Volume 14, Issue 12 (12-2016)                   IJRM 2016, 14(12): 743-754 | Back to browse issues page

XML Persian Abstract Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Sohrevardi S M, Nosouhi F, Khalilzade S H, Kafaie P, Karimi-Zarchi M, Halvaei I et al . Evaluating the effect of insulin sensitizers metformin and pioglitazone alone and in combination on women with polycystic ovary syndrome: An RCT. IJRM 2016; 14 (12) :743-754
URL: http://ijrm.ir/article-1-715-en.html
1- Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
2- Division of Endocrinology, Department of Internal Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
3- Department of Dermatology, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
4- Departments of Obstetrics and Gynecology, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran , drkarimi2001@yahoo.com
5- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
6- Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Abstract:   (3887 Views)
Background: Insulin resistance and hyperinsulinemia may play a role in pathogenesis of PCOS. One of the common therapeutic methods is using insulin-sensitizing drugs such as metformin and thiazolidinediones.
Objective: The purpose was to determine the effect of metformin and pioglitazone on clinical, hormonal and metabolic parameters in women with PCOS.
Materials and Methods: Eighty four women randomly received one of the following for 3 months: metformin (n=28) (500 mg three times a day), pioglitazone (30 mg daily) (n=28) and combination of both metformin and pioglitazone (n=28) (30 mg/day pioglitazone plus 500 mg metformin three times a day). Hormonal profile, fasting serum insulin, body weight, body mass index, menstrual status and waist to hip ratio were evaluated before and after treatment.
Results: Metformin and pioglitazone and combination therapy induced favorable changes in fasting serum insulin, HOMA-IR index, QUICKI, fasting glucose to insulin ratio in women with PCOS. Body weight, BMI, and waist to hip ratio increased significantly after treatment with pioglitazone but the data were similar after administration of metformin or combination therapy. Total testosterone level decreased significantly only after treatment with metformin. After 3 months in patients who received pioglitazone or combination therapy, menstrual cycles became regular in 71.4% and 73.9% respectively. While menstrual improvement happened only in 36.4% of the patients treated with metformin.
Conclusion: These findings suggest that insulin-sensitizing drugs induce beneficial effect in insulin resistance and menstrual cyclicity but only metformin ameliorated hyperandrogenemia in women with PCOS. Treatment with combination of metformin and pioglitazone did not show more benefit than monotherapy with each drug alone.Keywords:
Full-Text [PDF 455 kb]   (723 Downloads) |   |   Full-Text (HTML)  (537 Views)  
Type of Study: Original Article |

1. ESHRE TR, Group A-SPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25. [DOI:10.1016/j.fertnstert.2003.10.004]
2. Dunaif A. Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis 1. Endocrine Rev 1997; 18: 774-800. [DOI:10.1210/er.18.6.774]
3. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum Reprod 2013: des463. [DOI:10.1093/humrep/des463]
4. Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 1996; 81: 302-309.
5. Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol 2004; 60: 1-17. [DOI:10.1046/j.1365-2265.2003.01842.x]
6. Nestler JE, Jakubowicz DJ, Falcon de Vargas A, Brik C, Quintero N, Medina F. Insulin Stimulates Testosterone Biosynthesis by Human Thecal Cells from Women with Polycystic Ovary Syndrome by Activating Its Own Receptor and Using Inositolglycan Mediators as the Signal Transduction System 1. J Clin Endocrinol Metab 1998; 83: 2001-2005.
7. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 48-53. [DOI:10.1210/jc.2005-1329]
8. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006; 91: 492-497. [DOI:10.1210/jc.2005-1666]
9. Glueck C, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75: 46-52. [DOI:10.1016/S0015-0282(00)01666-6]
10. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 2767-2774. [DOI:10.1210/jcem.85.8.6738]
11. 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. [DOI:10.1093/humupd/dmu012]
12. Tang T, Norman RJ, Balen AH, Lord JM. Insulin‐sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D‐chiro‐inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003; CD003053. [DOI:10.1002/14651858.CD003053]
13. Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome-a reappraisal. Nat Rev Endocrinol 2008; 4: 272-283. [DOI:10.1038/ncpendmet0787]
14. Wang P, Streicher P, Glueck CJ. Treatment of polycystic ovary syndrome with insulin-lowering agents. Exp Opin Pharm 2002; 3: 1177-1189. [DOI:10.1517/14656566.3.8.1177]
15. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17: 2858-2864. [DOI:10.1093/humrep/17.11.2858]
16. Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Women's Health 2011; 3: 25. [DOI:10.2147/IJWH.S11304]
17. Stadtmauer LA, Wong BC, Oehninger S. Should patients with polycystic ovary syndrome be treated with metformin? Benefits of insulin sensitizing drugs in polycystic ovary syndrome-beyond ovulation induction. Hum Reprod 2002; 17: 3016-3026. [DOI:10.1093/humrep/17.12.3016]
18. Vitek W, Alur S, Hoeger KM. Off-label drug use in the treatment of polycystic ovary syndrome. Fertil Steril 2015; 103: 605-611. [DOI:10.1016/j.fertnstert.2015.01.019]
19. Ishibashi M, Egashira K, Hiasa K-i, Inoue S, Ni W, Zhao Q, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension 2002; 40: 687-693. [DOI:10.1161/01.HYP.0000036396.64769.C2]
20. Velazquez E, Mendoza S, Hamer T, Sosa F, Glueck C. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994; 43: 647-654. [DOI:10.1016/0026-0495(94)90209-7]
21. Velázquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997; 90: 392-395. [DOI:10.1016/S0029-7844(97)00296-2]
22. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998; 138: 269-274. [DOI:10.1530/eje.0.1380269]
23. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin Effects on Clinical Features, Endocrine and Metabolic Profiles, and Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled 6-Month Trial, followed by Open, Long-Term Clinical Evaluation 1. J Clin Endocrinol Metab 2000; 85: 139-146.
24. Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003; 361: 1894-1901. [DOI:10.1016/S0140-6736(03)13493-9]
25. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003; 327: 951. [DOI:10.1136/bmj.327.7421.951]
26. Stumvoll M, Häring H-U. Glitazones: clinical effects and molecular mechanisms. Ann Med 2002; 34: 217-224. [DOI:10.1080/ann.]
27. Baillargeon J-P, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004; 82: 893-902. [DOI:10.1016/j.fertnstert.2004.02.127]
28. Homburg R. Polycystic ovary syndrome-from gynaecological curiosity to multisystem endocrinopathy. Hum Reprod 1996; 11: 29-39. [DOI:10.1093/oxfordjournals.humrep.a019031]
29. Polson D, Wadsworth J, Adams J, Franks S. Polycystic ovaries-a common finding in normal women. Lancet 1988; 331: 870-872. [DOI:10.1016/S0140-6736(88)91612-1]
30. Ferriman D, Gallwey J. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21: 1440-1447. [DOI:10.1210/jcem-21-11-1440]
31. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 2003; 9: 505-514. [DOI:10.1093/humupd/dmg044]
32. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 2000; 73: 1149-1154. [DOI:10.1016/S0015-0282(00)00501-X]
33. Robert Y, Dubrulle F, Gaillandre L, Ardaens Y, Thomas-Desrousseaux P, Lemaitre L, et al. Ultrasound assessment of ovarian stroma hypertrophy in hyperandrogenism and ovulation disorders: visual analysis versus computerized quantification. Fertil Steril 1995; 64: 307-312. [DOI:10.1016/S0015-0282(16)57728-0]
34. Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419. [DOI:10.1007/BF00280883]
35. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85: 2402-2410. [DOI:10.1210/jcem.85.7.6661]
36. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002; 87: 569-574. [DOI:10.1210/jcem.87.2.8261]
37. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002; 77: 101-106. [DOI:10.1016/S0015-0282(01)02941-7]
38. Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P, Arteaga-Troncoso G, 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: 1360-1365. [DOI:10.1210/jc.2004-1965]
39. Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang P. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod 2003; 18: 1618-1625. [DOI:10.1093/humrep/deg343]
40. Romualdi D, Guido M, Ciampelli M, Giuliani M, Leoni F, Perri C, et al. Selective effects of pioglitazone on insulin and androgen abnormalities in normo‐and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod 2003; 18: 1210-1218. [DOI:10.1093/humrep/deg264]
41. Aroda VR, Ciaraldi TP, Burke P, Mudaliar S, Clopton P, Phillips S, 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: 469-476. [DOI:10.1210/jc.2008-1133]
42. Stabile G, Borrielli I, Artenisio AC, Bruno LM, Benvenga S, Giunta L, et al. Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome. J Pediatric Adolescent Gynecol 2014; 27: 177-182. [DOI:10.1016/j.jpag.2013.09.015]
43. Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis KA, 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: 203-209. [DOI:10.1016/j.fertnstert.2010.06.058]
44. Pavo I, Jermendy Gr, Varkonyi TT, Kerenyi Z, Gyimesi A, Shoustov S, et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 1637-1645. [DOI:10.1210/jc.2002-021786]
45. Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002; 10: 1008-1015. [DOI:10.1038/oby.2002.137]
46. Fonseca V. Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Am J Med 2003; 115: 42-48. [DOI:10.1016/j.amjmed.2003.09.005]
47. Kelly IE, Han TS, Walsh K, Lean M. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999; 22: 288-293. [DOI:10.2337/diacare.22.2.288]
48. Akazawa S, Sun F, Ito M, Kawasaki E, Eguchi K. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 2000; 23: 1067-1071. [DOI:10.2337/diacare.23.8.1067]
49. 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: 3835-3840. [DOI:10.1210/jc.2003-031737]
50. Qu J, Wang Y, Wu X, Gao L, Hou L, Erkkola R. Insulin resistance directly contributes to androgenic potential within ovarian theca cells. Fertil Steril 2009; 91: 1990-1997. [DOI:10.1016/j.fertnstert.2008.02.167]
51. Garmes HM, Tambascia MA, Zantut-Wittmann DE. Endocrine-metabolic effects of the treatment with pioglitazonein obese patients with polycystic ovary syndrome. Gynecol Endocrinol 2005; 21: 317-323. [DOI:10.1080/09513590500430575]
52. Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, et al. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. Am J Obstet Gynecol 2007; 196: 402. [DOI:10.1016/j.ajog.2006.12.025]
53. Mitkov M, Pehlivanov B, Terzieva D. Metformin versus rosiglitazone in the treatment of polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2006; 126: 93-98. [DOI:10.1016/j.ejogrb.2005.11.019]
54. Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res 2008; 34: 832-837. [DOI:10.1111/j.1447-0756.2008.00856.x]
55. Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate–induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003; 79: 562-566. [DOI:10.1016/S0015-0282(02)04843-4]
56. Cataldo NA, Abbasi F, McLaughlin TL, Lamendola C, Reaven GM. Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone. Fertil Steril 2001; 76: 1057- 1059. [DOI:10.1016/S0015-0282(01)02843-6]
57. Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod Toxicol 2004; 18: 619-621. [DOI:10.1016/j.reprotox.2004.02.014]
58. Kalyoncu NI, Yaris F, Ulku C, Kadioglu M, Kesim M, Unsal M, et al. A case of rosiglitazone exposure in the second trimester of pregnancy. Reprod Toxicol 2005; 19: 563-564. [DOI:10.1016/j.reprotox.2004.11.003]
59. Huang T, Chen PC, Wu MH, Lin CY. Metformin improved health-related quality of life in ethnic Chinese women with polycystic ovary syndrome. Health Qual Life Outcomes 2016; 14: 119. [DOI:10.1186/s12955-016-0520-9]
60. Ghaneei A, Jowkar A, Hasani Ghavam MR, Ghaneei ME. Cabergoline plus metformin therapy effects on menstrual irregularity and androgen system in polycystic ovary syndrome women with hyperprolactinemia. Iran J Reprod Med 2015; 13: 93-100.

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Designed & Developed by : Yektaweb