Anat Cell Biol.  2022 Jun;55(2):239-246. 10.5115/acb.21.242.

Combination of alpha lipoic acid and metformin supplement improve assisted reproductive technologies outcomes in polycystic ovary syndrome patients

• Jannatifar R
• Piroozmanesh H
• Sahraei SS
• Asa E

• KMID: 2531210
• DOI: http://doi.org/10.5115/acb.21.242

Abstract

We aimed to investigating the effects of metformin (MET) in combination with alpha lipoic acid (ALA) on hormonal and biochemical parameters, in polycystic ovary syndrome (PCOS) women undergoing intracytoplasmic sperm injection (ICSI). This experimental pilot study with a randomized design was carried out on 40 PCOS women in two groups: (1) MET group, administered 1,500 mg/day MET, and (2) MET (1,500 mg/day)+ALA (1,800 mg/day) group. Drugs were administered from the third day of the previous cycle until the day of oocyte aspiration (six weeks of treatment in total). MET+ALA significantly increased the number of maturated oocytes and the rate of fertilization when compared to the MET group. Combination MET+ALA could increase significantly the number of oocytes retrieval and the number of good-quality embryos. Also, the malondialdehyde (MDA) level decreased significantly in the MET+ALA group and the total antioxidant capacity (TAC) level increased significantly in the MET+ALA group compared to the MET group. Also, fasting blood sugar (FBS), insulin, luteinizing hormone (LH), and LH/follicle stimulating hormone (FSH) levels were significantly lower in the MET+ALA group. The pregnancy outcomes showed no significant difference in the rates of biochemical pregnancy, clinical pregnancy, miscarriage, and live births between the control and study groups. The combination of MET+ALA treatment could moderate the complications of PCOS and subsequently improve oocyte and embryo quality.

Keyword

Polycystic ovary syndrome; Alpha-lipoic acid; Metformin; Assisted reproductive techniques; Ovulation induction

Reference

References

1. McCartney CR, Marshall JC. 2016; CLINICAL PRACTICE. Polycystic ovary syndrome. N Engl J Med. 375:54–64. DOI: 10.1056/NEJMcp1514916. PMID: 27406348. PMCID: PMC5301909.

2. Fruzzetti F, Benelli E, Fidecicchi T, Tonacchera M. 2020; Clinical and metabolic effects of alpha-lipoic acid associated with two different doses of myo-inositol in women with polycystic ovary syndrome. Int J Endocrinol. 2020:2901393. DOI: 10.1155/2020/2901393. PMID: 32256570. PMCID: PMC7106925.

3. Escobar-Morreale HF. 2018; Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 14:270–84. DOI: 10.1038/nrendo.2018.24. PMID: 29569621.

4. Kalyanaraman B. 2013; Teaching the basics of redox biology to medical and graduate students: oxidants, antioxidants and disease mechanisms. Redox Biol. 1:244–57. DOI: 10.1016/j.redox.2013.01.014. PMID: 24024158. PMCID: PMC3757692.

5. Dadachanji R, Sawant D, Patil A, Mukherjee S. 2021; Replication study of THADA rs13429458 variant with PCOS susceptibility and its related traits in Indian women. Gynecol Endocrinol. 37:716–20. DOI: 10.1080/09513590.2021.1906854. PMID: 33779462.

6. Zuo T, Zhu M, Xu W. 2016; Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev. 2016:8589318. DOI: 10.1155/2016/8589318. PMID: 26770659. PMCID: PMC4684888.

7. Amini L, Tehranian N, Movahedin M, Ramezani Tehrani F, Ziaee S. 2015; Antioxidants and management of polycystic ovary syndrome in Iran: a systematic review of clinical trials. Iran J Reprod Med. 13:1–8. DOI: 10.15296/ijwhr.2016.04. PMID: 25653669. PMCID: PMC4306978.

8. Vartanyan EV, Tsaturova KA, Devyatova EA, Mikhaylyukova AS, Levin VA, Petuhova NL, Markin AV, Steptsova EM. 2017; Improvement in quality of oocytes in polycystic ovarian syndrome in programs of in vitro fertilization. Gynecol Endocrinol. 33(Suppl 1):8–11. DOI: 10.1080/09513590.2017.1399699. PMID: 29264980.

9. Genazzani A. 2020; Expert's opinion: integrative treatment with inositols and lipoic acid for insulin resistance of PCOS. Gynecol Reprod Endocrinol Metab. 1:146–57.

10. Canosa S, Paschero C, Carosso A, Leoncini S, Mercaldo N, Gennarelli G, Benedetto C, Revelli A. 2020; Effect of a combination of myo-inositol, alpha-lipoic acid, and folic acid on oocyte morphology and embryo morphokinetics in non-PCOS overweight/obese patients undergoing IVF: a pilot, prospective, randomized study. J Clin Med. 9:2949. DOI: 10.3390/jcm9092949. PMID: 32932604. PMCID: PMC7564928. PMID: 68f8605aa8094898bfbd5974ecf9b475.

11. Cheraghi E, Soleimani Mehranjani M, Shariatzadeh MA, Nasr Esfahani MH, Ebrahimi Z. 2014; Co-administration of metformin and N-acetyl cysteine fails to improve clinical manifestations in PCOS individual undergoing ICSI. Int J Fertil Steril. 8:119–28. PMID: 25083175. PMCID: PMC4107684. PMID: b42915d1da9b40c8a3d61fc0b1b8c7c9.

12. Genazzani A, Despini G, Santagni S, Prati A, Rattighieri E, Chierchia E, Simoncini T. 2014; Effects of a combination of alpha lipoic acid and myo-inositol on insulin dynamics in overweight/obese patients with PCOS. Endocrinol Metab Synd. 3:1000140. DOI: 10.4172/2161-1017.1000140.

13. Asa E, Tabatabaee R, Farrokhi A, Nejatbakhsh R. 2017; Relationship between meiotic spindles visualization and intracytoplasmic sperm injection outcomes in human oocytes. Anat Cell Biol. 50:26–32. DOI: 10.5115/acb.2017.50.1.26. PMID: 28417052. PMCID: PMC5386923.

14. Lu JC, Huang YF, Lü NQ. 2010; WHO laboratory manual for the examination and processing of human semen: its applicability to andrology laboratories in China. Zhonghua Nan Ke Xue. 16:867–71. Chinese. PMID: 21243747.

15. Blank C, DeCroo I, Weyers B, van Avermaet L, Tilleman K, van Rumste M, de Sutter P, Mischi M, Schoot BC. 2020; Improvement instead of stability in embryo quality between day 3-5: a possible extra predictor for blastocyst selection. Eur J Obstet Gynecol Reprod Biol. 253:198–205. DOI: 10.1016/j.ejogrb.2020.08.027. PMID: 32877773.

16. Urman B, Tiras B, Yakin K. 2004; Assisted reproduction in the treatment of polycystic ovarian syndrome. Reprod Biomed Online. 8:419–30. DOI: 10.1016/S1472-6483(10)60926-1. PMID: 15149566.

17. Mumusoglu S, Sipahi M, Bozdag G. Allahbadia GN, Ata B, Lindheim SR, Woodward BJ, Bhagavath B, editors. 2020. Polycystic ovarian syndrome and medically assisted reproduction. Textbook of Assisted Reproduction. Springer;Singapore: p. 241–8. DOI: 10.1007/978-981-15-2377-9_28.

18. Wu L, Sun Y, Wan J, Luan T, Cheng Q, Tan Y. 2017; A proteomic analysis identifies candidate early biomarkers to predict ovarian hyperstimulation syndrome in polycystic ovarian syndrome patients. Mol Med Rep. 16:272–80. DOI: 10.3892/mmr.2017.6604. PMID: 28534980. PMCID: PMC5482139.

19. Xue J, Li X, Liu P, Li K, Sha L, Yang X, Zhu L, Wang Z, Dong Y, Zhang L, Lei H, Zhang X, Dong X, Wang H. 2019; Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbiota in mice. Endocr J. 66:859–70. DOI: 10.1507/endocrj.EJ18-0567. PMID: 31270279.

20. Meng J, Zhu Y. 2021; Efficacy of simvastatin plus metformin for polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 257:19–24. DOI: 10.1016/j.ejogrb.2020.11.070. PMID: 33338947.

21. Santoso B, Rusnaidi , Widjiati . 2020; Effect of alpha lipoic acid on polycystic ovary syndrome with insulin resistance. Indian J Forensic Med Toxicol. 14:1015–20. DOI: 10.37506/ijfmt.v14i4.11632.

22. Kalem MN, Kalem Z, Gurgan T. 2017; Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles. J Endocrinol Invest. 40:745–52. DOI: 10.1007/s40618-017-0634-x. PMID: 28244019.

23. Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. 2001; Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril. 75:505–9. DOI: 10.1016/S0015-0282(00)01766-0. PMID: 11239532.

24. Cheraghi E, Mehranjani MS, Shariatzadeh MA, Esfahani MH, Ebrahimi Z. 2016; N-Acetylcysteine improves oocyte and embryo quality in polycystic ovary syndrome patients undergoing intracytoplasmic sperm injection: an alternative to metformin. Reprod Fertil Dev. 28:723–31. DOI: 10.1071/RD14182. PMID: 25482371.

25. Wu Y, Tu M, Huang Y, Liu Y, Zhang D. 2020; Association of metformin with pregnancy outcomes in women with polycystic ovarian syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. JAMA Netw Open. 3:e2011995. DOI: 10.1001/jamanetworkopen.2020.11995. PMID: 32744629. PMCID: PMC7399751.

26. Lei W, Gao Y, Hu S, Liu D, Chen Q. 2020; Effects of inositol and alpha lipoic acid combination for polycystic ovary syndrome: a protocol for systematic review and meta-analysis. Medicine (Baltimore). 99:e20696. DOI: 10.1097/MD.0000000000020696. PMID: 32791663. PMCID: PMC7386961.

27. Truong TT, Gardner DK. 2020; Antioxidants increase blastocyst cryosurvival and viability post-vitrification. Hum Reprod. 35:12–23. DOI: 10.1093/humrep/dez243. PMID: 31916568.

28. Sulaiman MA, Al-Farsi YM, Al-Khaduri MM, Saleh J, Waly MI. 2018; Polycystic ovarian syndrome is linked to increased oxidative stress in Omani women. Int J Womens Health. 10:763–71. DOI: 10.2147/IJWH.S166461. PMID: 30568513. PMCID: PMC6276615.

29. Xiang W, Wang L, Cheng S, Zhou Y, Ma L. 2019; Protective effects of α-lipoic acid on vascular oxidative stress in rats with hyperuricemia. Curr Med Sci. 39:920–8. DOI: 10.1007/s11596-019-2124-1. PMID: 31845223.

30. Zhang FF, Zhang Q, Wang YL, Wang FF, Hardiman PJ, Qu F. 2021; Intergenerational influences between maternal polycystic ovary syndrome and offspring: an updated overview. J Pediatr. 232:272–81. DOI: 10.1016/j.jpeds.2021.01.018. PMID: 33482217.