The The Relation between Genetic Variants of SLC47A1 (MATE1) and Response to Metformin Therapy in Iraqi Women with Polycystic Ovarian Syndrome
Keywords:Polycystic Ovarian Syndrome, metformin, MATE1, SLC47A1,SNP
Background: Metformin is widely used in polycystic ovary syndrome (PCOS), nevertheless, the treatment responsiveness reveals individual variation in patients with PCOS. Multidrug and toxins extrusion protein (MATE1) mediates metformin excretion in kidney and bile. MATE1 has been encoded by SLC47A1 gene. In this study the SNP (rs1961669 A>G) was analyzed. Aim: To investigate the clinical, hormonal and biochemical effects of three months metformin treatment in women with polycystic ovary syndrome and to study the relation between MATE1 (SLC47A1) gene polymorphism and response to metformin. Patients and Methods: This study was a prospective study; 231 women with PCOS were enrolled. All participated women with age range (18-40) were starting metformin tablet 500 mg per oral three times daily. Blood samples were taken from eligible patients to perform genetic analysis and estimation of follicle stimulating hormone, luteinizing hormone, total testosterone, fasting insulin, HbA1c, fasting blood glucose, sex hormone binding globulin and lipid profile. Results: The study showed that SLC47A1(rs1961669) (A>G) gene polymorphism has non-significant association with metformin response in PCOS. The comparison in demographic and biochemical parameters between pre and post metformin treatment results showed no improvement in clinical, hormonal and biochemical parameters. Conclusion: SLC47A1(rs1961669) (A>G) gene polymorphism had no association with clinical, hormonal and biochemical response to metformin in Iraqi women with polycystic ovarian syndrome
2. Kabel AM. Polycystic ovarian syndrome: insights into pathogenesis, diagnosis, prognosis, pharmacological and non-pharmacological treatment. Pharmaceutical Bioprocessing. 2016 ; 4(1) : 7-12.
3. Al-Tu'ma F J ; Farhan N H and Al-Safi WG. Association between fat mass and obesity Geners9939609 polymorphism with PCOS women in Iraqi population. Ijppr Human. 2015 ; 5(1) : 62-72.
4. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature Reviews Endocrinology. 2018 ; 14(5) : 270-284.
5. Al-Lami HB, Al-Tu’ma FJ and Al-Safi WG. Association between Anti-Müllerian Hormone and other Biomarkers with Ovarian Function in Polycystic Ovarian Syndrome of Iraqi Women. Journal of Contemporary Medical Sciences. 2020 ; 6(4) : 168 - 175.
6. Keen MA, Shah IH, Sheikh G. Cutaneous manifestations of polycystic ovary syndrome: A cross-sectional clinical study. Indian dermatology online journal. 2017 ; 8(2) : 104-110.
7. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015 ; 70(11) : 765-9.
8. Khan A, Karim N, Ainuddin JA. The Triad Of PCOS, Infertility And Metformin. 2019. JBUMDC. 2019 ; 9(1) : 67-71.
9. Liu W-W, Li D-H, Luo X-Z, Tang L-L, Shi Y-L. Therapeutic effect of metformin on patients with polycystic ovary syndrome with normal insulin sensitivity: A retrospective study. Reproductive and Developmental Medicine. 2019 ; 3(3) :153-158.
10. Fraga F, Romeiro GACS, de Sá LBPC, Arbex AK. Polycystic Ovary Syndrome and the Role of Metformin in Ovulation Induction. Health. 2018 ; 10(05) : 565-276.
11. Zhou K, Donnelly L, Yang J, Li M, Deshmukh H, Van Zuydam N, et al. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. The Lancet Diabetes & Endocrinology. 2014 ; 2(6) : 481-7.
12. Motohashi H, Inui K-i. Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K. Molecular aspects of medicine. 2013 ; 34(2-3) : 661-8.
13. Nies AT, Damme K, Schaeffeler E, Schwab M. Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs. Expert opinion on drug metabolism & toxicology. 2012 ; 8(12) : 1565-77.
14. Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proceedings of the National Academy of Sciences. 2005 ; 102(50) : 17923-8.
15. Pau CT, Cheang KI, Modi BP, Kasippillai T, Keefe CC, Shulleeta M, et al. The role of variants regulating metformin transport and action in women with polycystic ovary syndrome. Pharmacogenomics. 2016 ; 17(16) : 1765-73.
16. Cocksedge K, Saravelos S, Wang Q, Tuckerman E, Laird S, Li T. Does free androgen index predict subsequent pregnancy outcome in women with recurrent miscarriage? Human reproduction. 2008 ; 23(4) : 797-802.
17. Biswas S, Dey SK. A Comparative study for Diagnostic Evaluation of Polycystic Ovarian Syndrome (PCOS) by Estimation of High Sensitivity C-reactive protein (hsCRP) and Insulin Resistance. JMSCR. 2018 ; 6(5) :69-74.
18. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine reviews. 2016 ; 37(5) : 467-520.
19. Palomba S, Falbo A, Zullo F, Orio Jr F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocrine Reviews. 2009 ; 30(1) : 1-50.
20. Ou H-T, Chen P-C, Wu M-H, Lin C-Y. Metformin improved health-related quality of life in ethnic Chinese women with polycystic ovary syndrome. Health and quality of life outcomes. 2016 ; 14(1) : 119-129.
21. Hwang KR, Choi YM, Kim JJ, Chae SJ, et al. Effects of insulin-sensitizing agents and insulin resistance in women with polycystic ovary syndrome. Clinical and experimental reproductive medicine. 2013 ; 40(2) : 100-105.
22. Omran MYS. Metformin and polycystic ovary syndrome. International journal of health sciences. 2007 ; 1(1) : 75-80.
23. Kazerooni T, Dehghan-Kooshkghazi M. Effects of metformin therapy on hyperandrogenism in women with polycystic ovarian syndrome. Gynecological endocrinology. 2003 ; 17(1) : 51-6.
24. Aruna J, Mittal S, Kumar S, Misra R, Dadhwal V, Vimala N. Metformin therapy in women with polycystic ovary syndrome. International Journal of Gynecology & Obstetrics. 2004 ; 87(3) : 237-41.
25. Kurzthaler D, Hadziomerovic-Pekic D, Wildt L, Seeber BE. Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. Reproductive Biology and Endocrinology. 2014 ; 12(1) : 98-103.
26. De Leo V, La Marca A, Orvieto R, Morgante G. Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2000 ; 85(4) : 1598-600.
27. Li R, Yu G, Yang D, Li S, Lu S, Wu X, et al. Prevalence and predictors of metabolic abnormalities in Chinese women with PCOS: a cross-sectional study. BMC endocrine disorders. 2014 ; 14(1) : 76-83.
28. Mrozinska S, Wajda A, Czekanska P, Zdzierak B, Kialka M, Milewicz T. Metformin treatment decreased free androgen index among PCOS women. In19th European Congress of Endocrinology 2017 May 3 (Vol. 49). BioScientifica.
29. Nawrocka J, Starczewski A. Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance. Gynecological Endocrinology. 2007 ; 23(4) : 231-7.
30. Jakubowska J, Bohdanowicz-Pawlak A, Milewicz A, Szymczak J, Bednarek-Tupikowska G, Demissie M. Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment. Gynecological Endocrinology. 2008 ; 24(7) : 378-84.
31. Bredella MA, McManus S, Misra M. Impact of metformin monotherapy versus metformin with oestrogen‐progesterone on lipids in adolescent girls with polycystic ovarian syndrome. Clinical endocrinology. 2013 ; 79(2) : 199-203.
32. Singh B, Panda S, Nanda R, Pati S, Mangaraj M, Sahu PK, et al. Effect of metformin on hormonal and biochemical profile in PCOS before and after therapy. Indian Journal of Clinical Biochemistry. 2010 ; 25(4) : 367-70.
33. Kocer D, Bayram F, Diri H. The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome. Gynecological Endocrinology. 2014 ; 30(5) : 367-71.
34. Becker ML, Visser LE, Van Schaik RH, Hofman A, Uitterlinden AG, Stricker BHC. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes. 2009 ; 58(3) : 745-9.