Skip to main content
SpringerLink
Log in

The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

  • Review
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type 2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS.

Methods

We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool.

Results

Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95 kg; 95% CI 0.03–3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85 kg/m2; 95% CI 0.13–1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56 kg/m2; 95% CI 1.77–3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74 kg/m2; 95% CI 0.07–1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD − 0.20 mmol/L; 95% CI − 0.38 to − 0.03, p = 0.02) and fasting insulin levels (MD − 11.47 mmol/L; 95% CI − 20.20, − 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD − 0.62; 95% CI − 1.25–0.00, p = 0.05).

Conclusion

Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin.

PROSPERO Registration No.

CRD42020178783.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The datasets generated and analysed for this review are available upon compelling request to the authors.

References

  1. Barnard L, Ferriday D, Guenther N, Strauss B, Balen AH, Dye L. Quality of life and psychological well being in polycystic ovary syndrome. Hum Reprod. 2007;22(8):2279–86.

    Article  CAS  PubMed  Google Scholar 

  2. Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence. Ther Adv Endocrinol Metab. 2021;12:2042018821989238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ndefo UA, Eaton A, Green MR. Polycystic ovary syndrome: a review of treatment options with a focus on pharmacological approaches. P T. 2013;38(6):336–55.

    PubMed  PubMed Central  Google Scholar 

  4. Witchel SF, Oberfield SE, Pena AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019;3(8):1545–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abdalla M, Deshmukh H, Atkin SL, Sathyapalan T. miRNAs as a novel clinical biomarker and therapeutic targets in polycystic ovary syndrome (PCOS): a review. Life Sci. 2020;259: 118174.

    Article  CAS  PubMed  Google Scholar 

  6. Wu S, Divall S, Wondisford F, Wolfe A. Reproductive tissues maintain insulin sensitivity in diet-induced obesity. Diabetes. 2012;61(1):114–23.

    Article  CAS  PubMed  Google Scholar 

  7. Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, O’Keefe M, Ghazzi MN. Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome. Fertil Steril. 2003;79(4):932–7.

    Article  PubMed  Google Scholar 

  8. Salley KE, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome—a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007;92(12):4546–56.

    Article  CAS  PubMed  Google Scholar 

  9. Garruti G, Depalo R, Vita MG, et al. Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment. Reprod Biomed Online. 2009;19(4):552–63.

    Article  CAS  PubMed  Google Scholar 

  10. Essah PA, Wickham EP, Nestler JE. The metabolic syndrome in polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):205–25.

    Article  PubMed  Google Scholar 

  11. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353(20):2111–20.

    Article  CAS  PubMed  Google Scholar 

  12. Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2020;11:2042018820938305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev. 2002;18(Suppl 2):S10-15.

    Article  CAS  PubMed  Google Scholar 

  14. Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;356(24):2522–4.

    Article  CAS  PubMed  Google Scholar 

  15. Ajjan RA, Grant PJ. The cardiovascular safety of rosiglitazone. Expert Opin Drug Saf. 2008;7(4):367–76.

    Article  CAS  PubMed  Google Scholar 

  16. Bailey CJ. Thiazolidinediones. In: Enna SJ, Bylund DB, editors. xPharm: the comprehensive pharmacology reference. Elsevier; 2007. https://doi.org/10.1016/B978-008055232-3.61047-5.

  17. Valsamakis G, Lois K, Kumar S, Mastorakos G. Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS). Hormones (Athens). 2013;12(3):363–78.

    Article  PubMed  Google Scholar 

  18. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Babineau J. Product review: Covidence (systematic review software). J Can Health Libr Assoc. 2014;35(2):68–71.

    Article  Google Scholar 

  20. Das S, Chatterjee SS. Cabell’s blacklist: a new way to tackle predatory journals. Indian J Psychol Med. 2018;40(2):197–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Higgins JP, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. Wiley; 2019.

    Book  Google Scholar 

  23. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shahebrahimi K, Jalilian N, Bazgir N, Rezaei M. Comparison clinical and metabolic effects of metformin and pioglitazone in polycystic ovary syndrome. Indian J Endocrinol Metab. 2016;20(6):805–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sohrevardi SM, Nosouhi F, Hossein Khalilzade S, et al. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cetinkalp S, Karadeniz M, Erdogan M, Ozgen G, Saygl F, Ylmaz C. The effects of rosiglitazone, metformin, and estradiol-cyproterone acetate on lean patients with polycystic ovary syndrome. Endocrinologist. 2009;19(3):94–7.

    Article  CAS  Google Scholar 

  27. Kilicdag EB, Bagis T, Zeyneloglu HB, et al. Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study. Hum Reprod. 2005;20(4):894–9.

    Article  CAS  PubMed  Google Scholar 

  28. Lam PM, Tam WH, Ma RC, et al. The reproductive and metabolic effect of rosiglitazone on Chinese women with polycystic ovarian syndrome—a double-blind randomized placebo-controlled study. Fertil Steril. 2011;96(2):445–451.e441.

    Article  CAS  PubMed  Google Scholar 

  29. Cho LW, Kilpatrick ES, Keevil BG, Coady AM, Atkin SL. Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome. Clin Endocrinol. 2009;70(2):233–7.

    Article  CAS  Google Scholar 

  30. Li Y, Tan J, Wang Q, Duan C, Hu Y, Huang W. Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril. 2020;113(1):197–204.

    Article  CAS  PubMed  Google Scholar 

  31. Ziaee A, Oveisi S, Abedini A, Hashemipour S, Karimzadeh T, Ghorbani A. Effect of metformin and pioglitazone treatment on cardiovascular risk profile in polycystic ovary syndrome. Acta Med Indones. 2012;44(1):16–22.

    PubMed  Google Scholar 

  32. Brettenthaler N, De Geyter C, Huber PR, Keller U. 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(8):3835–40.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Yilmaz M, Karakoç A, Törüner FB, et al. The effects of rosiglitazone and metformin on menstrual cyclicity and hirsutism in polycystic ovary syndrome. Gynecol Endocrinol. 2005;21(3):154–60.

    Article  CAS  PubMed  Google Scholar 

  35. Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.

    Article  Google Scholar 

  36. Aroda VR, Ciaraldi TP, Burke P, et al. Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome: a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab. 2009;94(2):469–76.

    Article  CAS  PubMed  Google Scholar 

  37. Cataldo NA, Abbasi F, McLaughlin TL, et al. Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome. Hum Reprod. 2006;21(1):109–20.

    Article  CAS  PubMed  Google Scholar 

  38. Jensterle M, Janez A, Mlinar B, Marc J, Prezelj J, Pfeifer M. Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome. Eur J Endocrinol. 2008;158(6):793–801.

    Article  CAS  PubMed  Google Scholar 

  39. 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(4):399–406.

    Article  CAS  PubMed  Google Scholar 

  40. Steiner CA, Janez A, Jensterle M, Reisinger K, Forst T, Pfützner A. Impact of treatment with rosiglitazone or metformin on biomarkers for insulin resistance and metabolic syndrome in patients with polycystic ovary syndrome. J Diabetes Sci Technol. 2007;1(2):211–7.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Dereli D, Dereli T, Bayraktar F, Ozgen AG, Yilmaz C. Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease. Endocr J. 2005;52(3):299–308.

    Article  CAS  PubMed  Google Scholar 

  42. Anaforoglu I, Algun E, Incecayir O, Ersoy K. Higher metabolic risk with National Institutes of Health versus Rotterdam diagnostic criteria for polycystic ovarian syndrome in Turkish women. Metab Syndr Relat Disord. 2011;9(5):375–80.

    Article  PubMed  Google Scholar 

  43. Du Q, Wang YJ, Yang S, Wu B, Han P, Zhao YY. A systematic review and meta-analysis of randomized controlled trials comparing pioglitazone versus metformin in the treatment of polycystic ovary syndrome. Curr Med Res Opin. 2012;28(5):723–30.

    Article  CAS  PubMed  Google Scholar 

  44. Xu Y, Wu Y, Huang Q. Comparison of the effect between pioglitazone and metformin in treating patients with PCOS: a meta-analysis. Arch Gynecol Obstet. 2017;296(4):661–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang R, Zhao PF, Xu JH, Liu DD, Luo FD, Dai YH. Effects of placebo-controlled insulin-sensitizing drugs on hormonal parameters in polycystic ovary syndrome patients: a network meta-analysis. J Cell Biochem. 2018;119(3):2501–11.

    Article  CAS  PubMed  Google Scholar 

  46. Zhao H, Xing C, Zhang J, He B. 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. Reprod Health. 2021;18(1):171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009;339: b2942.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Froment P, Touraine P. Thiazolidinediones and fertility in polycystic ovary syndrome (PCOS). PPAR Res. 2006;2006:73986.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Naka KK, Kalantaridou SN, Kravariti M, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  50. Ortega-González C, Luna S, Hernández L, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(3):1360–5.

    Article  PubMed  Google Scholar 

  51. Batista JG, Soares JM, Maganhin CC, Simões RS, Tomaz G, Baracat EC. Assessing the benefits of rosiglitazone in women with polycystic ovary syndrome through its effects on insulin-like growth factor 1, insulin-like growth factor-binding protein-3 and insulin resistance: a pilot study. Clinics (Sao Paulo). 2012;67(3):283–7.

    Article  PubMed  Google Scholar 

  52. Li T, Zhang T, Cui T, et al. Involvement of endogenous testosterone in hepatic steatosis in women with polycystic ovarian syndrome. J Steroid Biochem Mol Biol. 2020;204:105752.

    Article  CAS  PubMed  Google Scholar 

  53. Glintborg D, Støving RK, Hagen C, et al. Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(10):5605–12.

    Article  CAS  PubMed  Google Scholar 

  54. Glintborg D, Hermann AP, Andersen M, et al. Effect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome. Fertil Steril. 2006;86(2):385–97.

    Article  CAS  PubMed  Google Scholar 

  55. Glintborg D, Frystyk J, Højlund K, et al. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome. Clin Endocrinol. 2008;68(2):165–74.

    Article  CAS  Google Scholar 

  56. Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen LC. Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo-controlled study. Hum Reprod. 2006;21(6):1400–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The rapid service fee and open access fee were funded by the authors.

Author information

Authors and Affiliations

  1. Allam Diabetes Centre, Academic Diabetes, Endocrinology and Metabolism, The University of Hull, Hull York Medical School (HYMS), Hull, UK

    Mohammed A. Abdalla, Najeeb Shah, Harshal Deshmukh & Thozhukat Sathyapalan

  2. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

  3. Applied Biomedical Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

  4. School of Medicine, The University of Western Australia, Perth, Australia

    Amirhossein Sahebkar

  5. College of Medicine and Health Sciences, The National Medical Library, United Arab Emirates University, Al Ain, United Arab Emirates

    Linda Östlundh

  6. College of Medicine and Health Sciences, Institute of Public Health, United Arab Emirates University, Al Ain, United Arab Emirates

    Rami H. Al-Rifai

  7. School of Postgraduate Studies and Research, RCSI Medical University of Bahrain, Al Sayh, Kingdom of Bahrain

    Stephen L. Atkin

  8. Dasman Diabetes Institute, Department of Translational Research, State of Kuwait, Kuwait City, Kuwait

    Mohammed A. Abdalla

Authors
  1. Mohammed A. Abdalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Najeeb Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harshal Deshmukh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amirhossein Sahebkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Linda Östlundh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rami H. Al-Rifai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen L. Atkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thozhukat Sathyapalan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mohammed Altigani Abdalla Ahmed; designed the review, completed the screening, assessed the quality, extracted, collected and analysed the data, wrote, revised and edited the final manuscript. Najeeb Shah; assessed the quality, extracted and collected the data, and revised and edited the final manuscript. Harshal Deshmukh; revised and edited the final manuscript. Amirhossein Sahebkar; revised and edited the final manuscript; Linda Östlundh; developed and performed the systematic search, assessed for predatory journals, and revised and edited the final manuscript. Rami H. Al-Rifai; participated in the critical discussion and revised and edited the final manuscript. Stephen L. Atkin: participated in the critical discussion and revised the final draft of the manuscript. Finally, Thozhukat Sathyapalan; acted as a mediator for assessing the quality of the evidence, supervised the study, participated in the critical discussion, and revised and edited the final manuscript.

Corresponding author

Correspondence to Mohammed A. Abdalla.

Ethics declarations

Conflict of Interest

Dr Mohammed A Abdalla is currently affiliated with Dasman Diabetes Institute, Department of Translational Research, State of Kuwait, Kuwait. Ms Linda Östlundh is now affiliated with Örebro University, Sweden. Najeeb Shah, Harshal Deshmukh, Amirhossein Sahebkar, Rami Al-Rifai, Stephen Atkin and Thozhukat Sathyapalen have nothing to declare.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Thus, no ethical approval was required.

Additional information

Prior Publication: This work was part of Dr Mohammed A Abdalla’s PhD thesis which was deposited at the University of Hull repository website https://hull-repository.worktribe.com.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 217 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdalla, M.A., Shah, N., Deshmukh, H. et al. The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Adv Ther (2024). https://doi.org/10.1007/s12325-024-02848-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12325-024-02848-3

Keywords

Search

Navigation