Relationship between interleukin-6 levels and ambulatory blood pressure in women with polycystic ovary syndrome
2009; Elsevier BV; Volume: 94; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2009.05.055
ISSN1556-5653
AutoresCemil Kaya, Recai Pabuçcu, Cemile Koca, Ali Kemal Oğuz, Aycan Fahri Erkan, Ayhan Korkmaz, Deniz Erbaş,
Tópico(s)Hormonal and reproductive studies
ResumoObjectiveTo determine 24-hour ambulatory blood pressures (ABP) in patients with polycystic ovary syndrome (PCOS) and its relationship with interleukin-6 (IL-6).DesignProspective controlled study.SettingUniversity hospital.Patient(s)Fifty-four PCOS patients.Intervention(s)Ambulatory blood pressure monitoring was conducted. Anthropometric, hormonal, metabolic, and inflammatory parameters, including plasma IL-6, C-reactive protein (CRP), fibrinogen, and nitric oxide (NO), were measured in each subject.Main Outcome Measure(s)Ambulatory blood pressure and plasma IL-6, CRP, fibrinogen, and NO.Result(s)Serum IL-6 levels of PCOS women in the highest systolic blood pressure (SBP) quartile were significantly higher than those of women in the lowest SBP quartile. The high serum IL-6 levels (serum IL-6 level ≥5.1 pg/mL) were associated with a higher probability of raised SBP (≥126 mm Hg), with an odds ratio of 2.2 (95% confidence interval 0.8–7.9). The systolic and diastolic (DBP) blood pressures were significantly related to serum IL-6 levels. The IL-6 levels were positively and significantly correlated with serum CRP levels. Interleukin-6 and CRP were negatively and significantly correlated with serum NO levels.Conlusion(s)The results suggest that raised plasma IL-6 levels may be related to ambulatory SBP and DBP in PCOS. To determine 24-hour ambulatory blood pressures (ABP) in patients with polycystic ovary syndrome (PCOS) and its relationship with interleukin-6 (IL-6). Prospective controlled study. University hospital. Fifty-four PCOS patients. Ambulatory blood pressure monitoring was conducted. Anthropometric, hormonal, metabolic, and inflammatory parameters, including plasma IL-6, C-reactive protein (CRP), fibrinogen, and nitric oxide (NO), were measured in each subject. Ambulatory blood pressure and plasma IL-6, CRP, fibrinogen, and NO. Serum IL-6 levels of PCOS women in the highest systolic blood pressure (SBP) quartile were significantly higher than those of women in the lowest SBP quartile. The high serum IL-6 levels (serum IL-6 level ≥5.1 pg/mL) were associated with a higher probability of raised SBP (≥126 mm Hg), with an odds ratio of 2.2 (95% confidence interval 0.8–7.9). The systolic and diastolic (DBP) blood pressures were significantly related to serum IL-6 levels. The IL-6 levels were positively and significantly correlated with serum CRP levels. Interleukin-6 and CRP were negatively and significantly correlated with serum NO levels. The results suggest that raised plasma IL-6 levels may be related to ambulatory SBP and DBP in PCOS. Inflammation is considered to play a key role in pathophysiologic mechanisms of atherosclerosis and cardiovascular disease (1Frishman W.H. 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Polycystic ovary syndrome is associated with endothelial dysfunction.Circulation. 2001; 103: 1410-1415Crossref PubMed Scopus (386) Google Scholar). According to these results, serum IL-6 levels may affect the regulation of blood pressure in PCOS. A few studies have shown either similar or increased office blood pressures in lean PCOS patients compared with lean control subjects (25Zimmermann S. Phillips R.A. Dunaif A. Finegood D.T. Wilkenfeld C. Ardeljan M. et al.Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance.J Clin Endocrinol Metab. 1992; 75: 508-513Crossref PubMed Scopus (0) Google Scholar, 26Holte J. Gennarelli G. Berne C. Bergh C. Bergh T. Lithell H. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state?.Hum Reprod. 1996; 11: 23-28Crossref PubMed Scopus (146) Google Scholar). More recently, Lugue-Ramirez et al. (27Lugue-Ramirez M. Alvarez-Blasco F. Mendieta-Azcona C. Botella-Carretero J.I. Escobar-Morreale H.F. Obesity is the major determinant of abnormalities in blood pressure found in young women with the polycystic ovary syndrome.J Clin Endocrinol Metab. 2007; 92: 2141Crossref PubMed Scopus (64) Google Scholar) reported that abnormalities in the regulation of blood pressure are frequent, and obesity is the major determinant of the abnormalities in blood pressure in young PCOS patients. However, the mechanism of abnormalities in blood pressure has not yet been elucidated in PCOS women. Twenty-four-hour ambulatory measurements are considered to provide more reliable prognostic information and to be a more accurate method than office measurements for revealing labile blood pressure or borderline hypertension (28Boggia J. Li Y. Thijs L. et al.Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study.Lancet. 2007; 370 (29): 1229Abstract Full Text Full Text PDF Scopus (668) Google Scholar). The predictive value of 24-hour blood pressure for cardiovascular events is greater than that seen for office blood pressure values in populations (29Mancia G. Facchetti R. Bombeli M. Grassi G. Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure.Hypertension. 2006; 47: 846-853Crossref PubMed Scopus (543) Google Scholar). Ambulatory blood pressure monitoring provides information not only about 24-hour average blood pressure but also about specific periods such as day, night, or morning (30Dolan E. Stanton A. Thijs L. et al.Superiority of ambulatory over clinic blood pressure measurement in predicting mortality. The Dublin Outcome Study.Hypertension. 2005; 46: 156-161Crossref PubMed Scopus (968) Google Scholar). As yet, the relation between ambulatory blood pressures (ABP) and IL-6 has not been specifically determined in PCOS. The principal goal of the present study was to establish the role of IL-6 as a possible determining factor, aside from obesity and other known metabolic risk factors, affecting the blood pressure of young women with PCOS, while taking into consideration the influence of CRP, fibrinogen, and NO. To address the above issues, we defined the patient's blood pressure as being in the high blood pressure (SBP ≥126 mm Hg and/or DBP and ≥80 mm Hg) or normal blood pressure (SBP <126 mm Hg and/or DBP <80 mm Hg) range according to the 24-hour figures obtained in the initial ABP. Specifically, we tested whether or not the serum IL-6 level was higher in PCOS patients with high blood pressure than those with normal blood pressure, and we investigated the relationship between IL-6 levels and CRP, fibrinogen, and NO, all of which are related to hypertension. The study group consisted of 54 PCOS patients. Patients were considered to have elevated or high blood pressure if their 24-hour daytime and nighttime values on ambulatory monitoring were ≥126 mm Hg systolic and/or 80 mm Hg diastolic. The reference normal values were identified by the PAMELA study (31Mancia G. Sega R. Bravi C. De Vito G. Valagussa F. Cesana G. Zanchetti A. Ambulatory blood pressure normality: results from the PAMELA study.J Hypertens. 1995; 13: 1377-1390Crossref PubMed Google Scholar). Hypertension is defined as a blood pressure ≥140/90 mm Hg. There was no reference data to be used considering ABP in our population. Therefore, we used the PAMELA study as a reference for ABP monitoring. Patients were considered to have normal blood pressure if their 24-hour daytime and nighttime values on ambulatory monitoring were <126 mm Hg systolic and/or 35 days), amenorrhea (absence of menstruation for 3 consecutive months), and luteal phase progesterone measurements 7 (34Ferriman D. Gallway J.D. Clinical assessment of body hair growth in women.J Clin Endocrinol Metab. 1961; 21: 1440-1447Crossref PubMed Scopus (2035) Google Scholar). Nonclassic adrenal 21-hyroxylase deficiency, hyperprolactinemia, and androgen-secreting tumors were excluded by appropriate tests before the diagnosis of PCOS was made. None of the PCOS patients had thyroid dysfunction, disorders of glucose intolerance, pregnancy, delivery, miscarriage, or surgery in the preceding 3 months, hypertension, smoking, cardiovascular events, hepatic or renal dysfunction, or sleep apnea. Any use of heparin or aspirin within 15 days of the test was also an exclusion criterion. None of the cases had received any drugs known to interfere with hormonal levels for at least 3 months before the study. All of the subjects were nonsmokers who did not consume alcoholic beverages on a regular basis. None of the subjects had restricted physical activity because of handicap or other reasons or were encouraged to excercise or to be engaged in work requiring physical activity. The study took place at the University of Ufuk. All subjects gave written informed consent, and the institutional review boards of the hospitals approved the study. Body mass index (BMI) was calculated as weight (kg)/height (m)2. BMI values of 30 kg/m2 obese (35Rebuffe-Scrive M. Cullberg G. Lundberg P.A. Lindstedt G. Björntorp P. Anthropometric variables and metabolism in polycystic ovarian disease.Horm Metab Res. 1989; 21: 391-397Crossref PubMed Scopus (124) Google Scholar). Weight and height were measured in light clothing without shoes. Waist circumference was measured at the narrowest level between the costal margin and iliac crest, and the hip circumference was measured at the widest level over the buttocks while the subject was standing and breathing normally. The waist-to-hip artio (WHR) was calculated. A WHR >0.72 was considered to be abnormal (36Ashwell M. Chinn S. Stalley S. Garrow J.S. Female fat distribution-a simple classification based on two circumference measurements.Int J Obes. 1982; 6: 143-152PubMed Google Scholar). Venous blood samples were obtained in the follicular phase of a spontaneous cycle. After a 3-day 300 g carbohydrate diet and 12-hour overnight fasting, serum samples were obtained for the measurements of serum FSH, LH, PRL, total T, DHEAS, and TSH, lipid profile [total cholesterol (C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)], and basal insulin levels. Plasma glucose was determined with glucose hexokinase (Cobas Integra 400 Plus; Roche Diagnostics, Mannheim, Germany). The insulin sensitivity index (ISI) was investigated by using basal insulin levels, fasting glucose, and homeostasis model assesment (HOMA-IR). The HOMA-IR was calculated as fasting glucose (mg/dL) × fasting insulin (μU/mL) × 0.055/22.5 (37Belli S.H. Graffigna M.N. Oneta A. Otero P. Schurman L. Levalle O.A. Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome.Fertil Steril. 2004; 81: 624-629Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 38Matthews D.R. Hosker J.P. Rudenski A.S. Naylor B.A. Tracher D.F. Turner R.I. Homeostasis model assessment: insulin resistance and β cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia. 1985; 28: 412-419Crossref PubMed Scopus (24815) Google Scholar). Serum levels of FSH, LH, PRL, total T, DHEA-S, insulin, and TSH were measured with specific chemiluminescence assays from Roche Diagnostics (Hitachi Elecsys 2010). Serum levels of 17-OH progesterone (17OH-P) and free T were measured by radioimmunoassay (RIA). Levels of total C, HDL-C, LDL-C, and TG were determined with enzymatic colorimetric assays (Roche Diagnostics). Samples were immediately centrifuged, and serum was separated and frozen at −20°C until assayed. The intra- and interassay coefficients of variation were <5% for all of the assays performed. Serum IL-6 levels were measured by ELISA (Human IL-6 ELISA Kit; Medical and Biological Laboratories Co., Nagoyai, Japan), with mean intra- and interassay coefficients of variation of 3.5% and 8.7%, respectively. Serum CRP was measured by latex immunoturbidometric methodology on an automated clinical analyzer system (Cobas Integra, Roche Diagnostics). Plasma fibrinogen levels were measured by fibrometer by the photo-optical technique (MT4C coagulometer; Diagnostic Stage, Asnieres-Sur-Seine, France). The NO production was assessed by measuring the plasma concentration of NO3− and NO2− with the nitrate reductase–Griess method, using a commercial kit (Cayman Chemical Co., Ann Arbor, MI). This assay kit has a detection limit of 2.5 μmol/L for nitrate/nitrite. Plasma samples were ultrafiltered through a 10-kDa microfuge ultrafiltration device (Millipore) and NO contents were assessed by a two-step process consisting of nitrate reductase–dependent conversion of nitrate to nitrite. This was followed by spectrophotometric detection (Bio-Rad Benchmark Microplate Reader) of total nitrite after Griess reaction at 540 nm (39Miranda K.M. Espey M.G. Wink D.A. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite.Nitric Oxide. 2001; 5: 62-71Crossref PubMed Scopus (2608) Google Scholar). The ABP measurements were performed using an Accutracker II blood pressure monitor (Suntech Medical Instruments, Raleigh, NC). The method of measurement is oscillatory and uses R-wave gating. Diastolic blood pressure was determined from phase 5 Korotkoff sounds. The blood pressure cuff (12 × 22 cm for lean patients, 14 × 30 cm for overweight and obese subjects) was attached to the patient's left arm and chest, and electrocardiogram electrodes were affixed by a skilled technician. Blood pressure was measured every 30 minutes between 6 a.m. and 10 p.m. and every 60 minutes between 10 p.m. and 6 a.m. during a 24-hour study period. Mean SBP and DBP values were calculated as means of the hourly averages. The period 6 a.m. and 10 p.m. was considered to be daytime and from 11 p.m. to 7 a.m. the next day nighttime, reflecting the usual sleeping habits of our population. Data are shown as mean ± SD or n (%). Data analysis was performed using SPSS for Windows, version 11.5 (SPSS, Chicago, IL). Shapiro-Wilk test was used to detect whether or not the continuous variables were normally distributed. Groups were compared using Student t or Mann Whitney U test as appropriate. Correlations between parametric variables and nominal parametric data were assessed by Pearson correlation coefficients. Multiple linear regression stepwise method was used to determine the independent predictors which mostly affected SBP and DBP: SBP and DBP as the dependent variable and stepwise (probability of F to enter ≤.05; probability of F to remove ≥0.10) introduction of anthropometric, hormonal, inflammatory, and metabolic factors as the independent variables after elimination of nonsignificant predictors from the prognostic model. Logistic regression analysis was performed to assess the association between elevated blood pressure and the categoric data of the IL-6 level (with cutoff value at 5.1 pg/mL, the highest quartile of IL-6 in this study) after adjustment for age, BMI, CRP, NO, fibrinogen, HOMA index, total C, LDL-C, HDL-C, and TG. The IL-6 levels were calculated among the subjects in different SBP or DBP quartiles by using analysis of variance. Statistical significance was defined as P<.05. The clinical, endocrine, and biochemical features of the subjects are summarized in Table 1. The majority of the subjects were young (83.2% of the subjects were <30 years of age, with a mean age of 28.8 ± 4.4 years and a range of 19–36 years), and 84% were nulligravidas. None of the patients had hypertension. None of the patients had DBP ≥80 mm Hg. Ambulatory SBP records are shown in Figure 1. During 24 hours, SBP was ≥126 mm Hg in 27.7% of patients. The SBP was ≥126 mm Hg in 38.8% of patients during daytime and in 20.3% of patients during nighttime (Table 2).Table 1Basic demographic data of the women with polycystic ovary syndrome.Characteristicn (%)Nulliparity84 (100)Age (y) <203 (5.5) 20–2942 (77.7) ≥309 (16.6)Body mass index (kg/m2) <2539 (72.2) ≥2515 (27.7)Waist-to-hip ratio <0.7211 (20.3) ≥0.7243 (79.6)Hirsutism34 (62.9) Open table in a new tab Table 2Inflammatory markers, nitric oxide, and heart rate characteristics between polycystic ovary syndrome patients with systolic blood pressure (SBP) <126 mm Hg and those with SBP ≥126 mm Hg.SBP (mm Hg)24 hDaytimeNighttimeVariable<126 (n = 39)≥126 (n = 15)<126 (n = 33)≥126 (n = 21)<126 (n =43)≥126 (n = 11)IL-6 (pg/mL)3.0 ± 1.74.8 ± 0.2aP<.01.2.8 ± 1.74.8 ± 0.4aP<.01.3.1 ± 1.84.0 ± 1.2CRP (mg/L)1.8 ± 0.693.7 ± 1.52aP<.01.1.4 ± 0.532.9 ± 1.53aP<.01.1.7 ± 0.692.9 ± 1.1Fibrinogen (μg/dL)306.0 ± 100.0404.0 ± 101.1305.8 ± 107.9363.4 ± 101.9318.9 ± 103.4383.8 ± 121.7Nitric oxide (μmol/L)15.9 ± 7.38.2 ± 5.3aP<.01.16.7 ± 7.010.3 ± 6.9bP<.05.14.4 ± 7.58.7 ± 4.4aP<.01.Heart rate (beats/min)69.7 ± 4.478.3 ± 4.1aP<.01.69.3 ± 4.779.0 ± 8.2aP<.01.68.5 ± 4.579.1 ± 9.1aP<.01.Note: Statistical significance was defined as P<.05. CRP = C-reactive protein; IL-6 = interleukin-6.a P<.01.b P<.05. Open table in a new tab Note: Statistical significance was defined as P<.05. CRP = C-reactive protein; IL-6 = interleukin-6. The IL-6 and CRP levels were statistically higher in women with SBP ≥126 mm Hg during 24 hours and during daytime than those with SBP <126 mm Hg. Although not statistically significant, the IL-6 and CRP levels were higher in women with SBP ≥126 mm Hg than those with SBP <126 mm Hg during nighttime. Fibrinogen levels were not different in women with SBP ≥126 mm Hg and those with SBP <126 mm Hg during 24 hours, daytime, and nighttime. Serum NO levels in women with SBP ≥126 mm Hg were lower than in women with SBP <126 mm Hg during 24 hours, daytime, and nightime (Table 2). Based on multiple linear regression analysis, SBP and DBP were significantly related to IL-6 (P<.001 and P<.001, respectively) as well as age (P=.01 and P=.04, respectively) (Table 3). Interleukin-6 explained 51% of overall change for 24-hour SBP measurements and 37.8% of overall change for 24-hour DBP measurements. Pure clarification coefficient for age was determined as 5%.Table 3Basic characteristics of subjects and the Pearson correlation analysis between blood pressure and anthropometric, hormonal, and metabolic variables.SBPDBPVariableMean ± SDrP valuerP valueAge (y)28.8 ± 4.40.27<.050.33<.05FSH (IU/L)4.8 ± 2.40.11NS0.13NSLH (IU/L)7.3 ± 4.9NS0.19NSBody mass index (kg/m2)24.4 ± 4.10.54<.0010.46<.001Waist-to-hip ratio0.79 ± 0.070.30.020.15NSTotal cholesterol (mg/dL)182.4 ± 30.70.69<.0010.62<.001LDL cholesterol (mg/dL)123.5 ± 28.30.19NS0.07NSHDL cholesterol (mg/dL)46.9 ± 5.00.35.0070.37.004TG (mg/dL)102.0 ± 31.30.16NS0.02NSFree T (pg/mL)1.9 ± 0.660.09NS0.12NSTotal T (ng/mL)0.59 ± 0.060.18NS0.16NSFasting insulin (μIU·min/mL)17.6 ± 5.00.49<.0010.47<.001Fasting glucose (mg/dL)82.9 ± 7.90.11NS0.13NSHOMA-IR3.3 ± 0.90.64<.0010.58<.001IL-6 (pg/mL)4.1 ± 0.40.71<.0010.62<.001CRP (mg/L)3.6 ± 1.60.37<.010.29<.05Nitric oxide (μmol/L)9.7 ± 4.2−0.44<.001−0.51<.001Note: Statistical significance was defined as P<.05. HDL = high-density lipoprotein; HOMA-IR = homeostasis method assessment of insulin resistance; LDL = low-density lipoprotein; TG = triglycerides; other abbreviations as in Table 2. Open table in a new tab Note: Statistical significance was defined as P<.05. HDL = high-density lipoprotein; HOMA-IR = homeostasis method assessment of insulin resistance; LDL = low-density lipoprotein; TG = triglycerides; other abbreviations as in Table 2. The age- and BMI-adjusted serum IL-6 levels among the subjects were categorized according to SBP or DBP quartiles. PCOS patients with SBP in the top quartile had significantly higher serum IL-6 levels compared with the bottom quartile (Fig. 2). PCOS patients with DBP in the top quartile also had significantly higher serum IL-6 levels compared with the bottom quartile (Fig. 3).Figure 3Serum interleukin-6 (IL-6) levels after adjustment for age and body mass index (BMI) among polycystic ovary syndrome women in different diastolic blood pressure (SBP) quartiles. The DBP quartiles were as follows: 1st: <65 mm Hg; 2nd 65–70 mm Hg; 3rd: 71:76 mm Hg; and 4th: ≥77 mm Hg. The age- and BMI-adjusted serum IL-6 levels were found to be statistically significant (P<.01 by ANOVA) between the 1st and 3rd and between the 2nd and 4th SBP quartiles. IL-6 levels were calculated among subjects in different SBP quartiles by using ANOVA as overall P value. The difference was found to be statistically significant (P<.001) between the 1st and 4th quartiles.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Using logistic regression analysis with adjustment for age, BMI, CRP, NO, fibrinogen, HOMA index, total C, LDL-C, HDL-C, and TG, the high serum IL-6 levels (serum IL-6 level ≥5.1 pg/mL, the highest quartile of IL-6 in this study) was associated with a higher probability of SBP ≥126 mm Hg, with an odds ratio of 2.2 (95% confidence interval 0.8–7.9; P<.001). The SBP and DBP were positively correlated with IL-6, CRP, age, and BMI, WHR, fasting insulin, HOMA index, LDL-C, and TG. The SBP and DBP were negatively correlated with NO and HDL-C (Table 4). Serum IL-6 levels were positively and significantly correlated with BMI (r = 0.27; P<.05), WHR (r = 0.24; P<.05), serum CRP levels (r = 0.47; P<.001), fasting insulin (r = 0.32; P<.05), and H
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