Changes of Serum Level of Homocysteine and Oxidative Stress Markers by Metformin and Inositol in Infertile Women with Polycystic Ovary Syndrome: A Double Blind Randomized Clinical Trial Study

Document Type : Original Article

Authors

1 Department of Obstetrics and Gynecology, School of Medicine, Research and Clinical Center for Infertility, Dezful University of Medical Sciences, Dezful, Iran

2 Department of Histology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran

3 Department of pharmacology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran

4 Department of Community Medicine, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran

5 School of Medicine, Dezful University of Medical Sciences, Dezful, Iran. Student of Medical Scinces/

6 Department of Histology, School of Medicine, Research and Clinical Center for Infertility Dezful University of Medical Sciences, Dezful, Iran

Abstract

Background: Hyperhomocysteinemia plays an important role in the anovulation in infertile women suffering from polycystic ovary syndrome (PCOS). However, long-term metformin therapy elevated homocysteine (Hcy) concentration in these individuals. Inositol increases serum insulin levels and improves ovulation. The aim of this study was to compare 
the effect of metformin and inofolic on the level of serum Hcy and oxidative markers in the infertile patients with PCOS.
Materials and Methods: Eighty PCOS infertile women undergoing in vitro fertilization in the Umm-al-Banin clinical 
center, Dezful, Iran from December 2018 to September 2019 were invited to participate in this double blind randomized clinical trial. They were divided into two groups; group A who received metformin (1000 mg twice/day) and folic acid (400 μg /day) and group B who used inofolic (inositol+ olic acid 200 μg twice/day) for 3 months. 
Results: The mean Hcy levels increased significantly by metformin (P=0.02), but not by inofolic. There was a decrease in the total antioxidant capacity (TAC) after metformin administration (P=0.01). In both groups, a significant increase in folic acid levels was observed after treatment (P=0.04). Also, no significant change in vitamin B12 and malondialdehyde levels was observed in both groups (P=0.08).
Conclusion: These findings indicate an increase in the serum Hcy levels as well as a remarkable decrease in TAC following metformin treatment. Given the rise in blood Hcy in PCOS patients, inofolic and other medications containing inositol can be prescribed instead of metformin (registration number: IRCT20190508043516N1).

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Main Subjects


1. 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(1): 19-25. 
2. Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019; 3(8): 1545-1573.
3. González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. 
Steroids. 2012; 77(4): 300-305.
4. Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic ovary syndrome. Diabetes Res Clin Pract. 2017; 130: 163-170.
5. Esmaeilzadeh S, Gholinezhad-Chari M, Ghadimi R. The effect of metformin treatment on the serum levels of homocysteine, folic acid, and vitamin B12 in patients with polycystic ovary syndrome. J Hum Reprod Sci. 2017; 10(2): 95-101.
6. Li D, Liu HX, Fang YY, Huo JN, Wu QJ, Wang TR, Hyperhomocysteinemia in polycystic ovary syndrome: decreased 
betaine-homocysteine methyltransferase and cystathionine β-synthase-mediated homocysteine metabolism. Reprod Biomed Online. 2018; 37(2): 234-241.
7. Chrysant SG, Chrysant GS. The current status of homocysteine as a risk factor for cardiovascular disease: a mini review. Expert Rev Cardiovasc Ther. 2018; 16(8): 559-565.
8. Razi Y, Eftekhar M, Fesahat F, Dehghani Firouzabadi R, Razi N, Sabour M, et al. Concentrations of homocysteine in follicular fluid and embryo quality and oocyte maturity in infertile women: a prospective cohort. J Obstet Gynaecol. 2021; 41(4): 588-593. 
9. Kilicdag EB, Bagis T, Zeyneloglu HB, Tarim E, Aslan E, Haydardedeoglu B, et al. Homocysteine levels in women with 
polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study. Hum Reprod. 2005; 20(4): 894-899.
10. Schaefer E, Nock D. The impact of preconceptional multiplemicronutrient supplementation on female fertility. Clin Med Insights Womens Health. 2019; 12: 1179562X19843868.
11. Unfer V, Facchinetti F, Orrù B, Giordani B, Nestler J. Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials. Endocr Connect. 2017; 6(8): 647-658.
12. Lauretta R, Lanzolla G, Vici P, Mariani L, Moretti C, Appetecchia M. Insulin-sensitizers, polycystic ovary syndrome and gynaecological cancer risk. Int J Endocrinol. 2016; 2016: 8671762.
13. Laganà AS, Garzon S, Casarin J, Franchi M, Ghezzi F. Inositol in polycystic ovary syndrome: restoring fertility through a 
pathophysiology-based approach. Trends Endocrinol Metab. 2018; 29(11): 768-780.
14. Formoso G, Baldassarre MPA, Ginestra F, Carlucci MA, Bucci I, Consoli A. Inositol and antioxidant supplementation: safety and efficacy in pregnancy. Diabetes Metab Res Rev. 2019; 35(5): e3154.
15. Salehpour S, Nazari L, Hoseini S, Saharkhiz N, Ghazi F, Sohrabi MR. A potential therapeutic role of myoinositol in the metabolic and cardiovascular profile of PCOS Iranian women aged between 30 and 40 years. Int J Endocrinol. 2016; 2016: 7493147.
16. Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myoinositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol. 2012; 28(7): 509-515.
17. Lesoine B, Regidor PA. Prospective randomized study on the influence of myoinositol in pcos women undergoing ivf in the improvement of oocyte quality, fertilization rate, and embryo quality. Int J Endocrinol. 2016; 2016: 4378507.
18. Cibula D. Is insulin resistance an essential component of PCOS?: the influence of confounding factors. Hum Reprod. 2004; 19(4): 757-759. 
19. Betteridge DJ. What is oxidative stress? Metabolism. 2000; 49(2 Suppl 1): 3-8.
20. Fenkci V, Fenkci S, Yilmazer M, Serteser M. Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril. 2003; 80(1): 123-127.
21. Donà G, Sabbadin C, Fiore C, Bragadin M, Giorgino FL, Ragazzi E, et al. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome. Eur J Endocrinol. 2012; 
166(4): 703-710.
22. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed). 1986; 293(6543): 355-359.
23. Yeon Lee J, Baw C-K, Gupta S, Aziz N, Agarwal A. Role of oxidative stress in polycystic ovary syndrome. Curr Women's Health Rev. 2010; 6(2): 96-107.
24. Thaler CJ. Folate metabolism and human reproduction. Geburtshilfe Frauenheilkd. 2014; 74(9): 845-851.
25. Regidor PA, Schindler AE, Lesoine B, Druckman R. Management of women with PCOS using myo-inositol and folic acid. New clinical data and review of the literature. Horm Mol Biol Clin Investig. 2018; 34(2): 20170067.
26. Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003; 254(5): 455-463.
27. Huijberts MS, Becker A, Stehouwer CD. Homocysteine and vascular disease in diabetes: a double hit? Clin Chem Lab Med. 2005; 43(10): 993-1000.
28. Sahin M, Tutuncu NB, Ertugrul D, Tanaci N, Guvener ND. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications. 2007; 21(2): 118-123.
29. Barnabé A, Aléssio AC, Bittar LF, de Moraes Mazetto B, Bicudo AM, de Paula EV, et al. Folate, vitamin B12 and homocysteine status in the post-folic acid fortification era in different subgroups of the Brazilian population attended to at a public health care center. Nutr J. 2015; 14: 19.
30. Bułdak Ł, Łabuzek K, Bułdak RJ, Kozłowski M, Machnik G, Liber S, et al. Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep. 2014; 66(3): 418-429.
31. Jamilian H, Jamilian M, Foroozanfard F, Afshar Ebrahimi F, Bahmani F, Asemi Z. Comparison of myo-inositol and metformin on mental health parameters and biomarkers of oxidative stress in women with polycystic ovary syndrome: a randomized, doubleblind, placebo-controlled trial. J Psychosom Obstet Gynaecol. 2018; 39(4): 307-314.
32. Diniz Vilela D, Gomes Peixoto L, Teixeira RR, Belele Baptista N, Carvalho Caixeta D, Vieira de Souza A, et al. The role of metformin in controlling oxidative stress in muscle of diabetic rats. Oxid Med 
Cell Longev. 2016; 2016: 6978625