Published on November 22, 2007
PLASMA ADIPONECTIN & RESISTIN And INSULIN RESISTANCE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME : PLASMA ADIPONECTIN & RESISTIN And INSULIN RESISTANCE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME BCLF, 04-07 September 2007, Antalya, Turkey Mine Yavuz Taslipinar1, Nedret Kilic2, Nilufer Bayraktar3, Ismail Guler4, Ebru Ofluoglu2, Hatice Pasaoglu2, Ozdemir Himmetoglu4: Mine Yavuz Taslipinar1, Nedret Kilic2, Nilufer Bayraktar3, Ismail Guler4, Ebru Ofluoglu2, Hatice Pasaoglu2, Ozdemir Himmetoglu4 1Department of Biochemistry, Etlik Ihtisas Hospital, Ankara, Turkey 2Department of Biochemistry, Gazi University Medical Faculty, Ankara, Turkey 3Biochemistry Laboratory, Baskent University Hospital, Ankara, Turkey 4Department of Obstetrics and Gynecology, Gazi University Medicine Faculty, Ankara, Turkey POLYCYSTIC OVARY SYNDROME (PCOS): POLYCYSTIC OVARY SYNDROME (PCOS) PCOS is the most common endocrine disorder in women of reproductive age It is defined by ; hyperandrogenism chronic anovulation and/or polycystic ovaries PCOS Research Diagnostic Criteria (National Instıtutes of Health, April, 1990) : PCOS Research Diagnostic Criteria (National Instıtutes of Health, April, 1990) Prevalence : Prevalence It affects 4-8% of women of reproductive age 30% of women with seconder amenorrhoea 75% of women with oligomenorrhoea 90% of women with hirsutism Because of this high prevalance values, diagnosis and treatment of PCOS is important Pathogenesis : Pathogenesis Although the syndrome was described more than half a century ago, the underlying cause of the disorder continues to be uncertain. Several theories have been proposed to explain the pathogenesis of PCOS Tsilchorozzidou et al. The pathophysiology of polycystic ovary syndrome, Clin Endocrinol, 2004 LH theory Ovarian theory Insulin theory Insulin Theory: Insulin Theory Insulin decreased effect at target cell Insulin Resistance (IR) Insulin receptor down regulation Hyperinsulinemia Polycystic ovary syndrome frequently is associated with IR accompanied by compensatory hyperinsulinemia, and IR is enhanced by the interaction between obesity and the syndrome Burghen GA et al. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1990;50:113– 6. Hyperinsulinemia is thought to result in increased androgen biosynthesis and decreased levels of sex-hormone-binding globulin (SHBG), thus playing a major role in the pathogenesis of hyperandrogenism Slide8: In addition to reproductive morbidity, insulin resistance and the resultant hyperinsulinism put patients at risk for long-term metabolic disorders such as diabetes, hypertension, dyslipidemia, and atherosclerosis Nestler JE. Insulin regulation of human ovarian androgens. Hum Reprod 1997;12(Suppl):53– 62 Slide9: IR, together with dyslipidaemia, impaired glucose tolerance, type 2 diabetes mellitus, and elevated systolic blood pressure, which are more prevalent in obese young women with PCOS than in weight matched controls, suggest that women with PCOS are at an increased risk of cardiovascular disease (CVD) A. Dunaif, Insulin resistance and the polycystic ovary syndrome: Mechanisms and implications for pathogenesis, Endocr. Rev. 18 (1997) 774–800 Adiponectin and Resistin: Adiponectin and Resistin The adipose tissue not only stores triglycerides as a source of energy but also is considered to be an endocrine organ that supervises energy metabolism through the expression of a variety of genes of secretory proteins as adiponectin and resistin Slide11: Adiponectin is a protein of 247 amino acids consisting of four domains, with a molecular weight of 30 kDa (adipocyte complement-related protein of 30 kd / Acrp 30) It belongs to a collagen superfamily sharing significant homology with collagen X and VIII, complement factor C1q, and tumor necrosis factor-alpha. It is product of human apM1 gene which is expressed exclusively in white adipose tissue Adiponectin is believed to have insulin-sensitizing, anti-atherogenic, and anti-inflammatory actions Stefan N, Stumvoll M. Adiponectin—its role in metabolism and beyond. Horm Metab Res 2002;34:469 –74. Kazumi T, Kawaguchi A, Sakai K, Hirano T, Yoshino G. Young men with high-normal blood pressure have lower serum adiponectin, smaller LDL size, and higher elevated heart rate than those with optimal blood pressure. Diabetes Care 2002;25:971– 6. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinaemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930 –5. Slide12: Circulating concentrations of adiponectin were decreased in subjects with obesity, type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease as compared with healthy individuals Hotta K et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000;20:1595–9. Matsubara M et al. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002;87:2764 –9. Kazumi T et alYoung men with high-normal blood pressure have lower serum adiponectin, smaller LDL size, and higher elevated heart rate than those with optimal blood pressure. Diabetes Care 2002;25:971– 6. Arita Y et al. Paradoxical decrease of an adipose-specific protein, adiponectin in obesity. Biochem Biophys Res Commun 1999;257:79–83. Slide13: Animal studies indicate the role of adiponectin as an important endogenous insulin sensitizer Impaired insulin sensitivity has been observed in adiponectin knock-out mice Administration of adiponectin to obese or diabetic mice reduces glucose excursion and improves insulin sensitivity Slide14: Women with PCOS are at high risk for developing type 2 diabetes Adiponectin levels have been reported to be lower in patients with type 2 diabetes There are limited data on the role of adiponectin in women with PCOS. Slide15: Resistin, a peptide hormone produced by adipocytes and macrophages, has the opposite effects to adiponectin on insulin sensitivity While the expression of adiponectin mRNA is reduced in obesity and in insulin resistant states, that of resistin is increased suggesting an association between the two adipokines in these states Slide16: Resistin, a novel 12.5 kDa cysteine-rich protein, is secreted by adipocytes, too. Serum resistin levels are significantly increased in insulin-resistant mice and genetic or diet-induced obese mice In addition, neutralization of endogenous resistin with antibodies significantly suppresses hyperglycaemia in diet-induced obese mice by improving insulin sensitivity Steppan et al., 2001 Slide17: Considering the association of PCOS with impaired glucose tolerance, diabetes mellitus, and atherosclerosis as well as inconsistent evidence with regard to adipocytokins as a possible link between IR; this study was performed to assess the adiponectin and resistin concentrations in women with the PCOS and age and weight matched healthy controls Material & Method : Material & Method Slide19: Study centers, GÜ Faculty of Medicine, Medical Biochemistry Department GÜ Faculty of Medicine, Obstetrics and Gynecology Department Twenty-five patients with PCOS were participated in this study. Study Cases: The diagnosis of PCOS was made by the presence of anovulation accompanied by hyperandrogenism after excluding other conditions that could present in a similar fashion Polycystic ovaries were defined, using ultrasound, by the presence of two or more of the following criteria: enlarged ovarian volume (>9 ml), 10 or more follicles 2–10 mm in diameter, and increased density and volume of stroma Adams et al., 1986; Polson et al.,1988 Study Cases Study Cases: Study Cases Patients with DM, hyperprolactinaemia, congenital adrenal hyperplasia, thyroid disorders, Cushing disease, hypertension, hepatic or renal dysfunction were excluded from the study Twenty-five age- and weight-matched healthy persons with regular ovulatory cycles were formed to serve as the control group The ethics committee of Gazi University, Faculty of Medicine in Ankara, Turkey approved the study protocol. All patients signed informed consent forms Methods : Height and weight were measured and the BMI was calculated in all patients and controls After a high carbohydrate diet for 3 days, a standard oral glucose tolerance test (OGTT) was performed Methods Methods: Methods Glucose Hexokinase method Cholesterol Cholesterol esterase method HDL Fotometric method Trigliseride Fotometric method LDL Friedewald calculation LDL-K= Total Chol-[ (HDL)+(VLDL)-TRG/5 ] BUN Enzimatic urease method Creatinin Picrate reaction Albumin Bromcresol green reaction Insulin, LH, FSH, T.Testosteron, PRL Chemilumminesans Estradiol, progesteron, DHEA-SO4 immunoassay method Serum total estriol, S.Testosteron, Radioimmunoassay (RIA) androstenedion, 17a-OH progesteron, OGTT and HOMA-IR (oral glucose tolerance test & homeostasis model insulin resistance index): OGTT and HOMA-IR (oral glucose tolerance test & homeostasis model insulin resistance index) A 2 h oral glucose tolerance test (OGTT) with 75 g of glucose load was performed after an overnight fast . Four blood samples were collected at 0, 30, 60 and 120 min and the plasma stored at -20°C until assayed for glucose and insulin. The homeostasis model (HOMA) insulin resistance index was calculated using the formula: Fasting Plasma Glucose X Fasting Serum Insulin / 405 Adiponectin and Resistin Assay : Adiponectin and Resistin Assay The resistin (HUMAN) ELISA kit was purchased from Phoenix Pharmaceuticals Inc. (USA) Adiponectin (HUMAN) ELISA kit was purchased from AviBion Orgenium Laboratories (Fınland) Statistics : Results are presented as means SD, and data were analyzed by using SPSS statistical package, version 10.0 for Windows (SPSS Inc., Chicago, IL) Differences between the PCOS and control groups were compared by Mann-Whitney U test Bivariate correlation analysis (calculation of Spearman’s coefficient) was used to assess the correlation between fasting plasma adiponectin and resistin and insulin resistance p<0.05 was considered significant Statistics Results & Conclusion : Results & Conclusion Table 1. Clinical features of groups: Table 1. Clinical features of groups b p>0.05 Table 2. Comparisons of patients and controls: Table 2. Comparisons of patients and controls aP<0,05 Slide30: Our present results demonstrate that PCOS patients in our study have hypoadiponectinaemia and this finding is possibly independent of the degree of obesity On the contrary, serum resistin levels are not different in PCOS patients Slide31: In most PCOS patients, obesity probably represents a secondary additional pathogenetic condition Obesity may effect cardiovascular, endocrine and metabolic features of patients with PCOS We could not exclude all obese patients in our study although we watched to choose control group not to give significant difference between BMI We found significantly higher HOMA values in PCOS group compared to controls, although BMI of the groups were not differ from each other Slide32: Resistin might therefore be expected to play a role in PCOS, and plasma levels in these patients might be expected to be elevated However, we found that plasma resistin levels in PCOS did not differ from those in normal cycling women of a similar age and with a similar BMI as similar with most previous studies showing no significant increase in serum resistin levels in PCOS patients Panidis et al., 2004; Seow et al., 2004, 2005; Carmina et al., 2005; Lu et al., 2005 Slide33: But, we showed that there was a positive correlation between resistin and HOMA To date, there was no conclusive evidence of a correlation between serum resistin and insulin resistance indices Slide34: In our study, we did not observe a direct correlation between adiponectin and multiple measures of insulin resistance (fasting insulin, HOMA-IR) But we reported a negative correlation between plasma adiponectin/resistin ratio and IR indices assessed in women with the PCOS Slide35: Currently, only a few studies on resistin and adiponectin levels in the PCOS have been published In view of the cardiovascular risk in women with the PCOS, we suggest that assessment of the adiponectin-to-resistin ratio might be potentially useful in prediction of the future cardiovascular risk in women with the polycystic ovary syndrome.