http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(11): 781–784 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.924099

HS-CRP

High-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of polycystic ovary syndrome in Indian adolescent women with polycystic ovary syndrome (PCOS) Mohd Ashraf Ganie1, Saqib Hassan2, Sobia Nisar3, Nasir Shamas2, Aafia Rashid2, Ishfaq Ahmed2, Syed Douhat2, Syed Mudassar4, Vicar M. Jan5, and Fouzia Rashid6 Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/08/15 For personal use only.

1

Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India, 2Department of Endocrinology, SheriKashmir Institute of Medical Sciences, Srinagar, India, 3Departments of Geriatric Medicine, All India of Medical Sciences, New Delhi, India, 4 Department of Clinical Biochemistry, Sheri-Kashmir Institute of Medical Sciences, 5Department of Cardiology, Sheri-Kashmir Institute of Medical Sciences, and 6Department of Clinical Biochemistry, University of Kashmir, Srinagar Abstract

Keywords

C-reactive protein (CRP) is a risk marker for type 2 diabetes mellitus and cardiovascular diseases. In polycystic ovary syndrome (PCOS), limited data are available on high-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of PCOS especially in Indian women. The objective was to determine serum hs-CRP concentration in adolescent women with and without PCOS and to assess possible correlations of serum hs-CRP levels with components of PCOS in Indian women. One hundred and sixty women with PCOS and sixty non-PCOS women having normal menstrual cycles were included. Clinical assessment included anthropometry, Ferriman–Gallwey (FG) score and blood pressure (BP) measurement. Laboratory evaluation included estimation of T4, TSH, LH, FSH, total testosterone, prolactin, cortisol, 17OHP, hs-CRP, lipid profile, and insulin, and glucose after 2-h oral glucose tolerance test. Homeostasis Model Assessment Insulin resistance index (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) and glucose intolerance was calculated. FG score, LH, FSH, total Testosterone, HOMA-IR and QUICKI were significantly different among women with or without PCOS (p50.01). Although hs-CRP levels showed a higher trend in women having PCOS, there was no significant difference between the groups (p40.05). A significant and positive correlation was found between hs-CRP and body mass index (BMI) (r ¼ 0.308, p50.01) among PCOS group. The results in Indian adolescent women suggest that hs-CRP levels may not per se be associated with PCOS, rather can be related to fat mass in this subset of subjects.

Body mass index, Ferriman–Gallwey score, HOMA-IR, hs C-reactive protein, insulin resistance, obesity, polycystic ovary syndrome, testosterone

Introduction Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting about 3–10% of women in child-bearing years [1–4]. It is classically characterized by hyperandrogenism, chronic anovulation and polycystic ovarian morphology on ultrasonography [4]. Evidence suggests that insulin resistance and its compensatory hyperinsulinemia is a central feature of PCOS [5]. Described by Stein and Leventhal as a gynecological disorder [6], PCOS is now believed to be associated with a constellation of metabolic derangements and cardiovascular risks including obesity, type 2 diabetes mellitus (DM), dyslipidemia, hypertension, metabolic syndrome, subclinical inflammation, endothelial dysfunction, and insulin resistance [5,7–12], suggesting that they may have an increased cardiovascular risk later in life. C-reactive protein (CRP), an acute-phase reactant produced by liver, is an extremely sensitive marker of chronic low-grade Address for correspondence: Dr. Mohd Ashraf Ganie, MBBS, MD, DM, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences – Ansari Nagar, New Delhi-29, India. Tel: +91-1126593968. Fax: 91-11-26589162, +91-9419041546/ +91-9968856888. E-mail: [email protected]

History Received 8 December 2013 Accepted 11 May 2014 Published online 19 August 2014

inflammation, atherosclerotic disease, and have been correlated with the risk of cardiovascular disease and type 2 DM [13–15]. During the last decade, several studies have analyzed the serum high-sensitivity C-reactive protein (hs-CRP) levels in women with PCOS in an attempt to link PCOS with risk of cardiovascular diseases (CVD). Studies have reported that serum hs-CRP levels are increased in women with PCOS [12,16,18–20], supporting the hypothesis that the risk of DM and CVD is increased by chronic inflammation in women with PCOS, whereas few studies documented no statistically significant difference between PCOS and control women [17,21–23]. On the other hand, some studies have shown that hs-CRP levels are associated with obesity rather than the presence of PCOS per se [17,19,21–25] while others suggest correlation of hs-CRP with glucose intolerance [24]. The results therefore are conflicting, equivocal and limited by small sample size, variable age of subjects and non-uniform methods of evaluation. There exists paucity in literature regarding hs-CRP levels in women with PCOS, especially the adolescents in a community where the background of CVD and DM is high. Therefore, the present study was conducted in adolescent Indian women with

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PCOS to estimate their serum hs-CRP concentration as compared to control women and to correlate these levels with metabolic risk markers such as anthropometric, hormonal and cardio metabolic parameters.

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Materials and methods This was an observational study conducted on 160 women with PCOS and 60 women without PCOS (regular-cycling) attending Endocrine clinic of a tertiary care hospital in North India. The study was conducted over a period of 2 years (January 2008 to January 2010). The study protocol was approved by the Institutional Ethics Committee and written informed consent was obtained from all the participants. All adolescent girls presenting with menstrual disturbances such as oligo-/amenorrhea (menstrual interval435 d or58 cycles/ year), amenorrhea (no menses in last 46 months), hyperandrogenism (androgenic alopecia, male pattern hair growth, or moderate to severe acne vulgaris), infertility or ultrasonographic evidence of PCOS and who qualified Androgen Excess Society 2006 criteria [26] for diagnosis of PCOS were informed about the study. One hundred and sixty consequent women who consented and found eligible were enrolled in the study. Women having thyroid dysfunction, hyperprolactinemia, Cushing’s syndrome, non-classical congenital adrenal hyperplasia (NCAH), and androgen secreting tumors were excluded from the study. Women consuming any hormonal preparations or drug(s) known or suspected to affect reproductive or metabolic functions or hs-CRP levels within 6 months of the study entry, or those having known DM, renal, hepatic, or cardiac dysfunction were also excluded. The non-PCOS group represented 60 apparently normal women having regular menstrual cycles (21–35 d), displaying no evidence of clinical or biochemical hyperandrogenism and having normal ovarian morphology on trans-abdominal ultrasonography. Clinical assessment A detailed history including menstrual cycle pattern, temporal profile and severity of unwanted hair growth, drug intake, family history of metabolic disorders, was taken at the time of enrollment. Clinical examination included measurement of body weight (kg), height (cm), waist and hip circumference (cm), BP and FG scoring. F-G score was done by a single observer and a score of 47 was taken as significant. Androgenic alopecia, acne vulgaris and acanthosis nigricans was graded and recorded. A single observer performed trans-abdominal ultrasonography to demonstrate any suggestion of polycystic ovarian morphology, i.e. presence of 10 or more peripheral follicles each measuring 2–8 mm in size with echogenic ovarian stroma and/or increased ovarian volume [27]. Biochemical assessment Oral glucose tolerance test (OGTT) was performed at 800–900 h after an overnight (10–12 h) fast. Blood samples were collected at 0, 60 and 120 min after an oral load of 75 -g anhydrous glucose dissolved in 200–300 ml of water. Blood samples (venous) were collected, separated in cold centrifuge at 4  C and aliqouted. The samples for glucose, lipid profile, liver function test and renal function tests were analyzed on the same day. The samples for LH, FSH, prolactin, total testosterone, insulin, cortisol (morning), 17OHP, T4, TSH and hs-CRP were stored at 70  C until assayed. Overnight dexamethasone suppressed cortisol or ACTH stimulated 17-OHP were done to rule out Cushing’s syndrome or NCAH respectively, after the baseline, if needed. The sampling was arranged in such a way that the hormones were collected from

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day 3 to day 7 (early follicular phase) of spontaneous or medroxyprogesterone induced menstrual cycles. Laboratory analysis Plasma glucose was measured by glucose-oxidase peroxidase method (GOD-POD, Nicholas Piramal Ltd., Mumbai, India) along with other biochemical parameters on autoanalyzer (Roche Hitachi 912, Minatoku, Tokyo, Japan). Analyses of hs-CRP levels were determined by ELISA (Bio-Rad Laboratories India Pvt. Ltd, Gurgaon, India). Hormonal assays were done by RIA/IRMA using commercial kits in duplicate and according to supplier protocol (Diagnostic Products Corporation, Los Angeles, CA and Immunotech and Medicorp Inc., Montreal Canada). Plasma insulin was measured by Electrochemiluminescence (Cobas e411, Roche Diagnostics Limited, Charles Avenue, West Sussex). Sensitivity, specificity, inter-assay, and intra-assay coefficients of variation were within the prescribed limits as per manufacturer’s protocol. Calculations Insulin resistance was calculated by the Homeostasis Model Assessment Insulin resistance index (HOMA-IR) by using the following formula: (fasting insulin in mIU/ml  fasting glucose in mg/dl)/405 and Quantitative Insulin Sensitivity Check Index (QUICKI) was computed as: 1/(log fasting insulin in mIU/ml + log glucose in mg/dl). Statistical analysis Data analysis was performed using the Statistical Package for Social Sciences (SPSS, Chicago, IL) version 17. The characteristic of distribution was tested with the Kolmogorov–Smirnov test. Parameters that did not fit the Gaussian distribution were logtransformed and evaluated. An unpaired t-test was used for the comparison of continuous variables between PCOS and nonPCOS group. Analysis of correlations between parameters was examined using Pearson’s correlation. Regression analysis was performed to determine variables that predicted serum hs-CRP levels. Probability (p) value less than 0.05 was considered statistically significant.

Results Clinical characteristics of women with PCOS and control women mare summarized in Table 1. The mean age of case and control women was comparable (22.3 ± 5.1 years in women with PCOS versus 23.4 ± 4.2 years in women without PCOS; p ¼ 0.13) as was body mass index (BMI) (23.75 ± 4.4 kg/m2 in the PCOS group versus 22.7 ± 2.8 kg/m2 in controls; p ¼ 0.10). FG score, LH, FSH, total testosterone, HOMA-IR and QUICKI showed significant differences between PCOS group compared to controls (p50.01). There was no significant difference in age, BMI, mean blood pressure (systolic and diastolic), LH/FSH ratio and blood glucose (fasting and post-OGTT) among women with PCOS as compared to controls. Serum hs-CRP levels were higher in PCOS group, but there was no significant difference between PCOS and non-PCOS group (p40.05) as shown in Table 2. Relationship between serum hs-CRP and the components of PCOS are summarized in Table 3. Serum hs-CRP levels correlated significantly and in positive direction with waist circumference (r ¼ 0.237, p50.01) and BMI (r ¼ 0.308, p50.01) in the PCOS group. However, no statistical correlation was found with other variables in PCOS women. Regression analysis showed that BMI independently ( ¼ 2.573, p50.001) predicted serum hs-CRP levels in women with PCOS.

High-sensitivity C-reactive protein levels and PCOS

DOI: 10.3109/09513590.2014.924099

Table 1. Characteristics of women with PCOS and without PCOS (control).

Variables

PCOS group

Non-PCOS group (control) p Value

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Clinical parameters Mean age (years) 22.3 ± 5.1 23.4 ± 4.2 0.13 No of cycles per year 9.25 ± 4.38 11.44 ± 3.44 0.01 Height (cm) 157.91 ± 6.62 158.16 ± 7.72 0.20 Weight (kg) 58.53 ± 11.80 57.98 ± 8.76 0.55 BMI (kg/m2) 23.7 ± 4.4 22.99 ± 2.8 0.19 Waist circumference (cm) 80.09 ± 12.3 76.1 ± 8 0.02 Hip circumference (cm) 87.03 ± 7.6 83.04 ± 6.94 0.01 Waist/Hip ratio (WHR) 0.91 ± 0.08 0.91 ± 0.04 0.81 Systolic blood pressure 117 ± 11.93 117.6 ± 7.6 0.72 (mm of Hg) Diastolic blood pressure 77.3 ± 7.76 78.6 ± 5.6 0.241 (mm of Hg) Ferriman–Gallwey (F-G) score 12.2 ± 4.1 2.0 ± 3.7 50.001

Table 2. Characteristics of women with PCOS and without PCOS (control).

Variables

PCOS group

non-PCOS group (control) p Value

Biochemical and hormonal parameters Fasting plasma glucose 91.1 ± 14.5 87.8 ± 14.6 (mg/dl) 1 h Post-glucose (mg/dl) 135.04 ± 29.3 128.06 ± 25.25 2 h Post-glucose (mg/dl) 118.5 ± 20.6 113.3 ± 17.4 Plasma total cholesterol 165.9 ± 33 167.1 ± 40.q (mg/dl) Plasma triglycerides (mg/dl) 129.9 ± 65.37 122.59 ± 57.2 Fasting plasma insulin 10.9 ± 7.9 4.2 ± 3.2 (mIU/ml) Luteinizing hormone (IU/l) 6.7 ± 5.3 4.5 ± 1.3 Follicle stimulating 5.8 ± 1.78 4.6 ± 1.7 hormone (IU/l) LH/FSH ratio 1.18 ± 0.9 1.0 ± 0.4 Total testosterone (ng/ml) 49.6 ± 37 33.8 ± 17 HOMA-IR 2.38 ± 1.8 0.96 ± 0.7 QUICKI 0.34 ± 0.03 0.41 ± 0.06 hs-CRP (mg/l) 1.82 ± 2.4 1.59 ± 0.7

0.13 0.21 0.41 0.820 0.820 50.001 0.002 50.001 0.392 0.002 50.001 50.001 0.456

Table 3. Correlation between hs-CRP and variables in women with polycystic ovary syndrome.

PCOS variables Clinical & anthropometric Mean age (years) BMI (kg/m2) Waist circumference (cm) Waist/Hip ratio (WHR) Systolic blood pressure (mm of Hg) Diastolic blood pressure (mm of Hg) Ferriman–Gallwey (F-G) score Biochemical & hormonal Fasting plasma glucose (mg/dl) Cholesterol (mg/dl) Fasting plasma insulin (mIU/ml) Luteinizing hormone (IU/l) Follicle stimulating hormone (IU/l) LH/FSH ratio Total testosterone (ng/ml) HOMA-IR QUICKI

Pearson correlation (r)

p Value

0.123 0.308 0.237 0.155 0.140 0.037 0.009

0.121 50.001 0.003 0.050 0.078 0.645 0.906

0.066 0.043 0.001 0.084 0.004 0.087 0.034 0.014 0.014

0.405 0.593 0.993 0.292 0.957 0.273 0.667 0.864 0.863

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Discussion Women with PCOS have cluster of metabolic derangements and the evidence regarding cardiovascular risk is conflicting [8,13,16,20–22]. During the last decade, there are several reports suggesting that PCOS is associated with an increase in subclinical atherosclerotic disease and endothelial dysfunction [14,16]. Many studies have reported that serum hs-CRP, a sensitive marker of chronic low-grade inflammation and a mediator of atherosclerotic disease, is increased in women with PCOS but there other reports which have negated these associations [21,22]. Therefore there exists a significant conflict in the results and it is not clearly known whether this increase in risk is related to endocrine abnormalities associated with PCOS per se, or whether it is a consequence of the anthropometric or metabolic alterations observed in women with PCOS. In this study, an attempt was made to study hs-CRP levels in a larger sample of Indian adolescent women with PCOS (qualified Androgen Excess Society 2006 criteria) unlikely to have other risk factors hat occur with advanced age. There was no significant difference between the two groups in terms of age and BMI (p40.05). We found that although serum hs-CRP level was higher in women with PCOS compared to non-PCOS women, this difference was not statistically significant. This is in agreement with studies [21–23], which have documented that hs-CRP level in women with PCOS and without PCOS are similar. A recent study conducted by Karoli et al. [22] on 50 Indian PCOS women also reported that hs-CRP was not significantly higher in women with PCOS than control women. The results are similar to ours except that there was association with HOMA-IR but their subjects were older (26.82 ± 3.26 years versus 22.3 ± 5.1 years) and heavier (26.2 ± 4.8 kg/m2 versus 23.7 ± 4.4) that could account for the significance. Our results support the findings documented by Oh et al. [21] and Karoli et al. [22], who reported that hs-CRP levels are not significantly elevated in Asian population compared to Caucasian and Hispanic population. Although Asian population has been shown to have higher prevalence of sub-inflammation and cardiovascular risk at lower BMI, the data suggest that Indian women with PCOS have no elevated cardiovascular risk than control women. Two studies suggesting elevated cardiovascular risk in Indian women had small number of subjects and did not assess hs-CRP levels. The risk may be elevated due to age and obesity not PCOS per se. On further exploration and assessing correlation of serum hs-CRP with various parameters (anthropometric, endocrine, and metabolic parameters) of PCOS, we did not find any significant correlation of hs-CRP with FG score, W/H ratio, systolic BP, diastolic BP, LH, FSH, LH/FSH ratio, total testosterone, fasting or post OGTT glucose, fasting insulin, HOMA-IR and QUICKI. Hyperandrogenism being one of the key features of PCOS has been suspected to have link with elevated cardiovascular link in women with PCOS [4,7]. In the present study there was no significant correlation between serum hs-CRP and hyperandrogenism (FG score or serum total testosterone). Therefore, hyperandrogenemia might not be linked to low-grade inflammation in women with PCOS. Insulin resistance being another dominant metabolic derangement characteristic of PCOS has been suggested to be associated with increased levels of inflammatory mediators in the blood of these subjects [5,11,12,28]. Also there are speculations that insulin resistance and hyperinsulinemia are independent contributors to cardiovascular risk [29,30]. However in this study, we did not find a significant correlation of hs-CRP with fasting glucose, fasting insulin, HOMA-IR and QUICKI in PCOS women.

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Our findings do not support the hypothesis that PCOS per se activates chronic low-grade inflammation, instead we found that hs-CRP levels correlated positively and significantly with known cardiovascular risk factors like BMI and waist circumference in women with PCOS. BMI was the dominant parameter independently determining hs-CRP values in women with PCOS. This was consistent with findings of previous studies documenting that the hs-CRP has a significant positive correlation with BMI [21,22,24,25]. The study had relatively larger sample (160 women with PCOS) compared to studies previously conducted, which were based on smaller (20–50) sample size. The women were younger and lean unlikely to have classical cardiovascular risk factors as confounders. However, the study had some limitations such as insulin resistance was not calculated based by euglycemic hyperinsulinemic clamp and endothelial dysfunction, carotid intimal thickness or coronary artery calcium scores were not done. We conclude that serum hs-CRP levels are not significantly elevated among Indian adolescent women with PCOS and it is predicted by BMI and not the PCOS per se. Therefore, Indian women with PCOS in the absence of classical cardiovascular risk factors may not have elevated cardiovascular risk. Well-designed, longitudinal studies are required to refute or accept this conclusion.

Acknowledgements The author(s) thank all participants and staff for their co-operation and valuable support.

Declaration of interest The authors report no declarations of interest.

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High-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of polycystic ovary syndrome in Indian adolescent women with polycystic ovary syndrome (PCOS).

C-reactive protein (CRP) is a risk marker for type 2 diabetes mellitus and cardiovascular diseases. In polycystic ovary syndrome (PCOS), limited data ...
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