Subgroup analysis was also performed according to age (<28, ≥28 years, or not available), country (Eastern or Western), BMI (<30 or ≥30 kg/m2), therapy duration (≤3 or >3 months), and dose (<2000 or ≥2000 mg/day). In the subgroup analysis, the overall pattern of pooled effect did not vary substantially by the potential sources of heterogeneity, including age, region, BMI, therapy duration, and dose. Decreased levels of IL-6 after metformin treatment in PCOS were observed in the groups with BMI <30 [SMD (95% CI) of −1.99 (−2.33 to −1.65)]. However, there was no change of serum IL-6 concentrations in patients with BMI ≥30 after metformin treatment (Table 7). Unfortunately, subgroup analysis showed obvious heterogeneity, and these variables were not found to be the main source of heterogeneity in all studies.
In the current meta-analysis, the results showed a significant decrease of serum CRP levels after metformin treatment in women with PCOS, especially in western obese women. In addition, we noticed that metformin treatment could decrease BMI in the CRP and IL-6 related studies. However, we found no significant changes in IL-6 levels during metformin treatment in the present study.
Similar to the findings of our meta-analysis, decreased levels of CRP have been observed in women with PCOS who were receiving 1000 to 2000 mg metformin daily for 6 months.[20,22,25] Insulin and glucose levels induced by activation of the AMP-kinase pathways have been shown to associate with CRP levels.[41,42] Decreased levels of CRP observed in women with PCOS after metformin administration may be the result of reduced insulin resistance and insulin levels. Elevated CRP levels are also associated with obesity in women with PCOS, and serum CRP and IL-6 levels reduced after even moderate weight loss in obese subjects. Interestingly, we observed a significant time and dose effect of metformin treatment on CRP levels in women with PCOS. Moreover, our study found that serum CRP levels decrease more in obese women with PCOS and their BMI reduced significantly after metformin treatment. In consistent with a study, it proved that higher dose metformin may be more efficient for BMI reduction in women with PCOS. However, Chen et al observed that CRP levels decreased more in the subgroup with a dose of <2000 mg/day than that of ≥2000 mg/day. The explanation could be that BMI, age, and clinical phenotypes influence the effect of metformin in PCOS. Thus, further investigations are needed to explore the optimal doses in PCOS women.
CRP is a classical marker of inflammation that is commonly used for cardiovascular disease risk stratification and improving cardiovascular risk prediction.[47,48] Large increases or sustained elevations in CRP over a 6-year period were associated with a subsequent increased risk of diabetes, cardiovascular events, and mortality. On the basis of this meta-analysis and previous work, metformin treatment in women with PCOS was associated with a significant decrease in CRP levels. Therefore, it may be suspected that metformin administration is effective for preventing cardiovascular disease in women with PCOS.
In this meta-analysis, we found that serum IL-6 levels did not decrease significantly in women with PCOS after metformin treatment. In contrast with our results, 1 study indicated that a significant change was observed in IL-6 concentration after treatment with 1500 mg of metformin daily for 3 months. Since the complexity of the factors that influence the effect of metformin on IL-6 levels, we could not identify the precise dose or duration of metformin therapy through our meta-analysis needed to maximize the decrease in IL-6 concentration in women with PCOS. IL-6, a major proinflammatory cytokine in chronic inflammation, has been shown to be closely associated with insulin resistance. Luque-Ramírez and Escobar-Morreale pointed out that serum IL-6 levels decreased during treatment with metformin in parallel to amelioration of insulin resistance. Meanwhile, another study suggested that metformin treatment response on low-grade chronic inflammatory markers in women with PCOS was related to insulin receptor substrate-2 (IRS-2) polymorphism. Therefore, our results could be explained by the differences in race and severity of insulin resistance. Unfortunately, subgroup analysis according to country revealed that IL-6 levels did not change significantly after metformin treatment in women with PCOS.
We noticed that metformin treatment could reduce BMI in women with PCOS, and decreased IL-6 levels after metformin treatment in PCOS were observed in the groups with BMI <30 in our study. Multiple regression analysis found that IL-6 levels correlated significantly with BMI of PCOS patients. Futhermore, short-term metformin therapy facilitated weight loss, and long-term therapy resulted in a reduction of IL-6 levels. So, the explanation could be that metformin-associated reduction of weight before significant changes in IL-6 parameter perhaps involves different mechanisms of action.
Overall, the strength of this study is stronger than any single study, as the included primary studies are quite homogeneous. First, the criteria of diagnosis of PCOS were clearly defined. Besides, subgroup analysis and meta-regression analysis were carried out on the basis of several potential relevant factors. Although significant heterogeneity was detected, the sensitivity analysis did not show that a single study influenced the pooled results and no publication bias was detected. This would undoubtedly enhance the persuasiveness of the study.
Nevertheless, several limitations must be admitted when considering the generalizability of these data. First, the most important limitation is the scarcity of high-quality, multicenter, large sample standard RCTs that directly assess the efficacy of metformin treatment in women with PCOS. Second, there was a wide gap of the number of objects in the recruited trails, ranging from 9 to 97, which may weaken the strength of pooled studies. Third, most of the studies included in the meta-analysis contained small numbers of cases, which is probably the reason for significant heterogeneity. Furthermore, obvious heterogeneity across the included studies was not eliminated by the subgroup analyses and the meta-regression analysis also could not determine the source of heterogeneity; it might reflect clinical heterogeneity related to physical activity, PCOS phenotypes, concomitant subclinical inflammatory diseases, etc.
This meta-analysis showed a significant decrease of serum CRP levels, especially in obese women, but no significant changes in IL-6 levels after metformin treatment in women with PCOS. In general, the data support that early metformin therapy may ameliorate the state of chronic inflammation in women with PCOS. Further investigation is required to determine whether these findings may prove to be of clinical significance for PCOS patients. Considering the obvious heterogeneity reported in the literature, further well-designed investigations with larger samples are needed to ascertain the long-term effects of metformin on chronic inflammation in PCOS.
. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Primers 2016;2:16057.
. Norman RJ, Dewailly D, Legro RS, et al. Polycystic ovary syndrome. Lancet 2007;370:685–97.
. Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol 2011;335:30–41.
. Shorakae S, Teede H, Lambert G, et al. The emerging role of chronic low-grade inflammation in the pathophysiology of polycystic ovary syndrome. Semin Reprod Med 2015;33:257–69.
. Spritzer PM, Lecke SB, Satler F, et al. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 2015;149:219–27.
. El-Mesallamy HO, Abd El-Razek RS, El-Refaie TA. Circulating high-sensitivity C-reactive protein and soluble CD40 ligand are inter-related in a cohort of women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2013;168:178–82.
. Nehir Aytan A, Bastu E, Demiral I, et al. Relationship between hyperandrogenism, obesity, inflammation and polycystic ovary syndrome. Gynecol Endocrinol 2016;32:709–13.
. Peng Z, Sun Y, Lv X, et al. Interleukin-6 levels in women with polycystic ovary syndrome: a systematic review and meta-analysis. PLoS One 2016;11:e0148531.
. Lin YS, Lin MW, Yang CT, et al. Interleukin-6 as an early chronic inflammatory marker in polycystic ovary syndrome with insulin receptor substrate-2 polymorphism. Am J Reprod Immunol 2011;66:527–33.
. Tumu VR, Govatati S, Guruvaiah P, et al. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J Assist Reprod Genet 2013;30:1541–6.
. Ogita M, Miyauchi K. C-reactive protein and cardiovascular disease. J Cardiol 2016;68:179.
. Escobar-Morreale HF, Luque-Ramirez M, Gonzalez F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril 2011;95:1048–58.
. Csenteri OK, Sándor J, Kalina E, et al. The role of hyperinsulinemia as a cardiometabolic risk factor independent of obesity in polycystic ovary syndrome. Gynecol Endocrinol 2017;33:34–8.
. Polak K, Czyzyk A, Simoncini T, et al. New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest 2017;40:1–8.
. Barber TM, Dimitriadis GK, Andreou A, et al. Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance. Clin Med (Lond) 2015;15:72–6.
. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860–7.
. Carmina E. Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 2013;40:40–50.
. Saisho Y. Metformin, inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015;15:196–205.
. An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol 2016;228:97–106.
. Morin-Papunen L, Rautio K, Ruokonen K, et al. Metformin reduces serum C - reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4649–54.
. 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;150:525–32.
. 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;21:1426–31.
. Celik O, Acbay O. Effects of metformin plus rosuvastatin on hyperandrogenism in polycystic ovary syndrome patients with hyperlipidemia and impaired glucose tolerance. J Obstet Gynaecol Res 2012;39:806–13.
. Mohiyiddeen L, Watson AJ, Apostolopoulos NV, et al. Effects of low-dose metformin and rosiglitazone on biochemical, clinical, metabolic and biophysical outcomes in polycystic ovary syndrome. J Obstet Gynaecol 2013;33:165–70.
. Fruzzetti F, Ghiadoni L, Virais A, et al. Adolescents with classical polycystic ovary syndrome have alterations in the surrogate markers of cardiovascular disease but not in the endothelial function. The possible benefits of metformin. J Pediatr Adolesc Gynecol 2016;29:489–95.
. Elkind-Hirsch K, Marriontaux O, Bhushan M, et al. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclist in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:2670–8.
. Heutling D, Schulz H, Nickel I, et al. Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment. J Clin Endocrinol Metab 2008;93:82–90.
. Jakubowska J, Milewicz A, Szymczak J, et al. Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment. Gynecol Endocrinol 2008;24:378–84.
. Jensterle M, Sebestjen M, Janez A, et al. Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur J Endocrinol 2008;159:399–406.
. Hoeger K, Davidson K, Kochman L, et al. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J Clin Endocrinol Metab 2008;93:4299–306.
. Sathyapalan T, Cho LW, Kilpatrickt ES, et al. A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS): a randomized open-label parallel study. Clin Endocrinol (Oxf) 2008;69:931–5.
. Cetinkalp S, Karadeniz M, Erdogan M, et al. The effects of rosiglitazone, metformin, and estradiol-cyproterone acetate on lean patients with polycystic ovary syndrome. Endocrinologist 2009;19:94–7.
. Aghamohammadzadeh N, Aliasgarzadeh A, Baglar L, et al. Comparison of metformin and cyproteroneestrodiol compound effect on hs c-reactive protein and serum androgen levels in patients with poly cystic ovary syndrome. Pak J Med Sci 2010;26:347–51.
. Luque-Ramírez 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;42:815–20.
. Esfahanian F, Zamani MM, Heshmat R, et al. Effect of Metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome. J Obstet Gynaecol Res 2013;39:806–13.
. Victor VM, Rovira-Llopis S, Diaz-Morales N, et al. Effects of metformin on mitochondrial function of leukocytes from polycystic ovary syndrome patients with insulin resistance. Eur J Endocrinol 2015;173:683–91.
. Mehrabian F, Ghasemi-Tehrani H, Mohamadkhani M, et al. Comparison of the effects of metformin, flutamide plus oral contraceptives, and simvastatin on the metabolic consequences of polycystic ovary syndrome. J Res Med Sci 2016;21:7.
. Sathyapalan T, Javed Z, Kilpatrickt ES, et al. Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017;86:384–7.
. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25.
. Carmina E. Diagnosis of polycystic ovary syndrome: from NIH criteria to ESHRE-ASRM guidelines. Minerva Ginecol 2004;56:1–6.
. Davis BJ, Xie Z, Viollet B, et al. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 2006;55:496–505.
. Asemi Z, Esmaillzadeh A. DASH diet, insulin resistance, and serum hs-CRP in polycystic ovary syndrome: a randomized controlled clinical trial. Horm Metab Res 2015;47:232–8.
. Moradi S, Mollabashi M, Kerman SR. Relation between C-reactive protein and body mass index in patients with polycystic ovarian syndrome. Gynecol Endocrinol 2011;27:480–5.
. Möller K, Ostermann AI, Rund K, et al. Influence of weight reduction on blood levels of C-reactive protein, tumor necrosis factor-(, interleukin-6, and oxylipins in obese subjects. Prostaglandins Leukot Essent Fatty Acids 2016;106:39–49.
. Bruno RV, de Avila MA, Neves FB, et al. Comparison of two doses of metformin (2.5 and 1 5 g/day) for the treatment of polycystic ovary syndrome and their effect on body mass index and waist circumference. Fertil Steril 2007;88:510–2.
. Chen Y, Li M, Deng H, et al. Impact of metformin on C-reactive protein levels in women with polycystic ovary syndrome: a meta-analysis. Oncotarget 2017;8:35425–34.
. Dregan A, Charlton J, Chowienczyk P, et al. Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study. Circulation 2014;130:837–44.
. Bekwelem W, Lutsey PL, Loehr LR, et al. White blood cell count, C-reactive protein, and incident heart failure in the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2011;21:739–48.
. Parrinello CM, Lutsey PL, Ballantyne CM, et al. Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J 2015;170:380–9.
. Kuo FC, Huang YH, Lin FH, et al. Circulating soluble IL-6 receptor concentration and visceral adipocyte size are related toinsulin resistance in Taiwanese adults with morbid obesity. Metab Syndr Relat Disord 2017;15:187–93.
. 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;26:163–70.
. 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;71:148–54.