http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(8): 553–556 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.829443

PCO

Studies of cardiovascular risk factors in polycystic ovary syndrome patients combined with subclinical hypothyroidism You-Juan Pei1, Ai-Ming Wang1, Yong Zhao1, Ling Yan1, Min Li1, Richard E. White2, and Gui Chun Han3 Reproductive Medical Center of Navy General Hospital, Hai Dian District, Beijing, China, 2Department of Basic Sciences, Philadelphia College of Osteopathic Medicine – Georgia Campus, Suwanee, GA, USA, and 3Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA

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Abstract

Keywords

Objective: To investigate cardiovascular risk factors in women with polycystic ovary syndrome (PCOS) combined with subclinical hypothyroidism (SCH). Patients: A place-controlled study was performed. Group 1: 29 patients with PCOS and SCH; Group II: 35 patients with PCOS and normal thyroid function; and Group III: 34 healthy women with normal thyroid function. Main measure indexes: Total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), Carotid Arterial Intima-Media Thickness (CIMT), free triiodothyronine 3 (FT3), free triiodothyronine 4 (FT4), thyroid stimulating hormone (TSH), fasting glucose, 1-hour oral glucose tolerance test (OGTT1), 2-hour oral glucose tolerance test (OGTT2), fasting insulin, insulin after 1 hour oral glucose (INS1), insulin after 2 h oral glucose (INS2), HOM-IR ¼ (fasting glucose  fasting insulin)/22.5. Results: TG, TC FIN, INS1, and HOM-IR levels were significantly higher, but the mean HDL level was significantly lower in Group I than in Group II (p50.05). LDL cholesterol, FGOGTT1, OGTT2, and insulin after 2 h oral glucose were not significantly higher in Group I than in Group II (p40.05). TG, TC, FIN and INS contents 2 h meal, HOM-IR levels were significantly higher, and the mean HDL cholesterol level was significantly lower in Group I than in Group III (p50.05). Blood glucose levels after 1 and 2 h were not significantly higher in Group I than in the Group III (p40.05). Carotid Arterial Intima-Media Thickness (CIMT) was significantly thicker in Group I than other two groups. Conclusions: The PCOS patients combined with SCH have higher risk of cardiovascular risk factors than in controls or in patients with PCOS.

Blood pressure, carotid arterial intima-media thickness, insulin release test, lipid parameters, oral glucose tolerance test, polycystic ovary syndrome, resting heart rate, subclinical hypothyroidism History Received 21 February 2013 Revised 10 July 2013 Accepted 24 July 2013 Published online 2 June 2014

Introduction

Materials and methods

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by oligoanovulation, oligomenorrhea, menstrual disturbances and androgen excess [1]. It is a systemic disease often referred to as a nervous-endocrine-metabolic disorder, and has an increasing incidence rate. In addition, most PCOS patients also exhibit insulin resistance, abnormal glucose tolerance and elevated lipid levels. Subclinical hypothyroidism (SCH) is defined as elevated serum thyroid stimulating hormone (TSH) level, with a normal serum free thyroxine (T4) value [2]. However, the diagnosis of SCH is dependent on the definition of the upper limit of normal for serum TSH, which is still a matter of controversy [3]. A cross-sectional study of 1581 thyroid subjects found that there was a positive correlation between TSH levels and index of insulin resistance as well as triglyceride [4]. In order to investigate the risk factors of cardiovascular disease in women with polycystic ovary syndrome (PCOS) with SCH, we conducted a study to compare these risk factors and the correlation between TSH and analyzed parameters.

Our study consisted of three patient groups. Subjects were patients who visited Department of Reproductive and Endocrine Medicine, Navy General Hospital (Beijing) between June 2010 and August 2011. PCOS was diagnosed according to the criteria of the Rotterdam European Society of Human Reproduction and Embryology-American Society for Reproductive Medicine-sponsored PCOS consensus workshop group [5]: (1) oligovulation (defined as the presence of oligomenorrhea, menstrual cycles 435 days, or amenorrhea: lack of menstrual period for 6 months or more) or anovulation; (2) clinical and/or biochemical signs of hyperadrogenism; (3) polycystic ovaries on ultrasound examination: the presence of 12 or more follicles measuring 2–9 mm in diameter in one or both ovaries, and/or ovarian volume more than 10 ml. A patient meeting two of the above three criteria were diagnosed as having polycystic ovarian syndrome. Subclinical hypothyroidism (SCH) is diagnosed according to the criteria of American Endocrine Society: serum thyroid stimulating hormone (TSH) above the defined upper limit of the reference range (TSH44.0 IU/L), with a serum free thyroxine (T4) within the reference range [2]. Patients who had hypertension, hypercholesterolemia, congenital adrenal hyperplasia, hypothyroidism or hyperthyroidism, Cushing’s disease, hyperprolactinemia, and who used specific medications (e.g. oral contraceptives, corticosteroids, GnRH

Address for correspondence: Ai-ming Wang, Reproductive Medical center of Navy General Hospital, No.6 Fucheng Road, Beijing 100048, China. Tel: 18600310258. E-mail: [email protected]

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agonists and antagonists, insulin-sensitizing drugs, antiandrogens, aspirin.) were excluded from the study within 3 months prior to enrollment.

Methods For each patient, the body mass index (BMI) was calculated by weight/high [2]. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured via brachial ascultation after a minumum of 20 min rest. Resting heart rate was measured with a cardio tachometer. Average blood pressure and heart rate were calculated from three individual measurements taken in all patients: 6:00 AM, 12:00 AM and 6:00 PM.

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Laboratory tests Serum was collected from all participiants between 8:00 AM and 10:00 AM after an overnight fast. TSH, FT3, FT4 and insulin were determined by electrochemiluminescence immunoassay for the autoanalyzer Beckman Coulter DXC-800 (Beijing, China). Fasting glucose, TC, HDL-C, LDL-C, and total TG were measured by standard enzymatic techniques by use of an autoanalyzer Beckman Coulter DXC-801 (Beijing, China). CIMT was measured by Three-dimensional color Doppler ultrasound instrument by JWFU HD-318C. Each patient was given a glucose tolerance test (drinking of 75 g glucose dissolved in 250–300 ml warm water), and plasma glucose and insulin levels were measured at 5 min, 1-h and 2-h after drinking the glucose solution. IR was defined by calculating the homeostasis model assessment insulin index (HOMA-IR) that used the following equation: HOMA-IR ¼ Fasting insulin (mU/ml)  fasting glucose (mmol/L)/22.5 [6]. Statistical analysis The data were analyzed with SPSS for Windows 16.0 package program. Nonparametric Tests was used to test the normality of distribution for continuous variables, and data were expressed as mean  standard deviation and 95% central ranges as appropriate; whereas means were compared among groups by a one-way analysis of variance (ANOVA). When equal variance was assumed, a LSD test was performed. If equal variance could not be assumed, a Dunnetts’T3 test was used. To analyze the effects of SCH on IR, serum lipids and glucose was applied with BMI, resting heart rate, SBP, DBP as covariates. p50.05 was considered statistically significant.

Results 1. THS levels were significantly higher in Group I than Group II (p50.05). In contrast, there was no difference in age, BMI, FT3, FT4, SBP, RBP, and resting heart rate between the two groups. TG, CIMT and TC levels were significantly higher, and the mean HDL-C was significantly lower in Group I than in the Group II (p50.05). This difference was not related to BMI, blood pressure, or heart rate. LDL levels, fasting glucose, OGTT-1hour, or OGTT-2hour was not different between the two groups (p40.05). In contrast, fasting insulin, INS-1hour, INS-2hour, and HOM-IR were significantly higher in Group I than Group II (p50.05), but this difference did not correlate with BMI, blood pressure, or heart rate. (Table 1) 2. BMI, TSH, SP, DP and heart rate levels were significantly higher in Group I than Group III (p50.05), whereas age, FT3 and FT4 were not different (p40.05). TG, TC and CIMT were significantly higher, and HDL was significantly lower in Group I than Group III (p550.05), while LDL was not different between two groups. Fasting glucose, fasting insulin, INS-1hour, INS2hour and HOM-IR were significantly higher in Group I than

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Table 1. Comparison of baseline characteristics and cardiovascular risk factors between Group I and Group II.

Variable Age (years) BMI (kg/m2) TSH (IU/L) FT3 (pmol/L) FT4 (pmol/L) Rate (time/min) SBP (mm/Hg) DBP (mm/Hg) TG (mmol/L) TC (mmol/L) HDL (mmol/L) LDL (mmol/L) OGTT0 (mmol/L) OGTT1 (mmol/L) OGTT2 (mmol/L) INS0 (mU/ml) INS1 (mU/ml) INS2 (mU/ml) HOM-IR CIMT (mm)

Group I Mean  SD; N ¼ 29

Group II Mean  SD; N ¼ 34

p

30.59  4.01 26.09  3.26 6.15  2.02 4.98  0.52 10.67  1.19 81.34  5.69 1.19E2  17.97 78.72  11.15 1.85  1.04 4.98  0.66 1.27  0.28 2.14  0.41 5.26  0.66 8.16  3.33 6.54  2.57 20.49  10.59 1.41E2  58.74 76.81  40.83 4.78  2.53 0.68  0.13

29.74  3.39 25.07  3.27 1.79  0.64 5.03  0.53 10.26  1.48 79.47  3.09 1.16E2  13.85 77.35  11.99 1.01  0.32 4.51  0.61 1.44  0.27 2.08  0.032 5.10  0.55 8.24  2.33 6.73  2.22 13.78  7.36 76.51  28.17 77.37  62.45 3.22  1.94 0.62  0.08

0.386 0.524 0.000 0.679 0.258 0.319 0.903 0.953 0.001 0.002 0.027 0.608 0.67 0.99 0.98 0.018 0.009 1.00 0.026 0.013

p50.05 was considered statistically significant. Data are shown with 95% central range. Table 2. Comparison baseline characteristics and cardiovascular risk factors between Group I and Group III.

Variable Age (years) BMI (kg/m2) TSH (IU/L) FT3 (pmol/L) FT4 (pmol/L) Rate (time/min) SBP (mm/Hg) DBP (mm/Hg) TG (mmol/L) TC (mmol/L) HDL (mmol/L) LDL (mmol/L) OGTT0 (mmol/L) OGTT1 (mmol/L) OGTT2 (mmol/L) INS0 (mU/ml) INS1 (mU/ml) INS2 (mU/ml) HOM-IR CIMT (mm)

Group I Mean  SD; N ¼ 29

Group III Mean  SD; N ¼ 35

p

30.59  4.01 26.09  3.26 6.15  2.02 4.98  0.52 10.67  1.19 81.34  5.69 1.19E2  17.97 78.72  11.15 1.85  1.04 4.98  0.66 1.27  0.28 2.14  0.41 5.26  0.66 8.16  3.33 6.54  2.57 20.49  10.59 1.41E2  58.74 76.81  40.83 4.78  2.54 0.68  0.13

30.69  4.16 22.21  1.86 2.00  0.79 4.94  0.44 11.21  1.51 73.46  4.98 1.03E2  7.99 72.86  4.93 0.80  0.19 4.18  0.47 1.66  0.35 2.08  0.51 4.89  0.29 7.08  1.79 5.75  1.21 8.40  3.17 52.33  20.97 32.88  16.08 1.83  0.72 0.57  0.09

0.918 0.000 0.000 0.753 0.128 0.000 0.000 0.037 0.000 0.000 0.000 0.11 0.023 0.33 0.35 0.000 0.000 0.000 0.000 0.000

p50.05 was considered statistically significant.

in Group III (p50.05). OGTT-1hour and OGTT-2hour had no obvious difference between 2 groups. (Table 2)

Discussion To our knowledge, we have reported, for the first time, that cardiovascular risk factors, TG, TC FIN, INS1 and HOM-IR levels of patients, were in the order of PCOS combined with SCH4PCOS4Normal. On the contrary, the order of HDL level was normal4PCOS4PCOS combined with SCH. The values of Carotid Arterial Intima-Media Thickness (CIMT) from patients with PCOS combined with SCH were higher than PCOS alone or normal subjects.

Cardiovascular risk factors

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DOI: 10.3109/09513590.2013.829443

PCOS is a gynecologic endocrinological disorder, afflicting 7% of women of child-bearing age [7]. It is very common to see many associated diseases among patients with PCOS, such as impaired glucose tolerance, insulin resistance, obesity and metabolic syndrome. Meanwhile, other diseases could be induced by these associated problems, such as hyperlipoidemia, diabetes mellitus, and cardiovascular diseases. Li [8] reported that PCOS patients exhibited significantly elevated BMI, TG, TC, LDL, FINS, FGLU and HOM-IR compared to control patients, while HDL was lower. A related study has reported that TG, TC, HDL, LDL in an insulin-resistant group were higher compared to patients in a non-insulin-resistant group [9]. The Costa EC also reported that blood lipid and insulin resistance index of patients with PCOS, especially with obesity, were much higher, and correlated closely with cardiovascular disease risk [10]. In addition, Verit [11] reported that PCOS with higher BMI, TG, TC, LDL, were higher risk in cardiovascular disease than normal. The present study (Tables 1 and 2) found that BMI, SBP, RBP, resting heart rate are higher in PCOS patients than normal, and that blood lipids (TG, TC, LDL) are also elevated in PCOS. In contrast, HDL was lower in PCOS patients. In addition, glucose tolerance and insulin measurements (FOGTT, OGTT1, OGTT2, FINS, INS1, INS2) were found to be higher in PCOS patients, and these findings are with previous studies. Both the present study and previous studies indicate that blood lipids in patients with PCOS are higher than normal, and these elevations accompany insulin resistance and impaired glucose tolerance. Subclinical hypothyroidism refers to endocrine system syndrome with increasing TSH levels (TSH44.0 IU/L) and normal FT4 and FT3. Generally, it may have no or little overt clinical symptoms, but it may damage a number of body systems due to its insidious and long-term nature. In recent years the incidence of subclinical hypothyroidism disease in adults has increased by 7–26% [12]. Its primary impact appears to be the potential for developing clinical hypothyroidism, and increasing cardiovascular dysfunction. Recently, a number of studies have suggested a relationship between subclinical hypothyroidism and CHD [13], but these results are not completely consistent. The present study reported that TSH, blood pressure, CIMT, resting heart rate and lipids were higher in PCOS combined with SCH than PCOS alone. Most studies indicate that subclinical hypothyroidism could also induce abnormal blood lipid metabolism, increasing blood pressure and impaired endothelial function [14]. The latest clinical study indicated that TC and LDL in a SCH group are much higher than the normal (p50.05) [15], and SCH has a clear correlation with blood lipids [16]. Further, this increased level of blood lipids is usually accompanied with IR. Rezzonico J has also shown that endogenous or exogenous SCH is related to IR [17]. Moreover, subclinical hypothyroidism has a close relationship with cardiovascular risk factors. Recently, Frias Lopez [18] reported that patients with subclinical hypothyroidism and diabetes mellitus exhibited increased risk factors for cardiovascular disease. Velkoska also reported that CIMT in patients with subclinical hypothyroidism exhibited increased plaque formation compared to normal controls, thus increasing the risk of atherosclerosis [19]. Subclinical hypothyroidism and PCOS are endocrine diseases which effect reproductive health in reproductive-age women, and will also increase the risk of cardiovascular disease in elderly women. Ganie MA’s indicated that triglyceride levels and TSH levels in patients with PCOS and subclinical hypothyroidism were higher than in a group of patients with PCOS alone [20]. Celik also reported that TG, fasting insulin, TSH and HOM-IR in patients with PCOS and subclinical hypothyroidism were higher than in patients with PCOS alone [3]. In this study, compared

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to Group III, blood lipids and insulin were higher in Group I (Table 2), and this increase was associated with higher TSH in subclinical hypothyroidism. TSH, blood lipids and insulin were significantly higher in Group I than in Group II (Table 2). We predict that patients with PCOS and subclinical hypothyroidism will have higher risk of in cardiovascular diseases such as hyperlipoidemia, CIMT, blood pressure, resting heart rate, hyperinsulinemia) than PCOS patients or normal subjects. Therefore, our findings suggest that patients with PCOS and subclinical hypothyroidism are most likely to exhibit hyperlipoidemia, hyperinsulinemia, diabetes. Further, cardiovascular diseases, diabetes would likely be increased in women as well. Although most patients with PCOS and subclinical hypothyroidism do not exhibit clinic symptoms, but its insidious and longterm nature may aggravate PCOS primary symptoms, such as hyperlipoidemia and hyperinsulinemia. Therefore, much attention should be paid to subclinical hypothyroidism while treating patients with PCOS (especially if these patients exhibit hyperlipoidemia and hyperinsulinemia). We propose that the incidence of cardiovascular disease in PCOS and SCH patients could be reduced if effective measures (e.g. early diagnosis and treatment) were instituted as soon as possible.

Declaration of interest All participants provided their written informed consent for each study. Ethics Committee in our hospital supports this study. The authors declare that they have no competing interests.

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Studies of cardiovascular risk factors in polycystic ovary syndrome patients combined with subclinical hypothyroidism.

To investigate cardiovascular risk factors in women with polycystic ovary syndrome (PCOS) combined with subclinical hypothyroidism (SCH)...
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