidemia can be

present, both in lean and obese PCOS. The pat-tern of dyslipidemia demonstrated in the currentstudy is consistent with previous publications show-ing abnormal lipid profiles in PCOS [51,52]. Theseinclude low HDL-cholesterol, with or without ele-vated TG. In addition, smaller HDL and LDL particlesand elevated postprandial TG responses were alsoreported [43].

In conclusion our results, although limited, pro-vide additional confirmatory evidence of endothe-lial dysfunction in women with PCOS which isneither related to BMI nor to insulin resistance.In young women with PCOS, obesity and insulinresistance probably may have an additive role withtime.

Conflict of interest

I certify that there is no actual or potential conflictof interest in relation to this article.

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(BMI) and Insulin Resistance