The association of urinary albumin excretion and metabolic complications in polycystic ovary syndrome

(1)

The association of urinary albumin excretion and metabolic complications in

polycystic ovary syndrome

Gamze S. Caglar

a,

*

, Efser Oztas

a

, Demet Karadag

b

, Recai Pabuccu

a

, Ayse A. Eren

c a_{University of Ufuk, Faculty of Medicine, Department of Obstetrics and Gynecology, Balgat, 06520 Ankara, Turkey}

b

University of Ufuk, Faculty of Medicine, Department of Radiology, Balgat, 06520 Ankara, Turkey

c

University of Ufuk, Faculty of Medicine, Department of Biochemistry, Balgat, 06520 Ankara, Turkey

1. Introduction

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age [1]. Recently, PCOS has gained attention due to crucial metabolic aspects which play important roles in both the pathogenesis and the long-term sequelae of the condition. Comorbidities associated with PCOS are hypertension, dyslipidemia, metabolic syndrome, impaired glucose tolerance and type 2 diabetes mellitus [2]. Moreover, in the majority of women with PCOS central obesity aggravates the above-men-tioned cardiovascular disease (CVD) risk factors[3]. Endothelial

dysfunction, a prognostic parameter for CVD, is an early event in the process of atherosclerosis. In several studies, subclinical atherosclerosis in women with PCOS has been evaluated by ultrasound examination of the carotid artery, conﬁrming signiﬁ-cantly higher carotid intima–media thickness (CIMT) in PCOS women compared with controls matched for age and body mass index (BMI)[4–7].

Urinary albumin excretion (UAE) is another marker assumed to reﬂect systemic endothelial leakiness and used for identifying cases at increased risk for CVD[8]. Usually, the application of UAE is for predicting nephropathy and CVD in diabetic patients. However, albuminuria independently indicates risk of death from CVD, regardless of diabetic or non-diabetic status[9,10]. Albumin-uria occurs at the start of the atherosclerotic process and reﬂects general vascular dysfunction [8]. UAE as a cardiovascular risk factor in cases of PCOS is less well established[11,12]. This study was planned to screen PCOS women for albuminuria and to A R T I C L E I N F O

Article history: Received 9 April 2010

Received in revised form 15 July 2010 Accepted 29 August 2010

Key words: Albuminuria Microalbuminuria Urinary albumin excretion Polycystic ovary syndrome

A B S T R A C T

Objective: This study was planned to screen polycystic ovary syndrome (PCOS) women for albuminuria and to evaluate the association between urinary albumin excretion (UAE) and metabolic disturbances of PCOS. In addition, this is the ﬁrst study in the literature evaluating the association between UAE and carotid intima–media thickness (CIMT) in PCOS cases.

Study design: The study population consisted of 65 PCOS women. The study was prospectively designed and performed in a university hospital. The diagnosis of PCOS was made according to the Rotterdam criteria: exclusion criteria were hyperprolactinemia, thyroid dysfunction, adrenal dysfunction, diabetes mellitus, hypertension, and pregnancy. Blood samples were collected in the follicular phase of a menstrual cycle and serum samples were analyzed for fasting glucose, insulin, and hormone and lipid proﬁles. Twenty-four hour urine specimens were collected for the detection of UAE. CIMT was estimated by visual assessment of the distance between the lumen–intima and intima–adventitia interfaces. Results: The mean age and BMI were 23 years and 23 kg/m2_{, respectively. The median UAE was 7 mg/day}

(range: 0.3–154 mg/day). The median UAE as micrograms of albumin per milligram of creatinine (uACR) was 5.6 (0.28–159). Regarding the uACR cutoff value (>6.93mg/mg), signiﬁcantly higher levels of triglycerides, 17 OH-progesterone, insulin resistance (HOMA index > 2.1) and increased CIMT were present in these cases. Microalbuminuria (uACR > 25mg/mg) was present in 6.2%. In the regression analyses serum HDL-C levels were found to be independent predictor for uACR > 2mg/mg (OR: 0.85) and estradiol levels were the independent predicting factor for uACR > 6.93mg/mg even after adjustments for age and BMI were performed (OR:1.02).

Conclusions: UAE, expressed as uACR > 6.93mg/mg, seems to be an associated sign of metabolic problems which might help in discriminating PCOS at risk of future CVD. Further studies are needed before routine use of albuminuria in PCOS cases for the detection of CVD risk.

* Corresponding author at: University of Ufuk, Faculty of Medicine, Department of Obstetrics and Gynecology, Balgat, 06520 Ankara, Turkey.

Tel.: +90 532 4418501; fax: +90 312 4355770.

E-mail address:gamzesinem@hotmail.com(G.S. Caglar).

Contents lists available atScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j o g r b

(2)

evaluate the association between UAE and the metabolic disturbances of PCOS. In addition, this is the ﬁrst study for evaluating the association between UAE and CIMT in PCOS. 2. Materials and methods

Sixty-ﬁve women with PCOS were enrolled in the study, which was approved by the Ethics Committee. Written informed consent was obtained from all participants. The diagnosis of PCOS was made as proposed at the Rotterdam Consensus Meeting[13](Table 1). Oligo-menorrhea was deﬁned as cycle intervals more than 35 days and amenorrhea as absence of menstruation for three consecutive months. Exclusion criteria were the following: hyperprolactinemia, thyroid dysfunction, adrenal dysfunction, diabetes mellitus, hypertension (blood pressure greater than 140 mm Hg systolic or 90 mm Hg diastolic), and pregnancy. None of the women had received any drugs known to interfere with hormone levels for at least 3 months before the study. All of the subjects were nonsmokers. Waist circumference was measured at the narrowest level between the costal margin and iliac crest. Body mass index (BMI) was calculated as weight (kg)/height (m)2_.

Subjects with BMI values of 30 kg/m2_{were considered obese and}

excluded. Systolic (SBP) and diastolic blood pressure (DBP) were measured twice in the right arm in a relaxed sitting position. The average of two measurements taken 15 min apart was used. The features of metabolic syndrome were identiﬁed[14].

2.1. Serum markers

Blood samples were collected during days 3–5 after spontane-ous menses, after overnight fasting for at least 12 h. In cases with oligoanovulation (luteal phase progesterone measurements less than 4 ng/mL) blood samples were taken after progesterone withdrawal bleeding. Levels of glucose, insulin, creatinine, hormone proﬁle (follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), total and free testosterone (Total-T and Free-T, respectively), dehydroepian-drosteone sulfate (DHEAS), 17 OH-progesterone (17OH-P) and thyroid-stimulating hormone (TSH)), and serum lipids (total cholesterol (Total-C), high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), and triglycerides (TG)) were deter-mined. Plasma glucose was determined with the glucose hexoki-nase method (Cobas Integra 400 Plus, Roche Diagnostics, Mannheim, Germany). Fasting glucose to insulin ratio (FIGR), homeostasis model assessment (HOMA-IR)[15](insulin glyce-glycemia in

m

mol/L/22.5), and quantitative insulin sensitivity check index (QUICK)[16](1/log insulin + log glycemia in mg/dL) were estimated. Insulin resistance (IR) was deﬁned as HOMA index > 2.1[17].

Serum levels of FSH, LH, E2, PRL, DHEAS, Total-T, insulin and TSH were measured with electrochemiluminescence assays. (ELECYS 2010 HITACHI, Roche Diagnostic, Germany). Serum levels of 17OH-P and Free-T were measured by radioimmunoassay. The serum levels of Total-C, HDL-C, LDL-C, and TG were determined with enzymatic colorimetric assays (Roche Diagnostic, Mannheim,

Germany). The intra- and interassay coefﬁcients of variation (CV) were <1.9% and <4%, respectively, for all assays performed. 2.2. Common CIMT measurement

Imaging was conducted using a high resolution ultrasound machine (Logic Q7, General Electric, USA) with a 7.5 MHz mechanical sector transducer in all cases. The posterior carotid wall at 1 cm of the common carotid artery was imaged in B-mode and CIMT was estimated by visual assessment of the distance between the lumen–intima and intima–adventitia interfaces in longitudinal frames acquired during arterial diastole [18]. The mean of measurements of CIMT made at the greatest thickness on both sides was used for statistical analyses. Ultrasonographic measurements were performed by the same experienced radiolo-gist.

2.3. Urine samples

Participants collected 24-h urine samples. Urinary albumin concentration was measured by an automated immunoturbidi-metric assay (ALBT2, Tina-Quant, Albumin Gen.2, Roche). Total protein (pyrogallol red) and immunoturbidimetric urine albumin assay were performed on the Roche, Cobas Integra 400 otoanalyzer (Roche Diagnostics, Mannheim, Germany). The immunoturbidi-metric assay had within-assay and between-assay CV of 0.94% and 1.4%, respectively. Urine creatinine was assayed by modified Jaffe reaction. Glomerular filtration rate (GFR) was calculated from serum creatinine with Cockcroft-Gault formula: GFR (mL/ min) = (140 Age) weight (0.85 for women)/Plasma creatinine 72. UAE is given as urinary albumin-to-creatinine ratio (uACR) defined as microgram of albumin per milligram of creatinine (

m

g/mg). The median value of uACR (6.93

m

g/mg) for women in the general population was taken as the cutoff value

[19]. Sex-speciﬁc uACR cutoff value for microalbuminuria in women is 25

m

g/mg[20].

2.4. Statistical analysis

Data analysis was performed using SPSS for Windows, version 11.5 (SPSS Inc., Chicago, IL, USA). Whether the distributions of continuous variables were normal or not was determined by the Shapiro Wilk test. Data were shown as mean standard deviation or median (minimum–maximum), where applicable. The mean differences between groups were compared by Student’s t test. Otherwise, Mann–Whitney U test was applied for the comparisons of the median values. Nominal data were analyzed by Chi-square or Fisher’s exact test, where appropriate. Multiple Logistic Regression analysis was used to determine the independent predictors which mostly affected uACR. Any variable whose univariable test had a p value <0.25 was accepted as a candidate for the multivariable model along with all variables of known clinical importance. Odds ratio and 95% conﬁdence intervals for independent variables were calculated. A p value less than 0.05 was considered statistically signiﬁcant. 3. Results

The baseline characteristics are given inTable 2. Amenorrhea/ oligo-menorrhea was present in 43 cases (66.1%). The mean SBP and DBP were 110 12 mm Hg and 64 8.8 mm Hg, respectively. The mean waist circumference was 71.9 7 cm. The fasting insulin and glucose levels, and insulin sensitivity indexes are inTable 2. The hormone and lipid parameters are given inTable 3. The median value of UAE was 7.0 (range from 0.3 to 154) mg/day and the median value of uACR was 5.6 (range from 0.28 to 159)

m

g/mg. Microalbuminuria (uACR > 25

m

g/mg) was present in 6.2% (n = 4) of the study Table 1

Diagnostic criteria for PCOS according to The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.

Revised 2003 criteria (diagnosis with 2 out of 3)a – Oligo- or anovulation

– Clinical and/or biochemical signs of hyperandrogenism

– Polycystic ovaries determined by ultrasonography (12 follicles of 2–9 mm diameter in each ovary and/or ovarian volume > 10 mL)

a

(3)

population. The mean CIMT measurements are given inTable 4. A signiﬁcantly positive correlation was found between UAE and waist circumference, SBP and DBP (r = 0.828; p < 0.001; r = 0.447, p < 0.001 and r = 0.310, p = 0.012, respectively). Only one case had PCOS plus a metabolic syndrome.

Among the 65 cases in the study, 55 (84.6%) had uACR > 2

m

g/mg and 10 (15.4%) had 2

m

g/mg. The age, BMI, indicators of IR (FIGR, HOMA-IR, QUICKI index) and hormones did not show any statistical difference when the groups with uACR 2

m

g/mg and >2

m

g/mg were compared (p > 0.05). In the lipid proﬁle, the only statistically signiﬁcant parameter was HDL-C levels. In cases with uACR > 2

m

g/ mg the mean HDL-C levels were signiﬁcantly lower than cases with uACR 2

m

g/mg (53.5 vs 64.0 mg/dL, respectively, p = 0.028). CIMT did not show any statistical difference between uACR 2

m

g/mg and >2

m

g/mg (p > 0.05).

When PCOS cases were further analyzed regarding uACR, it was found that 47.7% (n = 31) had uACR 6.93

m

g/mg, whereas 52.3% (n = 34) had uACR > 6.93

m

g/mg The mean SBP and DBP did not differ between the groups (SBP: 109 11 vs 111 10 mm Hg and DBP: 65 9 vs 63 8.1 mm Hg; p > 0.05). Among the endocrine parameters, serum LH, E2 and 17-OHP levels were statistically signiﬁcantly higher in cases with uACR > 6.93

m

g/mg (Table 3). The rate of IR (HOMA index > 2.1) was higher in cases with uACR > 6.93

m

g/mg than patients with uACR 6.93 (64.7% vs 35.3%, respectively; p = 0.019). In addition, signiﬁcantly higher levels of TG and CIMT were found in patients with uACR > 6.93

m

g/mg (Tables 3 and 4).

The number of cases with microalbuminuria (uACR > 25

m

g/mg) (n = 4) was too low for further analyses. For the prediction of uACR > 2

m

g/mg, all the independent variables that might have an effect on UAE and those that were found to be statistically signiﬁcant in cases with uACR > 2

m

g/mg were analyzed by Multiple Logistic

Regression analysis. The serum HDL-C levels were found to be independent predictor of uACR > 2

m

g/mg (Odds Ratio 0.85; 95% CI: 0.74–0.97; p = 0.012) after corrections for age and BMI were performed. When the Multiple Logistic Regression analyses were repeated for the prediction of uACR > 6.93

m

g/mg, estradiol levels were the independent predicting factor for uACR > 6.93

m

g/mg even after adjustments for age and BMI were performed (Odds Ratio 1.02; 95% CI: 1.00–1.04; p = 0.016).

4. Comments

In this study UAE and microalbuminuria were evaluated in young PCOS cases. UAE, expressed as uACR > 6.93

m

g/mg, seems to be an associated sign of metabolic problems, which might help in discriminating PCOS with risk for future CVD. Further studies are needed before routine use of albuminuria in PCOS cases for the detection of CVD risk.

UAE of 30 mg in overnight and 300 mg in 24-h urine samples is deﬁned as microalbuminuria [21]. The age and sex adjusted prevalence of microalbuminuria from a large sample of the general population (n = 40,619 subjects) was reported as 7.2% in all subjects and 6.6% in non-diabetics and non-hypertensives[22]. In our study, the rate (6.2%) of microalbuminuria (>25

m

g/mg uACR) is similar in PCOS. However, in another study[12], the rate of microalbuminuria was 16% in overweight/obese (BMI 32.9 kg/m2_{) PCOS cases having}

higher fasting insulin levels (15.2

m

IU/mL) when compared with our subjects (BMI 23.9 kg/m2_{, fasting insulin 9.2}

_m

_{IU/mL). Although the}

reported median of uACR in that study[12]and ours is very similar (5.7

m

g/mg vs 5.6

m

g/mg, respectively), the higher rates of microalbuminuria (>25

m

g/mg uACR) found in the previous study

[12]might be due to the above-mentioned differences in subjects. Previously it was suggested that IR precedes and contributes to the Table 2

Baseline characteristics and insulin sensitivity and resistance indexes of the all PCOS cases; subgroup analyses (uACR 6.93mg/mg and uACR > 6.93mg/mg groups). Parameter All PCOS cases (n = 65) uACR 6.93mg/mg (n = 31) uACR > 6.93mg/mg (n = 34) p value*

Age (years) (mean sd) 23.4 4.4 24.0 4.6 22.9 4.2 0.33

BMI (kg/m2_{) (mean sd)} _{23.9 3.6} _{24.3 3.7} _{23.2 3.3} _0.23

Fasting glucose (mg/dL) (mean sd) 87.5 8.3 87.6 6.8 87.4 9.5 0.93 Fasting insulin (mIU/mL) median (min–max) 9.2 (3–72) 8.8(3–57) 10.3(4–72) 0.19 FIGR median (min–max) 9.1 (1.3–32.3) 9.7 (1.7–32.3) 8.0 (1.3–19) 0.13 HOMA-IR median (min–max) 2.06 (0.5–16) 2.12 (0.5–16) 2.5 (0.8–16) 0.06 QUICKI median (min–max) 0.3 (0.2–0.4) 0.3 (0.2–0.3) 0.3 (0.2–0.4) 0.14 BMI: body mass index; WHR: waist to hip ratio; HOMA-IR: homeostasis model assessment; QUICKI: quantitative insulin sensitivity check index; FIGR: fasting glucose to insulin ratio.

*_{p values are for the comparison between uACR 6.93}_m_{g/mg and uACR > 6.93}_m_{g/mg groups.}

Table 3

The hormone and lipid proﬁle of all cases and subgroup analyses of uACR 6.93mg/mg and uACR > 6.93mg/mg groups.

Parameter All PCOS cases (n = 65) uACR 6.93mg/mg (n = 31) uACR > 6.93mg/mg (n = 34) p value*

FSH (mIU/mL) (mean sd) 5.7 1.6 5.3 1.5 6.1 1.6 0.05 LH (mIU/mL) (mean sd) 10.3 7.5 8.2 6.9 12.3 7.6* 0.00** Estradiol (pg/mL) (mean sd) 49.6 33.4 39.4 29 58.9 34.8* _0.00** PRL (ng/mL) median (min–max) 12.2 (1.0–35) 14.7 (1.3–35) 10.1 (1.0–33) 0.07 Total-T (ng/dL) (mean sd) 0.4 0.3 0.5 0.4 0.4 0.2 0.58 Free-T (pg/dL) (mean sd) 2.5 1.0 2.5 1.2 2.6 0.7 0.31 DHEAS (mg/dL) (mean sd) 259.7 105.9 271 126 249 83 0.92 17-OHP (ng/dL) (mean sd) 1.9 1.4 1.93 0.9 1.99 0.8* 0.04** Total-C (mg/dL) (mean sd) 164.0 35.2 167 38.5 161 32.3 0.66 LDL-C (mg/dL) (mean sd) 91.7 30.0 91.7 30.4 91.7 30.1 0.99 HDL-C (mg/dL) (mean sd) 55.1 13.9 57.1 14.0 53.2 13.8 0.26 TG (mg/dL) (mean sd) 84.8 43.9 77.7 48 92.7 37* 0.01** FSH: follicle-stimulating hormone, LH: luteinizing hormone, PRL: prolactin, TSH: thyroid-stimulating hormone, Total-T: total testosterone, Free-T: free testosterone, DHEAS: dehydroepiandrosteone sulfate, 17OH-P: 17 OH-progesterone, Total-C: total cholesterol, HDL-C: high-density cholesterol, LDL-C: low-density cholesterol, TG: triglycerides.

*

p values are for the comparison between uACR 6.93mg/mg and uACR > 6.93mg/mg groups.

**

(4)

development of microalbuminuria[23]. In addition, an independent association between the magnitude of IR and microalbuminuria was reported in type 2 diabetes mellitus[24]. Even if UAE was not correlated with IR indicators in our study, the insulin area under the curve during a 2-h glucose tolerance test was reported to be predictor of UAE in PCOS[12]. Considering the reported association of albuminuria with diabetic or non-diabetic degrees of hypergly-cemia[23,25,26], albuminuria can also be screened for detection of CVD risk associated with IR when evaluating PCOS cases.

Microalbuminuria has been reported as a cardiovascular and renal risk factor in diabetic and in non-diabetic individuals[10,27]. As the association between uACR and CVD extends as low as 0.5 mg/mmol (=4.06

m

g/mg), the threshold used to screen for microalbuminuria is suggested as irrelevant for CVD risk assess-ment[9]. After adjustment for age and sex, for every 0.4 mg/mmol (=3.5

m

g/mg) increase in uACR the hazard of all-cause death increased by 6.8% (95% CI, 5.6–8.0) and hospitalization for cardiac heart failure by 10.6% (95% CI, 8.4–13.0) [9]. Data from well-designed studies suggest that albuminuria below 2 mg/g of urinary creatinine (or excretion rate of 2 mg/day) should be considered normal [9,28]. The prevalence of albuminuria above this range (uACR > 2

m

g/mg) was 84.6% in our study. There are no data in the literature regarding the threshold level in PCOS. Studies with higher numbers of PCOS cases are needed to clarify UAE in these young patients.

The risk factors predisposing to CVD and type-2 diabetes mellitus are present in majority of PCOS cases[3]. Atherogenic dyslipidemia (high concentrations of TG and low concentrations of HDL-C) excess weight and IR all play dominant roles in developing metabolic problems in PCOS[3]. In this study, signiﬁcantly lower HDL-C levels were found in cases with uACR > 2

m

g/mg. Signiﬁ-cantly higher levels TG, 17-OHP, IR (HOMA index > 2.1) and increased CIMT are present in cases with uACR > 6.93

m

g/mg. All these ﬁndings might indicate a possible relationship between uACR > 6.93

m

g/mg and metabolic disturbances. Previous ﬁndings in PCOS showed 9% of metabolic syndrome in cases with uACR 7 mg/g and 30.9% in cases with uACR > 7 mg/g[11]. As previously suggested the threshold uACR can be taken as 7 mg/g in PCOS cases, which seems to be an associated sign of the presence of metabolic syndrome[11].

The ﬁndings of the Multi-Ethnic Study of Atherosclerosis[29]

and Prevention of Renal and Vascular Endstage Disease Interven-tion Trial [30] suggested that UAE is related to subclinical atherosclerosis measured by CIMT in individuals who are not at high risk for CVD. uACR was reported as a highly signiﬁcant risk predictor of carotid and femoral artery atherosclerosis in the general population and non-diabetic subjects [19]. In non-diabetics, for one unit increase in loge transformed uACR, the

Odds Ratio (95% CI) of carotid and femoral atherosclerosis was 1.41 (1.09–1.84) and 1.54 (1.19–1.99) (p = 0.010 and 0.001, respective-ly)[19]. Moreover, this relation was obtained far below the levels termed as microalbuminuria[19]. This study is the ﬁrst in the literature evaluating UAE and CIMT in PCOS reporting signiﬁcantly higher CIMT in cases with uACR > 6.93

m

g/mg. Although no association between UAE and CIMT was found in regression

analyses, the cases with uACR > 6.93

m

g/mg had significantly higher levels of 17-OHP. In a recent study[31], high concentrations of ischaemia-modified albumin were found and suggested as a new marker of developing cardiovascular disease in PCOS. This marker was positively correlated with androgen concentrations and hirsutism scores, which might reflect chronic ischaemic condition and oxidative stress in PCOS (31). Although hyperandrogenism was reported to be associated with atherosclerosis and cardiovas-cular risk in young women with PCOS, the role of excess androgens in atherosclerosis is yet to be clarified[32].

Estrogens inhibit early development of atherosclerosis but once the atherosclerosis has been established, estrogens increase the risk of damage[33]. Similar mechanisms by estrogens, mentioned above, may play a role for higher CIMT in the uACR > 6.93

m

g/mg group and estrogen as a predictive factor for increased amounts of UAE in this study. The number of patients in this study was too low to make a conclusion about this issue and further studies are needed.

Additionally, in accordance with a previous report[34], even high normal blood pressure is associated with signiﬁcant higher frequency of albuminuria. Therefore, regarding all data, albumin-uria may be biomarker of increased cardiovascular risk in PCOS. Considering the fact that detection of UAE in 24-h urine collection specimens is not practicable as a daily routine; a single morning urine sample, which shows high correlation with 24-h UAE rate, can be used[35]. UAE in spot urine samples may ﬁnd application in the routine assessment of metabolic disturbances in PCOS. Moreover, PCOS cases with abnormal albuminuria can be targeted for preventive strategies, like amelioration of insulin sensitivity and weight loss, that are expected to prevent end organ damage. Author contribution

G.S.C. collected the data, and performed the analysis and interpretation of data. E.O. contributed to the acquisition of data. Manuscript preparation was performed by G.S.C., R.P. and E.O. D.K. is the radiologist performing the carotid intima–media thickness measurements in all cases. A.A.E. performed the biochemical analyses of the serum and urine samples. Drafting the article or revising it critically for important intellectual content was performed by all authors. All authors have approved the ﬁnal version of the manuscript.

Acknowledgments

The authors wish to thank all patients for their participation in this study, and all personnel at the obstetrics and gynecology department for their enthusiastic contribution. This study has no ﬁnancial support.

References

[1] Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with signiﬁcant morbidity in women. J Clin Endocrinol Metab 1999;84(6):1897–9.

[2] Mak W, Dokras A. Polycystic ovary syndrome and the risk of cardiovascular disease and thrombosis. Semin Thromb Hemost 2009;35:613–20. Table 4

The results of the urine analyses and carotis intima–media thickness (CIMT) in PCOS and the subgroup analyses (uACR 6.93mg/mg and uACR > 6.93mg/mg groups). Parameter All PCOS cases (n = 65) uACR 6.93mg/mg (n = 31) uACR > 6.93mg/mg (n = 34) p value* CIMT (mm) (mean sd) 0.6 0.1 0.60 0.1 0.71 0.0*

0.00** GFR (mL/min) (mean sd) 156.9 34.7 150.3 32.0 158.3 34.4 0.34 UAE (mg/day) median (min–max) 7.0 (0.3–154) 4.2 (0.3–6.6) 10.9 (4.8–154) 0.00** uACR (mg/mg) median (min–max) 5.6 (0.28–159) 4.4 (0.2–6.5) 9.7 (7.0–159) 0.00** CIMT: carotid intima–media thickness; GFR: glomeruler ﬁltration rate; UAE: urinary albumin excretion; uACR: albumin creatinine ratio.

*

p values are for the comparison between uACR 6.93mg/mg and uACR > 6.93mg/mg groups.

**

(5)

[3] Garruti G, Depalo R, Vita MG, et al. Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment. Reprod Biomed Online 2009;19(4):552–63.

[4] Orio Jr F, Palomba S, Cascella T, et al. Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syn-drome. J Clin Endocrinol Metab 2004;89(9):4588–93.

[5] Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000;20(11):2414–21. [6] Talbott EO, Zborowski JV, Boudreaux MY, McHugh-Pemu KP, Sutton-Tyrrell K,

Guzick DS. The relationship between C-reactive protein and carotid intima– media wall thickness in middle-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89(12):6061–7.

[7] Carmina E, Orio F, Palomba S, et al. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am J Med 2006;119(4):356.e1–6.

[8] Koroshi A. Microalbuminuria, is it so important? Hippokratia 2007;11(3): 105–7.

[9] Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286(4):421–6.

[10] Mann JF, Yi QL, Gerstein HC. Albuminuria as a predictor of cardiovascular and renal outcomes in people with known atherosclerotic cardiovascular disease. Kidney Int Suppl 2004;92:S59–62.

[11] Patel AA, Bloomgarden ZT, Futterweit W. Premicroalbuminuria in women with polycystic ovary syndrome: a metabolic risk marker. Endocr Pract 2008;14(2):193–200.

[12] Duleba AJ, Ahmed IM. Predictors of urinary albumin excretion in women with polycystic ovary syndrome. Fertil Steril )2009;(February).

[13] The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;82(Suppl. 3):1193–7. [14] Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientiﬁc Statement. Circulation 2005;112(17):2735–52. [15] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412–9.

[16] Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85(7):2402–10.

[17] Hedblad B, Nilsson P, Engstrom G, Berglund G, Janzon L. Insulin resistance in non-diabetic subjects is associated with increased incidence of myocardial infarction and death. Diabet Med 2002;19:470–5.

[18] Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74(6):1399–406.

[19] Furtner M, Kiechl S, Mair A, et al. Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. Eur Heart J 2005;26(3):279–87.

[20] National Kidney Foundation Kidney Disease Outcomes Quality Initiative Ad-visory Board. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classiﬁcation, and stratiﬁcation. Am J Kidney Dis 2002;39:S46–64. [21] Ruggenenti P, Remuzzi G. Time to abandon microalbuminuria? Kidney Int

2006;70(7):1214–22.

[22] Hillege HL, Janssen WM, Bak AA, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Int Med 2001;249:519–26.

[23] Mykka¨nen L, Zaccaro DJ, Wagenknecht LE, Robbins DC, Gabriel M, Haffner SM. Microalbuminuria is associated with insulin resistance in nondiabetic sub-jects: the insulin resistance atherosclerosis study. Diabetes 1998;47(5): 793–800.

[24] Parvanova AI, Trevisan R, Iliev IP, et al. Insulin resistance and microalbumi-nuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion. Diabetes 2006;55(5):1456–62.

[25] Niskanen L, Turpeinen A, Penttila¨ I, Uusitupa MI. Hyperglycemia and compo-sitional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care 1998;21(11):1861–9.

[26] Haffner SM, Gonzales C, Valdez RA, et al. Is microalbuminuria part of the prediabetic state? The Mexico City Diabetes Study. Diabetologia 1993;36(10): 1002–1006.

[27] Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circu-lation 2002;106(14):1777–82.

[28] Arnlo¨v J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic indivi-duals: the Framingham Heart Study. Circulation 2005;112(7):969–75. [29] Kramer H, Jacobs Jr DR, Bild D, et al. Urine albumin excretion and subclinical

cardiovascular disease. The Multi-Ethnic Study of Atherosclerosis. Hyperten-sion 2005;46(1):38–43.

[30] Asselbergs FW, van Roon AM, Hillege HL, et al. Effects of fosinopril and pravastatin on carotid intima–media thickness in subjects with increased albuminuria. Stroke 2005;36(3):649–53.

[31] Guven S, Karahan SC, Bayram C, Ucar U, Ozeren M. Elevated concentrations of serum ischaemia-modiﬁed albumin in PCOS, a novel ischaemia marker of coronary artery disease. Reprod Biomed Online 2009;19(4):493–500. [32] Luque-Ramirez M, Mendita-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF.

Androgen excess is associated with the increased carotid intima media thickness observed in young women with polycystic ovary syndrome. Hum Reprod 2007;22(12):3197–203.

[33] The ESHRE Capri Workshop Group. Hormones and cardiovascular health in women. Hum Reprod Update 2006;12(5):483–97.

[34] Knight EL, Kramer HM, Curhan GC. High-normal blood pressure and micro-albuminuria. Am J Kidney Dis 2003;41:588–95.

[35] Chaiken RL, Khawaja R, Bard M, Eckert-Norton M, Banerji MA, Lebovitz HE. Utility of untimed urinary albumin measurements in assessing albuminuria in black NIDDM subjects. Diabetes Care 1997;20(5):709–13.