|Year : 2018 | Volume
| Issue : 2 | Page : 407-411
Interleukin-18 in lean polycystic ovary syndrome patients
Nabil A Elkafrawy1, Mohamed A Shabaan1, Said A Saleh2, Alaa A Dawood1, Rasha I Noor El-Din3, Shimaa K Zewain1
1 Endocrinology and Obesity Unit, Internal Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Clinical Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||25-Sep-2016|
|Date of Acceptance||13-Nov-2016|
|Date of Web Publication||27-Aug-2018|
Shimaa K Zewain
60 El-Gomhoria Street, Quesna, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of the study was to evaluate interleukin-18 (IL-18) levels in lean patients with polycystic ovary syndrome (PCOS).
PCOS is one of the common causes of infertility in women. Several studies have attempted to find the etiology and pathophysiology but with no definitive theory to date. Insulin resistance with obesity was considered a causative factor for a long period of time. In recent times researchers have been considering PCOS as a chronic low inflammatory state with subsequent elevation of inflammatory markers, which were correlated with the disease at different stages as diagnostic, staging, prognostic, or predictor markers.
Materials and methods
Between September 2015 and May 2016 this multidisciplinary prospective observational study recruited 20 consecutive lean patients (BMI < 25 kg/m2) who presented with infertility disorder at the obstetrics and gynecology clinic and were diagnosed with PCOS according to Rotterdam criteria. Patients with hypertension, diabetes mellitus, and fever within the last 3 weeks, or were currently smokers, or were receiving statins, aspirins, corticosteroids, and insulin-sensitizing drugs were excluded. An endocrinologist assessed the patients, and anthropometric measures were collected. Also, blood samples were collected and sent for estimation of lipid profile, insulin assessment, and IL-18.
Our study included 20 nonsmoker, nondiabetic, and nonhypertensive lean PCOS patients of a mean age of 24.7 years, mean BMI of 23, and mean waist-to-hip ratio of 0.8. The mean systolic blood pressure was 106.5 and the mean diastolic blood pressure was 70. Glucose homeostasis indices revealed mean fasting blood glucose of 84.9 with a mean fasting insulin of 14.2 and homeostatic model assessment (HOMA-IR) of 2.97. Mean IL-18 was 315.
Despite previous studies associating high IL-18 levels with obesity related to PCOS, we found that IL-18 is elevated in lean PCOS patients as well, revealing chronic low inflammatory state in those patients, which suggests that the pathophysiology of PCOS is not solely connected to obesity.
Keywords: interleukin-18, low inflammatory state, polycystic ovary syndrome
|How to cite this article:|
Elkafrawy NA, Shabaan MA, Saleh SA, Dawood AA, Noor El-Din RI, Zewain SK. Interleukin-18 in lean polycystic ovary syndrome patients. Menoufia Med J 2018;31:407-11
|How to cite this URL:|
Elkafrawy NA, Shabaan MA, Saleh SA, Dawood AA, Noor El-Din RI, Zewain SK. Interleukin-18 in lean polycystic ovary syndrome patients. Menoufia Med J [serial online] 2018 [cited 2018 Sep 19];31:407-11. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/407/239733
| Introduction|| |
Complex endocrine signaling between the brain and the ovaries is crucial for regulating and maintaining the female reproductive system. Abnormal levels of reproductive hormones often result in cycle irregularities . For instance, polycystic ovary syndrome (PCOS) accounts for 90–95% of women attending infertility clinics with anovulation, and biochemical hyperandrogenemia and clinical manifestations of hyperandrogenemia are principal features of PCOS .
PCOS is the most common complex endocrine disorder, affecting 4–12% of women of fertile age around the world. Recent studies have cited its prevalence to be as high as 12–21% . According to the Rotterdam criteria and National Institute of Health criteria, hyperandrogenism, chronic anovulation, and polycystic ovaries on ultrasonography are the three main clinical features of PCOS patients. PCOS is a complex heterogeneous disease, with obesity, insulin resistance, and metabolic syndrome being common in afflicted women .
Several studies suggest that chronic low-grade inflammation in PCOS is an important risk factor for long-term metabolic disorders, cardiovascular complications, and ovarian dysfunction. Moreover, there is a strong association between hyperandrogenism, insulin resistance, and abdominal obesity with inflammation in PCOS. Those studies considered PCOS as a proinflammatory state .
Many studies reported that in both lean and obese PCOS patients, circulating markers of low-grade inflammation are elevated, suggesting that inflammation can promote insulin resistance, atherosclerosis, and other pathologies associated with PCOS. In contrast, others have found that the accumulation of adipose tissue rather than the presence of PCOS is the primary cause of the proinflammatory response. Therefore, additional investigation is necessary to identify the specific contribution of PCOS to the development of the low-grade inflammatory response identified in these patients. The detection of a preclinical inflammatory process would be a useful prognostic and therapeutic monitoring tool for PCOS patients .
| Materials and Methods|| |
After obtaining the approval of the Menoufia Ethical Committee, between September 2015 and May 2016 a prospective observational study was conducted in Menoufia University Hospitals in a multidisciplinary clinic including a gynecologist and an endocrinologist and preliminary results were collected.
Twenty consecutive lean patients (BMI <25 kg/m 2) who presented at the clinic with infertility disorders were recruited for the study after exclusion of patients with diabetes mellitus, hypertension, family history of coronary artery disease, any known vascular, infectious or inflammatory diseases, using any medication (e.g., insulin-sensitizing drugs, statins, aspirin, and corticosteroids) in the preceding 3 months, currently smoking, or had fever and/or any inflammatory or infectious disorders within the previous 3 weeks.
After complete history taking, the endocrinologist examined every patient and collected anthropometric data such as height, weight, BMI, waist, hip, and waist-to-hip ratio (WHR). All measurements were taken when the patients were in the standing position with their feet together, abdomen relaxed, and arms at their sides. Waist circumference of the subjects was measured with the participants in the standing position by placing a soft tape measure midway between the lowest rib and the iliac crest. Hip circumference was measured at the level of the great trochanters.
WHR was calculated as waist circumference divided by hip circumference, and the BMI was calculated as body weight in kilograms divided by height in meters squared (kg/m 2).
Systolic and diastolic blood pressures were recorded, and patients were assessed for hirsutism. Hirsutism is defined as excess terminal hair that commonly appears in a male pattern in women. We used the most widely recognized scoring method, the Ferriman–Gallwey scale.
Ultrasound for evaluation of ovarian morphology was performed in all patients. The morphology of polycystic ovaries was considered if there were 12 or more follicles of 2–9 mm in diameter in the ovary and/or there was an enlarged ovary (>10 cm 3).
Diagnosis of PCOS was made on the basis of the criteria indicated by the Rotterdam Workshop – namely, by the presence of at least two of the following three features: (a) clinical hyperandrogenism (diagnosed by the presence of hirsutism); (b) chronic oligoanovulation [diagnosed by the presence of oligomenorrhea (fewer than nine cycles per year)]; and (c) PCOS morphology, after exclusion of secondary causes.
Patients were sent to our clinical pathologist to provide blood samples. Those samples were collected after a 12-h overnight fast. Samples were immediately centrifuged, serum was separated, and fasting blood glucose (FBS) was measured. Fasting insulin was assessed and insulin resistance by the homeostatic model assessment (HOMA-IR) was estimated: (glucose × insulin)/22.5. Insulin concentration is reported in μU/l and glucose in mmol/l. The constant of 22.5 is a normalizing factor. Lipid profile, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and finally interleukin-18 (IL-18), was measured using enzyme-linked immunosorbent assay.
The lipid accumulation product (LAP), a novel index of central lipid accumulation, predicts the risk for metabolic syndrome. LAP was calculated as [waist circumference (cm) − 58] × [triglyceride concentration (mmol/l)]. The formula includes the minimum sex-specific waist circumference of 58 cm for women.
All anthropometric data and serum measurements were collected. Being quantitative variables, they were expressed as mean (M) and SD. Statistical significance was tested using an IBM compatible computer and IBM SPSS statistics version 19 (IBM Corp. Released 2010. Armonk, NY) considering probability values less than 0.05 as statistically significant.
| Results|| |
This study was carried out with preliminary results of 20 lean (BMI <25 kg/m 2) PCOS patients selected from the endocrine and gynecological and obstetric outpatient clinics of the Menoufia University Hospital from September 2015 to May 2016.
The mean age of the participants was 24.7 ± 3.4, the mean BMI was 23 ± 1.5, the mean WHR was 0.8 ± 0.02, the mean systolic blood pressure was 106.5 ± 8.7, and the mean diastolic blood pressure was 70 ± 8.1 [Table 1].
The lipid profile of the studied patients showed abnormalities as the mean total cholesterol was 163.4 ± 28.4, the mean HDL was 50.4 ± 5.7, the mean LDL was 99.2 ± 35.6, the mean triglycerides was 99.1 ± 46.7, and the mean LAP was 21.9 ± 19.5 [Table 2].
Concerning the parameters for insulin resistance and IL-18, the study participants were normoglycemic (the mean FBS was 84.9 ± 4.2), but we detected disturbed insulin resistance parameters as the mean fasting insulin was 14.2 ± 1 and the mean HOMA-IR was 2.97 ± 0.3. Finally, the mean IL-18 of the included participants was 315 ± 42.2 [Table 3].
| Discussion|| |
PCOS is the most common cause of infertility in women of reproductive age. It is a multifactorial disorder presenting with major features such as hyperandrogenism, hyperinsulinemia, obesity, insulin resistance, anovulation, and cystic follicles in the ovary .
The fundamental defect that causes PCOS remains elusive, but the pathogenesis is likely multifactorial in origin. Insulin resistance and compensatory hyperinsulinemia are important in the pathogenesis of PCOS. Although the cellular and molecular mechanisms of insulin resistance in patients with PCOS have been investigated extensively, the exact mechanisms remain unknown .
PCOS is a proinflammatory state. There are numerous studies in the literature reporting elevations of circulating inflammatory molecules in PCOS. It remains unclear whether their elevations are related to PCOS itself or are a function of obesity and/or abdominal adiposity .
We conducted our study to evaluate IL-18 levels in lean patients with PCOS. We assessed 20 lean PCOS patients. The mean age of the participants was 24.7 ± 3.4. This is in accordance with the findings of Yang et al. , who studied three groups, with the second group consisting of 29 lean PCOS patients with a mean age of 28 ± 3 years. This is an expected finding as middle-aged female patients with PCOS usually had fertility disorders forcing them to seek medical advice in their child-bearing period.
We considered BMI of 25 kg/m 2 as the cutoff point between lean and obese subjects. In our study the mean BMI of lean subjects was 23 ± 1.5, which again agrees with the study of Yang et al. , whose second group had a mean BMI of 22.1 ± 3.4.
Yang et al.  noted that 'increase visceral adiposity is characteristic finding in PCOS and play an important role in the development of insulin resistance and hyperandrogenism and increase cardiovascular mortality by mechanism including low grade inflammation and secretion of inflammatory cytokines. Central obesity as indicated by increased waist circumference and WHR has been adopted as more accurate predictor of obesity-related metabolic abnormalities'.
Therefore, we assessed the WHR in our study subjects and found the mean WHR to be 0.8 ± 0.02. This is in agreement with the findings of Lindholm et al. , whose study included a group of 10 lean PCOS patients with a mean WHR of 0.77 ± 0.77. These figures illustrate an increase in central adiposity despite leanness, and this is revealed in many studies to be the source of many cytokines that play an important role in the pathophysiology of PCOS.
It is still unclear whether women with PCOS have a higher prevalence of hypertension in comparison with reproductively healthy women. Most of our subjects were normotensive, with mean systolic blood pressure of 106.5 ± 8.7 and mean diastolic pressure of 70 ± 8.1. This is again in agreement with the study by Lindholm et al. , in whose study the mean systolic blood pressure in the lean PCOS group was 119 ± 11 and mean diastolic blood pressure group was 72 ± 9.
The lipid profile of the subjects was also assessed to evaluate metabolic hazards that accompany PCOS. We found total cholesterol in the normal range of 163.4 ± 28.4 and accepted triglycerides of 99.1 ± 46.72.3, mean LDL of 99.2 ± 35.6, and mean HDL of 50.4 ± 5.7.
Nascimento et al.  noted that BMI is the most commonly used indicator to assess obesity. This indicator evaluates generalized obesity and does not measure body fat distribution. In this respect a new index called the LAP has been proposed. When we assessed LAP in our study subjects, we found a mean LAP of 21.9 ± 19.5. So, despite we selected our subjects of lean type of PCOS patients, we got another elevated parameter disordered fat distribution with increase in central adiposity that is usually claimed in many studies for the production of many metabolic active substances and cytokines.
Insulin resistance is found in ∼50–70% of women with PCOS, which is independent of obesity and contributes to its pathogenesis. In our study, we measured FBS, fasting insulin, and HOMA-IR in the study subjects to assess insulin resistance.
We reported that despite normal levels of mean FBS of 84.9 ± 4.2 in our study subjects, they had significant increase of surrogate markers of insulin resistance as fasting insulin was 14.2 ± 1; HOMA-IR was also higher, with a mean level of 2.97 ± 0.3. These findings again emphasize the insulin resistance mechanisms involved in the pathophysiology of PCOS even in the absence of obesity, as in our study subjects.
The mean IL-18 in our patients was 315 ± 42.2. This is in agreement with the results of Yang et al. , who found a mean IL-18 of 172.5 ± 64.0 in the lean PCOS group. The results were also in concordance with those of Lindholm et al. , who reported nearly the same levels of IL-18 (215 ± 50). We detected an increase in the circulating level of IL-18 as noted in other studies, which concurs with the new theory of considering PCOS as a state of chronic low-grade inflammation rather than considering these markers as a part of the obesity process usually accompanying the PCOS.
These markers have to be studied in more detail, by correlating them with different stages and types of PCOS, to increase the probability of being used as markers in the diagnosis or prognosis of the syndrome.
| Conclusion|| |
Despite previous studies associating elevated IL-18 with obesity related to PCOS, we found that IL-18 is elevated in lean PCOS patients as well, revealing the chronic low inflammatory state in those patients, which suggests that the pathophysiology of the syndrome is not solely connected to obesity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Harris LA, Selgrade JF. Modeling endocrine regulation of the menstrual cycle using delay differential equations. Math Biosci 2014; 257
Elsayed MA, Sanad ZF, Emara MA, Hamza HA. Anti-Müllerian hormone, visceral fat, and ovarian stromal Doppler to predict response to ovulation induction in polycystic ovary syndrome. Menoufia Med J 2014, 27
Chen L, Xu WM, Zhang D. Association of abdominal obesity, insulin resistance, and oxidative stress in adipose tissue in women with polycystic ovary syndrome. Fertil Steril 2014; 102
Peng Z, Sun Y, Lv X, Zhang H, Liu C, Dai S. Interleukin-6 levels in women with polycystic ovary syndrome: a systematic review and meta-analysis. PLoS One 2016; 11
Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol 2011; 335
Marino JS, Iler J, Dowling AR, Chua S, Bruning JC, Coppari R, Hill JW. Adipocyte dysfunction in a mouse model of polycystic ovary syndrome (PCOS): evidence of adipocyte hypertrophy and tissue-specific inflammation. PLoS One 2012; 7
Pandey V, Singh A, Singh A, Krishna A, Pandey U, Tripathi YB. Role of oxidative stress and low-grade inflammation in letrozole-induced polycystic ovary syndrome in the rat. Reprod Biol 2016; 16
Lee H, Oh JY, Sung YA. Adipokines, insulin-like growth factor binding protein-3 levels, and insulin sensitivity in women with polycystic ovary syndrome. Korean J Intern Med 2013; 28
Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril 2011; 95
Yang Y, Qiao J, Li R, Li M. Is interleukin-18 associated with polycystic ovary syndrome? Reprod Biol Endocrinol 2011; 9
Lindholm Å, Blomquist C, Bixo M, Dahlbom I, Hansson T, Poromaa IS, Burén J. No difference in markers of adipose tissue inflammation between overweight women with polycystic ovary syndrome and weight-matched controls. Hum Reprod 2011; 26
Nascimento JX, Chein MB, de Sousa RM, Ferreira AD, Navarro PA, Brito LM. Importance of lipid accumulation product index as a marker of CVD risk in PCOS women. Lipids Health Dis 2015; 14
[Table 1], [Table 2], [Table 3]