Treatment of Polycystic Ovary Syndrome (PCOS) with Metformin Ameliorates Insulin Resistance in Parallel with the Decrease of Serum Interleukin-6 Concentrations

Abstract

Low-grade chronic inflammation underlies the pathogenesis of insulin-resistant disorders such as polycystic ovary syndrome (PCOS). We aimed to study if the changes observed in the insulin sensitivity of PCOS patients during treatment with oral contraceptives or metformin associate changes in the serum inflammatory markers interleukin-6 (IL-6) and interleukin-18 (IL-18). In a randomized open-label clinical trial (NLM Identifier NCT00428311), 34 PCOS patients were allocated to receive oral treatment with metformin (850 mg twice daily) or with the Diane³⁵ Diario contraceptive pill (35 μg of ethynylestradiol plus 2 mg of cyproterone acetate) for 24 weeks. Changes in serum IL-6 and IL-18 levels and insulin sensitivity index were monitored throughout the study. Eighteen women without hyperandrogenism served as controls for serum interleukin concentrations. PCOS women treated with metformin showed a decrease in IL-6 levels throughout the study compared with women treated with Diane³⁵ Diario (−33% change vs. +23% change, F=3.709, p=0.048; intention-to-treat analysis: F=5.569, p=0.011). There were no statistically significant changes in IL-18 concentrations with any treatment. The decrease in IL-6 levels in women receiving metformin occurred in parallel to the increase in the insulin sensitivity index (r=−0.579, p=0.048; intention-to-treat analysis, r=−0.687, p=0.001). In conclusion, serum IL-6 levels decreased during treatment with metformin in parallel to amelioration of insulin resistance, whereas oral contraceptives slightly increased circulating IL-6 levels without changing insulin sensitivity. Both drugs had a neutral effect on serum IL-18 concentrations.

Key words

hyperandrogenism - insulin resistance - insulin sensitizers - oral contraceptives - inflammation

References

• 1 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report.  Fertil Steril. 2009;  91 456-488
• 2 Escobar-Morreale HF, San Millan JL. Abdominal adiposity and the polycystic ovary syndrome.  Trends Endocrinol Metab. 2007;  18 266-272
• 3 Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.  Endocr Rev. 2005;  26 251-282
• 4 Alvarez-Blasco F, Botella-Carretero JI, San Millan JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women.  Arch Intern Med. 2006;  166 2081-2086
• 5 Luque-Ramírez M, Alpañés M, Escobar-Morreale HF. The determinants of insulin sensitivity, beta-cell function, and glucose tolerance are different in patients with polycystic ovary syndrome and in women who do not have hyperandrogenism.  Fertil Steril. 2010 Jan 22;  . [Epub ahead of print]
• 6 Escobar-Morreale HF. Polycystic ovary syndrome: treatment strategies and management.  Expert Opin Pharmacother. 2008;  9 2995-3008
• 7 Papanicolaou DA, Vgontzas AN. Interleukin-6: the endocrine cytokine.  J Clin Endocrinol Metab. 2000;  85 1331-1333
• 8 Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.  J Clin Endocrinol Metab. 1997;  82 4196-4200
• 9 Escobar-Morreale HF, Villuendas G, Botella-Carretero JI, Sancho J, San Millan JL. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women.  Diabetologia. 2003;  46 625-633
• 10 Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes.  Diabetes. 2002;  51 3391-3399
• 11 Escobar-Morreale HF, Calvo RM, Villuendas G, Sancho J, San Millan JL. Association of polymorphisms in the Interleukin 6 receptor complex with obesity and hyperandrogenism.  Obes Res. 2003;  11 987-996
• 12 Villuendas G, San Millan JL, Sancho J, Escobar-Morreale HF. The –597 G/A and –174 G/C polymorphisms in the promoter of the interleukin 6 gene (IL6) are associated with hyperandrogenism.  J Clin Endocrinol Metab. 2002;  87 1134-1141
• 13 Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K. Interleukin-18: a novel cytokine that augments both innate and acquired immunity.  Adv Immunol. 1998;  70 281-312
• 14 Escobar-Morreale HF, Botella-Carretero JI, Villuendas G, Sancho J, San Millan JL. Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity.  J Clin Endocrinol Metab. 2004;  89 806-811
• 15 Zhang YF, Yang YS, Hong J, Gu WQ, Shen CF, Xu M, Du PF, Li XY, Ning G. Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome.  Endocrine. 2006;  29 419-423
• 16 Chandrasekar B, Patel DN, Mummidi S, Kim JW, Clark RA, Valente AJ. Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation.  J Biol Chem. 2008;  283 4200-4209
• 17 Yang YS, Li XY, Hong J, Gu WQ, Zhang YF, Yang J, Song HD, Chen JL, Ning G. Interleukin-18 enhances glucose uptake in 3T3-L1 adipocytes.  Endocrine. 2007;  32 297-302
• 18 Luque-Ramirez M, Alvarez-Blasco F, Botella-Carretero JI, Martinez-Bermejo E, Lasuncion MA, Escobar-Morreale HF. Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2007;  92 2453-2461
• 19 Luque-Ramirez M, Alvarez-Blasco F, Botella-Carretero JI, Sanchon R, San Millan JL, Escobar-Morreale HF. Increased body iron stores of obese women with polycystic ovary syndrome are a consequence of insulin resistance and hyperinsulinism and are not a result of reduced menstrual losses.  Diabetes Care. 2007;  30 2309-2313
• 20 Luque-Ramirez M, Alvarez-Blasco F, Uriol Rivera MG, Escobar-Morreale HF. Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin.  Hum Reprod. 2008;  23 1594-1601
• 21 Luque-Ramirez M, Alvarez-Blasco F, Escobar-Morreale HF. Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients.  Obesity (Silver Spring). 2009;  17 3-9
• 22 Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF. Effects of metformin versus ethinyl-estradiol plus cyproterone acetate on ambulatory blood pressure monitoring and carotid intima media thickness in women with the polycystic ovary syndrome.  Fertil Steril. 2009;  91 2527-2536
• 23 Luque-Ramirez M, Mendieta-Azcona C, del Rey Sanchez JM, Maties M, Escobar-Morreale HF. Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking.  Eur J Endocrinol. 2009;  160 469-480
• 24 Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR Polycystic ovary syndrome. Boston: Blackwell Scientific Publications; 1992: 377-384
• 25 Pall ME, Lao MC, Patel SS, Lee ML, Ghods DE, Chandler DW, Friedman TC. Testosterone and bioavailable testosterone help to distinguish between mild Cushing's syndrome and polycystic ovarian syndrome.  Horm Metab Res. 2008;  40 813-818
• 26 Escobar-Morreale HF, Sanchon R, San Millan JL. A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs.  J Clin Endocrinol Metab. 2008;  93 527-533
• 27 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care. 1999;  22 1462-1470
• 28 Tai MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves.  Diabetes Care. 1994;  17 152-154
• 29 Diamanti-Kandarakis E, Paterakis T, Alexandraki K, Piperi C, Aessopos A, Katsikis I, Katsilambros N, Kreatsas G, Panidis D. Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin.  Hum Reprod. 2006;  21 1426-1431
• 30 Ibanez L, de Zegher F. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of metformin at the start and after more than one year of therapy.  J Clin Endocrinol Metab. 2005;  90 39-43
• 31 Tsilchorozidou T, Mohamed-Ali V, Conway GS. Determinants of interleukin-6 and C-reactive protein vary in polycystic ovary syndrome, as do effects of short- and long-term metformin therapy.  Horm Res. 2009;  71 148-154
• 32 Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schonbeck U, Libby P. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells.  Arterioscler Thromb Vasc Biol. 2006;  26 611-617
• 33 LaPensee CR, Hugo ER, Ben-Jonathan N. Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways.  Endocrinology. 2008;  149 5415-5422
• 34 Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G, Giugliano D. Weight loss reduces interleukin-18 levels in obese women.  J Clin Endocrinol Metab. 2002;  87 3864-3866

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