Effect of Metformin on Homocysteine Levels in Lean PCOS Patients

Abstract

Aim: Increased levels of homocysteine have been considered as a significant risk factor for cardiovascular disease. Elevated levels have been demonstrated in polycystic ovary syndrome (PCOS) patients, and have been found to be associated with insulin resistance in PCOS. This study aimed to determine the basal homocysteine levels and insulin sensitivity status in previously untreated lean PCOS patients and to evaluate the effect of metformin as a long term treatment modality. Material and Methods: Twenty-five lean (BMI <25kg/m2) patients with PCOS were recruited to the study. Metformin 500mg orally twice daily was administered for 6 months. Before and after initiation of the study, after 12h fasting, homocysteine, insulin, glucose, FSH, LH, estradiol, progesterone, prolactin, free testosterone levels were measured and 75g OGTTs were performed. Normality was assessed with the Shapiro-Wilk test. Paired Student’s t-test or Wilcoxon signed-rank test was used as appropriate, categorical variables were analyzed with the McNemar test, and correlations were evaluated with Spearman analysis (p<0.05). Results: Pre-treatment (pre) and posttreatment (post) homocysteine levels were within normal levels (median (min-max)) (pre:6.1μmol/L (1.2-25.3), post: 6.2μmol/L (2.0-20.0), p=0.59). Metformin treatment significantly reduced fasting blood glucose (pre:93.7±9.6mg/dL; post:84.8±8.8mg/dL, p=0.003), fasting insulin (pre: 18.1±9.5μU/mL; post: 12.3±5.2μU/mL, p=0.02), and logHOMA (pre: 0.59±0.16, post: 0.37±0.17, p<0.001) values. Conclusion: Homocystein levels were within normal range in previously untreated lean PCOS patients. Insulin resistance was present in significant proportion of patients which also decreased after treatment. However, metformin treatment had no significant effect on homocysteine values.

Keywords

• Homocysteine
• Insulin resistance
• Metformin
• PCOS

Ethical Statement

2003/03-3. 03.04.2003

Metforminin Zayıf PKOS Hastalarında Homosistein Düzeyleri Üzerindeki Etkisi

Abstract

Amaç: Homosistein düzeylerindeki artış kardiyovasküler hastalıklar için önemli bir risk faktörü olarak kabul edilmektedir. Polikistik over sendromu (PKOS) hastalarında yüksek düzeyler gösterilmiş ve PKOS’ta insülin direnci ile ilişkili olduğu bildirilmiştir. Bu çalışmanın amacı, daha önce tedavi görmemiş zayıf PKOS hastalarında bazal homosistein düzeylerini ve insülin duyarlılığını belirlemek ve metforminin uzun süreli bir tedavi yöntemi olarak etkisini değerlendirmektir. Gereç ve Yöntemler: Yirmi beş zayıf (VKİ <25 kg/m²) PKOS hastası çalışmaya dahil edildi. Metformin 500 mg oral yoldan günde iki kez 6 ay boyunca uygulandı. Çalışmanın başlangıcında ve 6. ayda, 12 saatlik açlık sonrası homosistein, insülin, glikoz, FSH, LH, östradiol, progesteron, prolaktin ve serbest testosteron düzeyleri ölçüldü ve 75 g OGTT yapıldı. Verilerin normal dağılıma uygunluğu Shapiro- Wilk testi ile değerlendirildi. Parametrik veriler eşleştirilmiş Student t-testi, nonparametrik veriler Wilcoxon işaretli sıralar testi ile analiz edildi. Kategorik değişkenler McNemar testi ile karşılaştırıldı; korelasyon analizlerinde Spearman testi kullanıldı (p<0,05 anlamlı kabul edildi). Bulgular: Tedavi öncesi ve sonrası homosistein düzeyleri normal seviyelerdeydi (medyan (min-maks)) (öncesi: 6,1 μmol/L (1,2-25,3), sonrası: 6,2 μmol/L (2,0-20,0), p=0,59). Metformin tedavisi açlık kan şekeri (öncesi: 93,7 ± 9,6 mg/dL; sonrası: 84,8 ± 8,8 mg/dL, p=0,003), açlık insülin (öncesi: 18,1 ± 9,5 μU/mL; sonrası: 12,3 ± 5,2 μU/mL, p=0,02) ve logHOMA (öncesi: 0,59 ± 0,16, sonrası: 0,37 ± 0,17, p<0,001) değerlerini anlamlı şekilde azalttı. Sonuç: Daha önce tedavi görmemiş zayıf PKOS hastalarında homosistein düzeyleri normal sınırlardaydı. Hastaların önemli bir kısmında insülin direnci mevcuttu ve metformin tedavisi sonrasında bu direnç belirgin olarak azaldı. Ancak metformin tedavisinin homosistein düzeyleri üzerinde anlamlı bir etkisi olmadı.

Keywords

• Homosistein
• Polikistik over sendromu
• Metformin
• İnsulin direnci

Ethical Statement

2003/03-3. 03.04.2003

References

1. 1. Parua S, Purkait MP, Bhattacharjee A, Thangarajan R, Rammohan S, Islam K, Bhattacharya K, Syamal AK. Exploring Female Infertility: A Comprehensive Review of Polycystic Ovary Syndrome (PCOS) and Its Impact on Reproductive Health. Obesity Medicine. 2025 May 17:100619.
2. 2. Prosperi S, Chiarelli F. Insulin resistance, metabolic syndrome and polycystic ovaries: an intriguing conundrum. Frontiers in Endocrinology. 2025 Oct 1;16:1669716.
3. 3. Dahan MH, Reaven G. Relationship among obesity, insulin resistance, and hyperinsulinemia in the polycystic ovary syndrome. Endocrine. 2019 Jun;64(3):685-9.
4. 4. Zhu JL, Chen Z, Feng WJ, Long SL, Mo ZC. Sex hormone-binding globulin and polycystic ovary syndrome. Clinica chimica acta. 2019 Dec 1;499:142-8.
5. 5. Qu X, Donnelly R. Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in polycystic ovary syndrome. International journal of molecular sciences. 2020 Nov 1;21(21):8191.
6. 6. Zeng W, Luo Y, Ou J, Gan D, Huang M, Tomlinson B, Jiang Y. Metformin in polycystic ovary syndrome: unraveling multi-stage therapeutic mechanisms from puberty to longterm health outcomes. Frontiers in Pharmacology. 2025 Aug 18;16:1654372.
7. 7. Hincapie MA, Badeghiesh A, Baghlaf H, Dahan MH. Association between pre-gestational diabetes in women with polycystic ovary syndrome and adverse obstetric outcomes. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2025 Jan 1;304:109-14.
8. 8. Nestler JE. Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement. Hum Reprod 2002;17:1950-1953.

9. 9. 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.
10. 10. van Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost 2000; 26: 281-289.
11. 11. Knekt P, Alfthan G, Aromaa A, et al. Homocysteine and major coronary events: a prospective population study amongst women. J Intern Med 2001; 249: 461-465.
12. 12. Fonseca V, Guba SC, Fink LM. Hyperhomocysteinemia and the endocrine system: implications for atherosclerosis and thrombosis. Endocr Rev 1999;20: 738-759.
13. 13. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345:1593-1600.
14. 14. Schachter M, Raziel A, Friedler S, Strassburger D, Bern O, Ron-El R. Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine. Hum Reprod 2003;18: 721-727.
15. 15. 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; 81:19-25.
16. 16. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 2003; 9: 505-514.
17. 17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
18. 18. Katz A, Nambi SS, Mather K, 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.
19. 19. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462-1470.
20. 20. Mather KJ, Hunt AE, Steinberg HO, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 2001; 86: 5457-5464
21. 21. Liu M, Fan F, Liu B, Jia J, Jiang Y, Sun P, He D, Liu J, Li Y, Huo Y, Li J. Joint effects of plasma homocysteine concentration and traditional cardiovascular risk factors on the risk of new-onset peripheral arterial disease. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2020;13:3383.
22. 22. Balint B, Jepchumba VK, Guéant JL, Guéant-Rodriguez RM. Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall. Biochimie. 2020 Jun 1;173:100-6.
23. 23. Steed MM, Tyagi SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxidants & redox signaling. 2011 Oct 1;15(7):1927-43.
24. 24. Ahmad A, Corban MT, Toya T, Sara JD, Lerman B, Park JY, Lerman LO, Lerman A. Coronary microvascular endothelial dysfunction in patients with angina and nonobstructive coronary artery disease is associated with elevated serum homocysteine levels. Journal of the American Heart Association. 2020 Oct 6;9(19):e017746.
25. 25. Li T, Wu RJ, Liang QQ, Niu LN, Shang Y, Xue LM. Analysis of serum homocysteine concentration in patients less than 35 years of age with polycystic ovary syndrome and hyperandrogenism. Ginekologia Polska. 2022 Aug 23.
26. 26. Orio F Jr, Palomba S, Di Biase S, et al. Homocysteine levels and C677T polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 673-679.
27. 27. Vrbikova J, Bicikova M, Tallova J, Hill M, Starka L. Homocysteine and steroids levels in metformin treated women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2002; 110: 74-76.
28. 28. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. 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.
29. 29. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65: 946- 949.
30. 30. Sam S, Ehrmann DA. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia. 2017 Sep;60(9):1656-61.
31. 31. Sills ES, Genton MG, Perloe M, Schattman GL, Bralley JA, Tucker MJ. Plasma homocysteine, fasting insulin, and androgen patterns among women with polycystic ovaries and infertility. J Obstet Gynaecol Res 2001; 27:163-168.