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Departments of Endocrinology (H.F.E.-M., J.I.B.-C., G.V., J.S.) and Molecular Genetics (J.L.S.M.), Hospital Ramón y Cajal, E-28034 Madrid, Spain
Address all correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar Km 9100, E-28034 Madrid, Spain. E-mail: hescobarm.hrc{at}salud.madrid.org.
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Abstract |
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Sixty consecutive women with PCOS and 34 healthy women were recruited. Serum levels of IL-18 and lipid and hormone profiles were measured. The insulin sensitivity index was calculated from glucose and insulin concentrations during an oral glucose tolerance test. Data were submitted to a multivariate general linear model introducing age as a covariate.
Serum IL-18 levels were increased in PCOS patients compared with controls (P = 0.031) and in obese women compared with lean women (P = 0.018). No interaction between PCOS and obesity was found, suggesting that the influence of PCOS on serum IL-18 concentrations studied here was not different in lean women compared with obese women and that the influence of obesity on serum IL-18 concentrations was the same in the PCOS and control groups. Serum IL-18 levels correlated, after logarithmic transformation, with body mass index (r = 0.38; P < 0.0002), waist-to-hip ratio (r = 0.33; P < 0.001), and total testosterone levels (r = 0.24; P < 0.02), and inversely with the insulin sensitivity index (r = -0.23; P < 0.03).
In conclusion, PCOS and obesity induce an increase in serum IL-18 levels, which are also associated with several indexes of global and visceral adiposity and with insulin resistance.
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Introduction |
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During the past years, serum markers of inflammation are being increasingly recognized as predictors of atherosclerosis and cardiovascular disease (3, 4). The increased concentration of these inflammatory markers clusters with other cardiovascular risk factors, such as dyslipidemia, glucose intolerance and type 2 diabetes, hypertension, and obesity, and in fact, chronic low-grade inflammation has been proposed to play a role in the pathogenesis of insulin resistance and the metabolic syndrome (5).
Proinflammatory genotypes may influence hyperandrogenism and PCOS. On the one hand, Kelly et al. (6) have reported increased serum C-reactive protein (CRP) levels in PCOS patients. On the other, we have recently found that common polymorphisms in the genes encoding TNF-
, type 2 TNF receptor, IL-6, and the IL-6 signaling molecule gp130 are associated with hyperandrogenism and PCOS, or influence hyperandrogenic phenotypic traits (7, 8, 9, 10). However, serum levels of CRP, IL-6, soluble intercellular adhesion molecule-1, TNF-, and type 2 TNF receptor were not increased in our PCOS patients when compared with a control group of healthy women matched for body mass index (BMI) and prevalence of smoking, suggesting that serum concentrations of these inflammatory markers did not accurately reflect the inflammatory process underlying PCOS (11). Of note, serum levels of CRP and IL-6 were higher in obese subjects when compared with lean women irrespective of the presence or absence of PCOS (11), in conceptual agreement with the contribution of adipose tissue to the secretion of inflammatory cytokines.
IL-18 is a proinflammatory cytokine that induces the production of TNF- (12), which in turn promotes the synthesis of IL-6 (13), and IL-6 regulates the synthesis of CRP in the liver (14). Like IL-6 and CRP, IL-18 is considered a strong risk marker for cardiovascular death (15).
Recently, Esposito et al. (16, 17) reported that serum IL-18 concentrations are increased in obese women and decrease after weight loss. Moreover, serum IL-18 concentrations correlated with surrogate indexes of insulin resistance, such as the waist-to-hip ratio (WHR) and fasting insulin levels (16), suggesting that the increase in serum IL-18 levels is related not only to obesity but also to insulin resistance. Therefore, IL-18 might be a useful serum marker of the inflammatory process associated with obesity and insulin resistance.
To further expand knowledge about the relationship between IL-18, insulin resistance, and obesity, and given that PCOS can be considered as a human model of insulin resistance irrespective of the presence or absence of obesity (11), in the present study we have studied serum IL-18 levels in our series of PCOS patients.
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Subjects and Methods |
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Sixty consecutive patients diagnosed with PCOS (BMI, 31.3 ± 8.7 kg/m2; age, 25.5 ± 6.7 yr) and 34 nonhyperandrogenic women (BMI, 30.7 ± 7.5 kg/m2; age, 31.7 ± 8.0 yr) were included in the study. The PCOS and control groups were matched primarily for BMI and secondarily for prevalence of smokers. The control group included consecutive patients submitted to one of the authors (H.F.E.-M.) for treatment of obesity and healthy lean volunteers. None of the controls had signs or symptoms of hyperandrogenism, menstrual dysfunction, or a history of infertility.
The diagnosis of PCOS was based on endocrine criteria (18). All of the patients had oligoovulation as indicated by oligomenorrhea or amenorrhea or regular menstrual cycles with serum progesterone less than 4 ng/ml between d 22 and 24 of the menstrual cycle. Menstrual calendars and basal body temperature charts served to confirm oligoovulation as needed. In addition, patients presented with hirsutism, as defined by a modified Ferriman-Gallwey score above 7 (19), acne, alopecia, and/or increased circulating total or free testosterone, androstenedione, or dehydroepiandrosterone-sulfate (DHEAS) levels. Finally, hyperprolactinemia, androgen-secreting tumors, and congenital adrenal hyperplasia were ruled out in all of the patients.
None of the PCOS patients and controls had any clinical evidence of atherosclerosis or cardiovascular disease. Fasting glucose levels were less than 110 mg/dl and blood pressure was less than or equal to 140/90 mm Hg in all participants with the exception of four PCOS patients and one control who had undiagnosed and untreated hypertension. All of the subjects were Caucasian and had not taken hormonal medications, including contraceptive pills, for the last 6 months. Data from some of the patients and controls have been published previously (7, 8, 9, 11).
The ethics committee of the Hospital Ramón y Cajal approved the study, and informed consent was obtained from all participants or their legal representatives.
Protocol
Clinical and anthropometrical variables, including hirsutism score, BMI, and WHR were determined by a single investigator in all subjects.
Samples were obtained between d 5 and 10 of the menstrual cycle or during amenorrhea after excluding pregnancy. After a 3-d 300-g carbohydrate diet and 12-h overnight fasting, samples were obtained for the measurement of serum IL-18, lipid profile, total testosterone, androstenedione, DHEAS, LH, FSH, estradiol, sex hormone-binding globulin (SHBG), and calculated free testosterone (20). Then, a 75-g oral glucose tolerance test was performed, and samples were obtained for measurement of serum insulin and plasma glucose at 0, 30, 60, 90, and 120 min. Samples were immediately centrifuged, and serum was separated and frozen at -20 C until assayed.
Serum IL-18 levels were measured by ELISA (Human IL-18 ELISA Kit, Medical & Biological Laboratories Co. Ltd., Nagoya, Japan) with a lower limit of detection of 12.5 pg/ml and mean intra- and interassay coefficients of variation of 7.3 and 7.5%, respectively. The technical characteristics of the assays employed for plasma glucose, lipid profile, and serum hormone measurements have been described elsewhere (7, 8, 9, 21). The composite insulin sensitivity index (ISI) was calculated from the circulating glucose and insulin concentrations during the oral glucose tolerance test according to Matsuda and DeFronzo (22).
Statistical analysis
Data are represented as means ± SD unless otherwise stated. Variables were tested for normality using the Kolmogorov-Smirnov statistic. Logarithmic or square root transformations were applied as needed to ensure normal distribution of the variables.
Data were submitted to a full-factorial multivariate general linear model (GLM) to reduce the probability of a type 1 error (i.e. the probability of finding significant differences after repeating multiple tests simply by chance), considering the large number of variables studied here (23).
Dependent variables included hirsutism score, WHR, mean blood pressure, ISI, serum IL-18 concentrations, serum glucose and lipid levels, and hormone concentrations. Independent variables were obesity and PCOS. The interaction of both independent variables was also analyzed. Because the controls were older compared with the PCOS patients, age was introduced as a covariate. The GLM also calculated the univariate analysis for all the dependent variables.
Correlation analysis, linear regression analysis, 
2 tests, and Fisher’s exact tests were also used as described below. Statistical analyses were performed using SPSS 10 for the Macintosh (SPSS Inc., Chicago, IL). P < 0.05 was considered statistically significant.
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Results |
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2 = 0.336 and P = 0.657 for obesity, and 2 = 0.018 and P = 1.0 for smoking).
The multivariate GLM analysis detected differences in the dependent variables between PCOS patients and controls (Wilks’ 
= 0.299; F = 7.711; P < 0.0001) and between obese and lean women (Wilks’ = 0.562; F = 2.559; P < 0.002). However, there was no statistically significant interaction between PCOS and obesity (Wilks’ = 0.816; F = 0.741; P = 0.776; observed power, 0.503), and although the relatively small sample size precluded a definite conclusion, this lack of statistically significant interaction suggested that the influence of PCOS on the variables studied here was not different in lean women compared with obese women and that the influence of obesity on the variables studied here was the same in the PCOS and control groups. Because of the inclusion of age as a covariate, all analyses were corrected for the difference in age between PCOS patients and healthy controls.
The univariate analyses are shown in Fig. 1
and Tables 1 and 2. Serum IL-18 concentrations were increased in lean and obese PCOS patients compared with their nonhyperandrogenic counterparts (P = 0.031), and obese women presented with increased IL-18 levels (P = 0.018) irrespective of the presence or absence of PCOS (Fig. 1). In other words, our data suggest that both PCOS and obesity were independently associated with an increase in serum IL-18 levels.
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, and the analysis of obese subjects compared with lean women is shown in Table 2.
PCOS patients presented with increased hirsutism scores, total testosterone, free testosterone, DHEAS, and androstenedione levels, whereas SHBG and estradiol concentrations were reduced. There was an almost significant increase in mean blood pressure in PCOS patients. No significant differences were observed between PCOS patients and controls in LH and FSH levels and in serum lipid concentrations (Table 1).
The ISI was reduced, and fasting and postload serum insulin was increased, in PCOS patients compared with controls. Therefore, in our series, having PCOS is equivalent to being insulin resistant independently of the degree of obesity. The WHR showed a small but highly significant increase in PCOS patients, and this increase in WHR may be related to the insulin resistance of these women (Table 1).
The effect of obesity on the individual variables was also evaluated by the GLM analysis. The BMI was 35.8 ± 6.4 kg/m2 in the obese subgroup (n = 60) and 22.7 ± 2.7 kg/m2 in the lean subgroup (n = 34). Obese women were older than lean subjects (28.9 ± 8.0 yr vs. 25.5 ± 7.0; P = 0.041), yet the comparisons between the obese and lean groups were corrected for the difference in age because of the inclusion of age as a covariate in the GLM.
Obese women presented with increased free testosterone levels, whereas hirsutism scores and SHBG and high-density lipoprotein (HDL) concentrations were reduced, compared with lean women. No significant differences were observed in mean blood pressure; total testosterone, androstenedione, DHEAS, LH, FSH, and estradiol levels; or cholesterol, low-density lipoprotein (LDL), and triglycerides. The ISI was reduced, and the WHR and fasting glucose and insulin levels were higher, in obese women compared with lean women (Table 2).
Considering PCOS patients and control women as a whole, serum IL-18 concentrations correlated weakly, after logarithmic transformation, with BMI, WHR, and total testosterone levels and inversely with the ISI (Fig. 2). No correlation was observed with age and with estradiol levels (data not shown).
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, type 2 TNF receptor, and soluble intercellular adhesion molecule-1 were also measured. In these subjects, serum IL-18 concentrations correlated weakly, after logarithmic transformation, with the logarithms of serum CRP (r = 0.35; P < 0.005), serum type 2 TNF receptor (r = 0.44; P < 0.001), and soluble intercellular adhesion molecule-1 (r = 0.43; P < 0.001) but not with the logarithm of serum IL-6 (r = 0.24; P = 0.054) or with serum TNF- levels (r = 0.22; P = 0.078).
Linear regression analysis, including serum IL-18 concentrations after logarithmic transformation as the dependent variable and stepwise (probability of F to enter 
0.05; probability of F to remove 
0.10) introduction of BMI, WHR, ISI, and total testosterone levels as independent variables, showed that BMI and the WHR determined 18.3% of serum IL-18 concentrations [log(IL-18) = 1.778 + 0.007 x BMI in kg/m2 + 0.520 x WHR; R2 = 0.183; F = 10.2; P < 0.0005], whereas ISI and total testosterone levels were removed from the regression equation. Therefore, serum IL-18 levels appear to be determined both by overall and by visceral adiposity, the latter possibly explaining the increased levels found in PCOS patients, who had increased WHR and were insulin resistant compared with controls, independently of obesity.
Serum IL-18 levels were a strong predictor of cardiovascular death in patients with angina (15), but precise IL-18 cutoff values have not been provided for this association. The risk for future cardiovascular death in patients with angina increased with each quartile increase in serum IL-18 concentrations, the upper two quartiles of IL-18 having the highest probability of death from cardiovascular causes (15). To evaluate whether the magnitude of the increase in serum IL-18 levels found in our PCOS and obese women puts them in a high cardiovascular risk group, we have analyzed the distribution of PCOS patients compared with controls and of obese women compared with lean women, according to the different IL-18 quartiles. PCOS patients were more frequently in the upper quartiles compared with controls (Table 3). Although a similar tendency was observed for obese women compared with lean individuals, this tendency did not reach statistical significance (Table 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our present results confirm and expand preliminary data from Esposito et al. (16) showing that the increase in IL-18 levels found in obese women correlated with surrogate markers of insulin resistance such as fasting insulin and WHR. In our series, serum IL-18 concentrations were determined by obesity, but especially by visceral adiposity, which was increased both in PCOS patients compared with controls and in obese women compared with lean individuals. These increases in visceral adiposity were associated with decreased insulin sensitivity. Of note, we have assessed insulin resistance from glucose and insulin levels obtained during a standard 75-g oral glucose tolerance test, a method that, although less accurate than the euglycemic hyperinsulinemic clamp, is much more precise than the measurement of fasting glucose and insulin levels used in previous reports (16).
The relationships of serum IL-18 levels with obesity and with insulin resistance may be a particularly useful characteristic of IL-18 as a cardiovascular inflammatory marker, given that other serum inflammatory markers, such as CRP and IL-6, were mainly dependent on obesity, but not on insulin resistance, in a preliminary report of our series of PCOS patients and controls (11). However, the relationship between inflammatory cardiovascular risk markers and insulin resistance may be gender specific (25), and therefore our present and previous results should be applied only to premenopausal women.
IL-18 is a pleiotropic proinflammatory cytokine that induces the production of TNF- (12), and this action results secondarily in synthesis of IL-6 (13) and CRP (14). However, serum IL-18 concentrations only correlated weakly with serum CRP, and not with serum IL-6, in the subset of patients previously tested for other inflammatory markers, suggesting distinct mechanisms in the relationship between IL-18, PCOS, insulin resistance, and obesity. Considering that IL-18 is an early mediator in the inflammatory pathway, we can speculate that serum IL-18 levels might be a sensitive marker of the chronic inflammatory process underlying insulin resistance, in contrast with other cardiovascular risk markers such as serum CRP or IL-6 concentrations, that depend mostly on obesity (11) in conceptual agreement with the contribution of adipose tissue to the secretion of inflammatory cytokines.
The correlations of IL-18 levels with BMI and WHR observed in our study also suggest that IL-18 may be produced by adipose tissue, especially by omental fat (16). Therefore, it is also possible that the increased serum IL-18 concentrations present in PCOS women are only a consequence of the predominant visceral deposition of fat associated with the syndrome, rather than having any pathogenic role. Yet we are not aware that to date, IL-18 secretion by adipose tissue has been explored or reported elsewhere, and this possibility needs to be addressed by future studies.
Finally, mounting evidence suggests that IL-18 is involved in the pathogenesis of atherosclerosis (26, 27, 28) and may serve as a cardiovascular risk marker (15, 16, 17, 29). Although the definite demonstration of increased cardiovascular morbidity and mortality in PCOS women is still pending (30), cardiovascular risk factors cluster in these patients (31), and increased prevalence of coronary artery calcification (32), carotid atherosclerosis (33, 34), and impairment in carotid viscoelastic properties (35) have been reported in PCOS. Therefore, the increase in serum IL-18 concentrations associated with PCOS might be related to the presence of subclinical atherosclerosis in these women.
In summary, PCOS and obesity result in increased serum IL-18 concentrations. The finding of increased circulating IL-18 might be explained by several hypotheses, which are not mutually exclusive. 1) Adipose tissue, especially visceral fat, might produce IL-18, explaining the increase in serum IL-18 levels present in PCOS patients, who have visceral adiposity when compared with controls, and also the increase in obese women when compared with lean subjects. 2) Given the substantial evidence indicating that inflammatory cytokines act through paracrine and autocrine mechanisms to induce insulin resistance (36, 37), IL-18 might also be involved in the pathogenesis of insulin resistance, explaining the increase in PCOS patients (who are insulin resistant). 3) The increase in serum IL-18 levels might result from early atherosclerotic changes, not yet clinically evident because of the young age of the participants in our study. 4) As reported for TNF-, type 2 TNF receptor, IL-6, and gp130 (7, 8, 9, 10), genetic variability in the gene encoding IL-18 (38) might be related to PCOS, obesity, and insulin resistance.
In conclusion, PCOS and obesity induce an increase in serum IL-18 levels, which are also associated with several indexes of global and visceral adiposity and with insulin resistance. The precise mechanisms underlying these associations require additional studies.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CRP, C-reactive protein; DHEAS, dehydroepiandrosterone-sulfate; GLM, general linear model; HDL, high-density lipoprotein; ISI, insulin sensitivity index; LDL, low-density lipoprotein; PCOS, polycystic ovary syndrome; WHR, waist-to-hip ratio.
Received August 5, 2003.
Accepted October 31, 2003.
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References |
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, P = 0.018 between obese and lean women. No statistically significant interaction between PCOS and obesity was observed, suggesting that the influence of PCOS on serum IL-18 concentrations studied here was not different in lean women compared with obese women and that the influence of obesity on serum IL-18 concentrations was the same in the PCOS and control groups.