Top

Reproductive Health

Published in:

Open Access 01-12-2021 | Insulins | Research

Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis

Authors: Han Zhao, Chuan Xing, Jiaqi Zhang, Bing He

Published in: Reproductive Health | Issue 1/2021

Abstract

Background

Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS.

Methods

We identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed.

Results

Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + d-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31–93.58]). Myo-inositol + d-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + d-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: − 0.72 [95% CI (− 1.11)–(− 0.34)] to − 0.89 [95% CI (− 1.460)–(− 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events.

Conclusions

Ours is the first study to report that for women with PCOS, myo-inositol combined with d-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined with d-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone.

Trial registration PROSPERO CRD42020211524

Available only for authorised users

Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;267(2):2056–676. https://doi.org/10.1038/nrdp.2016.57.CrossRef

Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6–15. https://doi.org/10.1016/j.fertnstert.2016.05.003.CrossRefPubMed

Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ, International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364–79. https://doi.org/10.1016/j.fertnstert.2018.05.004.CrossRefPubMedPubMedCentral

Aversa A, La Vignera S, Rago R, Gambineri A, Nappi RE, Calogero AE, Ferlin A. Fundamental concepts and novel aspects of polycystic ovarian syndrome: expert consensus resolutions. Front Endocrinol (Lausanne). 2020;11:516. https://doi.org/10.3389/fendo.2020.00516.CrossRef

McCartney CR, Marshall JC. CLINICAL PRACTICE. Polycystic Ovary Syndrome. N Engl J Med. 2016;375(1):54–64. https://doi.org/10.1056/NEJMcp1514916

Renato P. Metformin in women with PCOS, Pros. Endocrine. 2015;48(2):422–6. https://doi.org/10.1007/s12020-014-0311-1.CrossRefPubMed

Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097.CrossRefPubMedPubMedCentral

Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007;7:16. https://doi.org/10.1186/1472-6947-7-16.CrossRefPubMedPubMedCentral

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–7. https://doi.org/10.1093/humrep/deh098.CrossRef

10.

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF, Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237–45. https://doi.org/10.1210/jc.2006-0178.CrossRefPubMed

11.

Chinese Endocrinologist Association, Chinese Medical Doctor Association. Endocrinologist consensus on the management of polycystic ovary syndrome. Chin J Endocrinol Metab. 2018;34(1):1–7. https://doi.org/10.3760/cma.j.issn.1000-6699.2018.01.001.CrossRef

12.

Zawadri J. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. Polycystic ovary syndrome. Current issues in endocrinology and metabolism. 1992.

13.

Ahmad J, Shukla N, Khan AR, Ahmed F, Siddiqui MA. Comparison of metabolic effects of metformin and rosiglitazone in the management of polycystic ovary syndrome [PCOS]: a prospective, parallel, randomized, open-label study. Diabetes Metab Syndr. 2008;2(1):37–46. https://doi.org/10.1016/j.dsx.2007.12.003.CrossRef

14.

Mohiyiddeen L, Watson AJ, Apostolopoulos NV, Berry R, Alexandraki KI, Jude EB. Effects of low-dose metformin and rosiglitazone on biochemical, clinical, metabolic and biophysical outcomes in polycystic ovary syndrome. J Obstet Gynaecol. 2013;33(2):165–70. https://doi.org/10.3109/01443615.2012.745839.CrossRefPubMed

15.

Yilmaz M, Bukan N, Ayvaz G, Karakoç A, Törüner F, Cakir N, Arslan M. The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod. 2005;20(12):3333–40. https://doi.org/10.1093/humrep/dei258.CrossRefPubMed

16.

Sangeeta S. Metformin and pioglitazone in polycystic ovarian syndrome: a comparative study. J Obstet Gynaecol India. 2012;62(5):551–6. https://doi.org/10.1007/s13224-012-0183-3.CrossRefPubMedPubMedCentral

17.

Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis KA, Makrigiannakis A, Katsouras CS, Chrousos GP, Tsatsoulis A, Michalis LK. Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study. Fertil Steril. 2011;95(1):203–9. https://doi.org/10.1016/j.fertnstert.2010.06.058.CrossRefPubMed

18.

Jensterle M, Sebestjen M, Janez A, Prezelj J, Kocjan T, Keber I, Pfeifer M. Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur J Endocrinol. 2008;159(4):399–406. https://doi.org/10.1530/EJE-08-0507.CrossRefPubMed

19.

Ortega-González C, Cardoza L, Coutiño B, Hidalgo R, Arteaga-Troncoso G, Parra A. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J Endocrinol. 2005;184(1):233–9. https://doi.org/10.1677/joe.1.05844.CrossRefPubMed

20.

Zeng H, Huang Y, Wu J, Xie TQ, Liu DK, Huang QL, Chen Z, Liu JP. Effects of pioglitazone hydrochloride and metformin hydrochloride tablets on metabolic parameters and hormones in polycystic ovary syndrome. Prog Obstet Gynecol. 2020;29(11):7–10. https://doi.org/10.13283/j.cnki.xdfckjz.2020.11.031.CrossRef

21.

Wang X, Gao S, Zhang X. Metformin and pioglitazone plus metformin for patients with polycystic ovary syndrome combined with insulin resistance. Cent South Pharm. 2014. https://doi.org/10.7539/j.issn.1672-2981.2014.02.023.CrossRef

22.

Liang N, Zhang Z. Effects of metformin and pioglitazone on sexual hormones and metabolic level in patients with polycystic ovary syndrome. Guangxi Med J. 2019;41:148–52. https://doi.org/10.11675/j.issn.0253-4304.2019.02.02.CrossRef

23.

Sohrevardi SM, Nosouhi F, Hossein Khalilzade S, Kafaie P, Karimi-Zarchi M, Halvaei I, Mohsenzadeh M. Evaluating the effect of insulin sensitizers metformin and pioglitazone alone and in combination on women with polycystic ovary syndrome: an RCT. Int J Reprod Biomed. 2016;14(12):743–54.PubMedPubMedCentral

24.

Jamilian M, Farhat P, Foroozanfard F, Afshar Ebrahimi F, Aghadavod E, Bahmani F, Badehnoosh B, Jamilian H, Asemi Z. Comparison of myo-inositol and metforminon clinical, metabolic and genetic parameters in polycystic ovary syndrome: a randomized controlled clinical trial. Clin Endocrinol. 2017;87(2):194–200. https://doi.org/10.1111/cen.13366.CrossRef

25.

Shokrpour M, Foroozanfard F, Afshar Ebrahimi F, Vahedpoor Z, Aghadavod E, Ghaderi A, Asemi Z. Comparison of myo-inositol and metformin on glycemic control, lipid profiles, and gene expression related to insulin and lipid metabolism in women with polycystic ovary syndrome: a randomized controlled clinical trial. Gynecol Endocrinol. 2019;35(5):406–11. https://doi.org/10.1080/09513590.2018.1540570.CrossRefPubMed

26.

Fruzzetti F, Perini D, Russo M, Bucci F, Gadducci A. Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017;33(1):39–42. https://doi.org/10.1080/09513590.2016.1236078.CrossRefPubMed

27.

Nehra J, Kaushal J, Singhal SR, Ghalaut VS. A comparative study of myo inositol versus metformin on biochemical profile in polycystic ovarian syndrome in women. Int J Pharm Res. 2017;8(4):1664–70. https://doi.org/10.13040/IJPSR.0975-8232.8(4).1664-70.CrossRef

28.

Du J, Wu RR, Lin XF, Ke WN, Du Y. Clinical effect of myo-inositol combined with D-chiro-inositol on insulin resistant polycystic ovary syndrome. China Med. 2018;13(9):1389–93. https://doi.org/10.3760/j.issn.1673-4777.2018.09.027.CrossRef

29.

Pizzo A, Laganà AS, Barbaro L. Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol. 2014;30:205–8. https://doi.org/10.3109/09513590.2013.860120.CrossRefPubMed

30.

Le Donne M, Metro D, Alibrandi A, Papa M, Benvenga S. Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci. 2019;23:2293–301. https://doi.org/10.26355/eurrev_201903_17278.CrossRefPubMed

31.

Nordio M, Proietti E. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci. 2012;16:575–81.PubMed

32.

Li XB, Kuang H, Luo Y, Chen QX. Clinical observation of berberine in intervening insulin resistance of polycystic ovary syndrome. J Guangzhou Univ Tradit Chin Med. 2017;1(2):172–7. https://doi.org/10.13359/j.cnki.gzxbtcm.2017.02.006.CrossRef

33.

Wang P, Wang H, Wang Y. Clinical analysis of metformin combined with berberine in the treatment of obese polycystic ovary syndrome. Chin Prim Health Care. 2016;30:77–8. https://doi.org/10.3969/j.issn.1001-568X.2016.10.0032.CrossRef

34.

Wang LX, Kong YZ, Ren YW, Shen M. Therapeutic effect of berberine combined with dfformin for women with polycystic ovary syndrome and insulin resistance. J Zhejiang Chin Med Univ. 2011;5:713–5. https://doi.org/10.3969/j.issn.1005-5509.2011.05.034.CrossRef

35.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng H-Y, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. https://doi.org/10.1136/bmj.l4898.CrossRefPubMed

36.

Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Mak. 2013;33(5):607–17. https://doi.org/10.1177/0272989X12458724.CrossRef

37.

Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. https://doi.org/10.1186/1471-2288-5-13.CrossRefPubMedPubMedCentral

38.

Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71. https://doi.org/10.1016/j.jclinepi.2010.03.016.CrossRefPubMed

39.

Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010;162(2):193–212. https://doi.org/10.1530/EJE-09-0733.CrossRefPubMed

40.

Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–85. https://doi.org/10.1007/s00125-017-4342-z.CrossRefPubMedPubMedCentral

41.

Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic ovary syndrome. Diabetes Res Clin Pract. 2017;130:163–70. https://doi.org/10.1016/j.diabres.2017.06.011.CrossRefPubMed

42.

Panunzi S, Maltese S, Verrastro O, Labbate L, De Gaetano A, Pompili M, Capristo E, Bornstein SR, Mingrone G. Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: a hierarchical network meta-analysis. Diabetes Obes Metab. 2020. https://doi.org/10.1111/dom.14304.10.1111/dom.14304.CrossRef

43.

Lebovitz HE. Thiazolidinediones: the forgotten diabetes medications. Curr Diabetes Rep. 2019;19(12):151. https://doi.org/10.1007/s11892-019-1270-y.CrossRef

44.

Xing C, Li CZ, He B. Insulin sensitizers for improving the endocrine and metabolic profile in overweight women with PCOS. J Clin Endocrinol Metab. 2020;105(9):2950–63. https://doi.org/10.1210/clinem/dgaa337.CrossRefPubMedCentral

45.

Sortino MA, Salomone S, Carruba MO, Drago F. Polycystic ovary syndrome: insights into the therapeutic approach with inositols. Front Pharmacol. 2017;8:341. https://doi.org/10.3389/fphar.2017.00341.CrossRefPubMedPubMedCentral

46.

Bevilacqua A, Bizzarri M. Inositols in insulin signaling and glucose metabolism. Int J Endocrinol. 2018;2018:1968450. https://doi.org/10.1155/2018/1968450.CrossRefPubMedPubMedCentral

47.

Ravanos K, Monastra G, Pavlidou T, Goudakou M, Prapas N. Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality? Eur Rev Med Pharmacol Sci. 2017;21(23):5491–8. https://doi.org/10.26355/eurrev_201712_13940.CrossRefPubMed

48.

Facchinetti F, Orrù B, Grandi G, Unfer V. Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials. Gynecol Endocrinol. 2019;35(3):198–206. https://doi.org/10.1080/09513590.2018.1540578.CrossRefPubMed

49.

Arentz S, Smith CA, Abbott J, Bensoussan A. Nutritional supplements and herbal medicines for women with polycystic ovary syndrome; a systematic review and meta-analysis. BMC Complement Altern Med. 2017;17(1):500. https://doi.org/10.1186/s12906-017-2011-x.CrossRefPubMedPubMedCentral

50.

Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017;11(11):CD003053. https://doi.org/10.1002/14651858.CD003053.pub6.CrossRefPubMed

51.

Gateva A, Unfer V, Kamenov Z. The use of inositol(s) isomers in the management of polycystic ovary syndrome: a comprehensive review. Gynecol Endocrinol. 2018;34(7):545–50. https://doi.org/10.1080/09513590.2017.1421632.CrossRefPubMed

52.

Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, Ma Y, Zhang Y, Zhang H, Guan Y. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99–105. https://doi.org/10.1530/EJE-11-0616.CrossRefPubMed

53.

Rondanelli M, Infantino V, Riva A, Petrangolini G, Faliva MA, Peroni G, Naso M, Nichetti M, Spadaccini D, Gasparri C, Perna S. Polycystic ovary syndrome management: a review of the possible amazing role of berberine. Arch Gynecol Obstet. 2020;301(1):53–60. https://doi.org/10.1007/s00404-020-05450-4.CrossRefPubMedPubMedCentral

54.

Ju J, Li J, Lin Q, Xu H. Efficacy and safety of berberine for dyslipidaemias: a systematic review and meta-analysis of randomized clinical trials. Phytomedicine. 2018;50:25–34. https://doi.org/10.1016/j.phymed.2018.09.212.CrossRefPubMed

55.

Xie L, Zhang D, Ma H, He H, Xia Q, Shen W, Chang H, Deng Y, Wu Q, Cong J, Wang CC, Wu X. The effect of berberine on reproduction and metabolism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized control trials. Evid Based Complement Altern Med. 2019. https://doi.org/10.1155/2019/7918631.CrossRef

56.

Li MF, Zhou XM, Li XL. The effect of berberine on polycystic ovary syndrome patients with insulin resistance (PCOS-IR): a meta-analysis and systematic review. Evid Based Complement Altern Med. 2018;2018:2532935. https://doi.org/10.1155/2018/2532935.CrossRef

Title: Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis
Authors: Han Zhao
Chuan Xing
Jiaqi Zhang
Bing He
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Insulins
Glitazone
Polycystic Ovary Syndrome
Metformin
Polycystic Ovary Syndrome
Insulins
Testosterone
Published in: Reproductive Health / Issue 1/2021
Electronic ISSN: 1742-4755
DOI: https://doi.org/10.1186/s12978-021-01207-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Geographic variation and associated factors of long-acting contraceptive use among reproductive-age women in Ethiopia: a multi-level and spatial analysis of Ethiopian Demographic and Health Survey 2016 data

Reproductive health interventions for Inuit youth in the north: a scoping review

Influence of perceived stress on prenatal depression in Surinamese women enrolled in the CCREOH study

'Does HPV affect my fertility?' Reproductive concerns of HPV-positive women: a qualitative study

Duration of third stage labour and postpartum blood loss: a secondary analysis of the WHO CHAMPION trial data

Determinants of practice of preconception care among women of reproductive age group in southern Ethiopia, 2020: content analysis