Treatment with Metformin and Combination of Metformin Plus Pioglitazone on Serum Levels of IL-6 and IL-8 in Polycystic Ovary Syndrome: A Randomized Clinical Trial

Durr-e-Shewar Ali; Mohsin Shah; Asif Ali; Muhammad Omar Malik; Farhat Rehman; Haroon Badshah; Ehtesham Ehtesham; Salvatore Giovanni Vitale

doi:10.1055/a-1018-9606

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2019; 51(11): 714-722
DOI: 10.1055/a-1018-9606

Endocrine Care

Treatment with Metformin and Combination of Metformin Plus Pioglitazone on Serum Levels of IL-6 and IL-8 in Polycystic Ovary Syndrome: A Randomized Clinical Trial

Authors

Durr-e-Shewar Ali‡

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Mohsin Shah‡

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Asif Ali

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Muhammad Omar Malik

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Farhat Rehman

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Haroon Badshah

²Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
Ehtesham Ehtesham

¹Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
Salvatore Giovanni Vitale

³Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Messina, Italy

Abstract

Elevated serum levels of inflammatory mediators in conditions such as PCOS reflect a low-grade chronic inflammation and this has been attributed to be associated with insulin-resistance in PCOS. Therefore, insulin-sensitizing agents are suggested to improve both reproductive as well as metabolic aspects of PCOS. This study aimed to compare the effects of metformin taken alone with that of a combination of metformin and pioglitazone on menstrual cycle, hormonal parameters, insulin resistance, and inflammatory biomarkers in women with PCOS. One hundred and six women with PCOS participated in the study. All subjects were randomized into two-arm intervention groups (Arm 1 and 2). Participants in Arm-1 received metformin (500 mg BD) daily while those in Arm-2 a combination of metformin (500 mg BD) and pioglitazone (15 mg BD) for 12 wks. Serum levels of IL-6 and IL-8 were measured using ELISA whereas insulin resistance was assessed using HOMA-IR. At baseline women with PCOS had significantly elevated circulating concentrations of IL-6 and IL-8. Treatment decreased IL-6 in both the groups, however, only the combination group showed a significant decrease (p=0.005). Serum IL-8 level had a significant decrease after treatment in both groups (p <0.001). HOMA-IR and insulin levels also decreased in both the groups (both p <0.001). Testosterone, FSH, and prolactin significantly decreased in both groups. LH also decreased in both groups, however, the change was significant only in the combination group (p=0.013). Combination of metformin and pioglitazone therapy was more effective as compared to metformin alone in reducing the levels of IL-6 and IL-8 as well as insulin resistance in PCOS.

Key words

PCOS - IL-6 - IL-8 - insulin resistance - metformin - pioglitazone

Full Text

References

References
1 Azziz R, Woods KS, Reyna R. et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745-2749
2 McCartney CR, Marshall JC. Polycystic ovary syndrome. N Engl J Med 2016; 375: 54-64
3 Orio Jr. F, Palomba S, Cascella T. et al. The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 2-5
4 Sangeeta S. Metformin and pioglitazone in polycystic ovarian syndrome: a comparative study. J Obstet Gynecol India 2012; 62: 551-556
5 Duleba AJ, Dokras A. Is PCOS an inflammatory process?. Fertil Steril 2012; 97: 7-12
6 Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: A systematic review and meta-analysis. Hum Reprod Update 2014; 20: 748-758
7 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223-1236
8 Adashi EY. The potential relevance of cytokines to ovarian physiology. J Steroid Biochem Mol Biol 1992; 43: 439-444
9 Brannstrom M. Potential role of cytokines in ovarian physiology: The case for interleukin-1. The ovary 2004; 261-271
10 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772
11 Ridker PM, Hennekens CH, Buring JE. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843
12 Yudkin JS, Stehouwer CDA, Emeis JJ. et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol 1999; 19: 972-978
13 Festa A, D’Agostino Jr. R, Howard G. et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: 42-47
14 Wu M-H, Hsiao K-Y, Tsai S-J. Endometriosis and possible inflammation markers. Gynecol Minim Invasive Ther 2015; 4: 61-67
15 Norman RJ, Dewailly D, Legro RS. et al. Polycystic ovary syndrome. The Lancet 2007; 370: 685-697
16 Kelly CC, Lyall H, Petrie JR. et al. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001; 86: 2453-2455
17 Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: A systematic review and metaanalysis. Fertil Steril 2011; 95: 1048-1058
18 Luque-Ramirez M, Escobar-Morreale HF. Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations. Horm Metab Res 2010; 42: 815-820
19 Younis A, Hawkins K, Mahini H. et al. Serum tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1 and paraoxonase-1 profiles in women with endometriosis, PCOS, or unexplained infertility. J Assist Reprod Genet 2014; 31: 1445-1451
20 Apostolakis S, Vogiatzi K, Amanatidou V. et al. Interleukin 8 and cardiovascular disease. Cardiovasc Res 2009; 84: 353-360
21 Tanti J-F, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 2009; 9: 753-762
22 Ciaraldi TP, Aroda V, Mudaliar SR. et al. Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: Effects of pioglitazone and metformin treatment. Metabolism 2013; 62: 1587-1596
23 Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-445
24 Bergheim I, Luyendyk JP, Steele C. et al. Metformin prevents endotoxin-induced liver injury after partial hepatectomy. J Pharmacol Exp Ther 2006; 316: 1053-1061
25 Isoda K, Young JL, Zirlik A. et al. Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arterioscler Thromb Vasc Biol 2006; 26: 611-617
26 Morin-Papunen L, Rautio K, Ruokonen A. et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 4649-4654
27 Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996; 45: 1661-1669
28 Ohata Y, Harada T, Miyakoda H. et al. Serum interleukin-8 levels are elevated in patients with ovarian endometrioma. Fertil Steril 2008; 90: 994-999
29 Samy N, Hashim M, Sayed M. et al. Clinical significance of inflammatory markers in polycystic ovary syndrome: their relationship to insulin resistance and body mass index. Dis Markers 2009; 26: 163-170
30 Mohlig M, Spranger J, Osterhoff M. et al. The polycystic ovary syndrome per se is not associated with increased chronic inflammation. Eur J Endocrinol 2004; 150: 525-532
31 Olszanecka-Glinianowicz M, Banaś M, Zahorska-Markiewicz B. et al. Is the polycystic ovary syndrome associated with chronic inflammation per se?. Eur J Obstet Gynecol Reprod Biol 2007; 133: 197-202
32 Zahra M, Shah M, Ali A. et al. Effects of metformin on endocrine and metabolic parameters in patients with polycystic ovary syndrome. Horm Metab Res 2017; 49: 103-108
33 Lizneva D, Kirubakaran R, Mykhalchenko K. et al. Phenotypes and body mass in women with polycystic ovary syndrome identified in referral versus unselected populations: Systematic review and meta-analysis. Fertil Steril 2016; 106: 1510-1520
34 Huang A, Brennan K, Azziz R. Prevalence of hyperandrogenemia in the polycystic ovary syndrome diagnosed by the National Institutes of Health 1990 criteria. Fertil Steril 2010; 93: 1938-1941
35 Boulman N, Levy Y, Leiba R. et al. Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease. J Clin Endocrinol Metab 2004; 89: 2160-2165
36 Long X, Li R, Yang Y. et al. Overexpression of IL-18 in the proliferative phase endometrium of patients with polycystic ovary syndrome. Reprod Sci 2017; 24: 252-257
37 Li Y, Zheng Q, Sun D. et al. Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome. J Cell Physiol 2019; 234: 7435-7447
38 Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol 2014; 6: 1
39 Diamanti-Kandarakis E, Paterakis T, Alexandraki K. et al. Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Hum Reprod 2006; 21: 1426-1431
40 Ibáñez L, Valls C, Ferrer A. et al. Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. J Clin Endocrinol Metab 2002; 87: 2870-2874
41 Nestler JE, Unfer V. Reflections on inositol (s) for PCOS Therapy: Steps Toward Success. Taylor & Francis; 2015
42 Muscogiuri G, Palomba S, Laganà AS. et al. Current insights into inositol isoforms, mediterranean and ketogenic diets for polycystic ovary syndrome: from bench to bedside. Curr Pharm Des 2016; 22: 5554-5557
43 Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: Systematic review and meta-analysis. BMJ 2003; 327: 951
44 Brettenthaler N, De Geyter C, Huber PR. et al. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89: 3835-3840
45 Takemura Y, Osuga Y, Yoshino O. et al. Metformin suppresses interleukin (IL)-1β-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells. J Clin Endocrinol Metab 2007; 92: 3213-3218
46 Jakubowska J, Bohdanowicz-Pawlak A, Milewicz A. et al. Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment. Gynecol Endocrinol 2008; 24: 378-384
47 Legro RS, Barnhart HX, Schlaff WD. et al. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab 2008; 93: 792-800
48 Chang HH, Hsueh Y-S, Cheng YW. et al. Association between polymorphisms of OCT1 and metabolic response to metformin in women with polycystic ovary syndrome. Int J Mol Sci 2019; 20: 1720
49 Xu X, Du C, Zheng Q. et al. Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: A systematic review. BMC Womens Health 2014; 14: 93
50 Wu Y, Li P, Zhang D. et al. Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway. Exp Ther Med 2018; 15: 2120-2127