Abstract
Background: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder frequently associated with insulin resistance and increased cardiometabolic risk.
Objective: To evaluate the effects of combined supplementation with L-glutathione, D-chiro-inositol, Myo-inositol, and N-acetylcysteine on metabolic and hepatic insulin-related parameters in overweight/obese women with PCOS.
Methods: Over 12 weeks, a total of 32 overweight/obese women with PCOS (mean BMI 30.72 ± 0.96 kg/m²) received daily oral integrative therapy comprising reduced L-glutathione (50 mg), D-chiro-inositol (500 mg), Myo-inositol (100 mg), and N-acetylcysteine (150 mg). The patients had received no hormonal or insulin-sensitizing treatments during the prior six months. Clinical and laboratory assessments were conducted before and after treatment, evaluating hormonal parameters during the follicular phase, as well as fasting glucose, insulin, C-peptide, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and the Hepatic Insulin Extraction index (calculated as insulin/ C-peptide).
Results: After 12 weeks, significant reductions were observed in fasting glucose, fasting insulin, Homeostatic Model Assessment for Insulin Resistance (from 3.24 ± 0.31 to 2.23 ± 0.32; p=0.02), and the Hepatic Insulin Extraction index (from 5.78 ± 0.35 to 4.94 ± 0.44; p=0.006). No changes were observed in C-peptide levels. Subgroup analysis showed that these improvements remained significant in patients with a first-degree family history of type 2 diabetes mellitus, but not in patients without such a history.
Conclusions: Combined supplementation with L-glutathione, D-chiro-inositol, Myo-inositol, and N-acetylcysteine was associated with reductions in insulin resistance markers in overweight/obese women with PCOS, especially among those with a family history of diabetes. L-glutathione and N-acetylcysteine, through their antioxidant effects, may improve insulin-degrading enzyme expression and activity in the liver, thereby increasing hepatic insulin clearance and reducing compensatory hyperinsulinemia and insulin resistance.
References
1. Singh S, Pal N, Shubham S, et al. Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics. J Clin Med. 2023;12(4):1454. https://doi.org/10.3390/jcm12041454
2. Deswal R, Narwal V, Dang A, Pundir CS. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review. J Hum Reprod Sci. 2020;13(4):261-271. https://doi.org/10.4103/jhrs.JHRS_95_18
3. Houston EJ, Templeman NM. Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS. J Endocrinol. 2025;265(2):e240269. https://doi.org/10.1530/JOE-24-0269
4. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379. https://doi.org/10.1016/j.fertnstert.2018.05.004
5. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981-1030. https://doi.org/10.1210/er.2011-1034
6. Lebovitz HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S135-148. https://doi.org/10.1055/s-2001-18576
7. Fitz V, Graca S, Mahalingaiah S, et al. Inositol for Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis to Inform the 2023 Update of the International Evidence-based PCOS Guidelines. J Clin Endocrinol Metab. 2024;109(6):1630-1655. https://doi.org/10.1210/clinem/dgad762
8. Genazzani AD. Inositol as putative integrative treatment for PCOS. Reprod Biomed Online. 2016;33(6):770-780. https://doi.org/10.1016/j.rbmo.2016.08.024
9. Genazzani AD, Battipaglia C, Semprini E, et al. Familial Diabetes in Obese PCOS Predisposes Individuals to Compensatory Hyperinsulinemia and Insulin Resistance (IR) Also for Reduced Hepatic Insulin Extraction (HIE). Endocrines. 2022;3(2):296-302. https://doi.org/10.3390/endocrines3020024
10. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care. 2008;31 Suppl 2:S262-S268. https://doi.org/10.2337/dc08-s264
11. Srikanthan K, Feyh A, Visweshwar H, Shapiro JI, Sodhi K. Systematic Review of Metabolic Syndrome Biomarkers: A Panel for Early Detection, Management, and Risk Stratification in the West Virginian Population. Int J Med Sci. 2016;13(1):25-38. https://doi.org/10.7150/ijms.13800
12. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79(6):1542-1556. https://doi.org/10.1016/j.jhep.2023.06.003
13. Riazi K, Azhari H, Charette JH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851-861. https://doi.org/10.1016/S2468-1253(22)00165-0
14. Mantovani A, Scorletti E, Mosca A, Alisi A, Byrne CD, Targher G. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism. 2020;111S:154170. https://doi.org/10.1016/j.metabol.2020.154170
15. Paschou SA, Polyzos SA, Anagnostis P, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Endocrine. 2020;67(1):1-8. https://doi.org/10.1007/s12020-019-02085-7
16. Arvanitakis K, Chatzikalil E, Kalopitas G, et al. Metabolic Dysfunction-Associated Steatotic Liver Disease and Polycystic Ovary Syndrome: A Complex Interplay. J Clin Med. 2024;13(14):4243. https://doi.org/10.3390/jcm13144243
17. International evidence-based guideline for the assessment and management of polycystic ovary syndrome - 2023. Reprod Endocrinol. 2023;(69):59-79. https://doi.org/10.18370/2309-4117.2023.69.59-79
18. Petrillo T, Semprini E, Tomatis V, et al. Putative Complementary Compounds to Counteract Insulin-Resistance in PCOS Patients. Biomedicines. 2022;10(8):1924. https://doi.org/10.3390/biomedicines10081924
19. Croze ML, Soulage CO. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie. 2013;95(10):10. https://doi.org/10.1016/j.biochi.2013.05.011
20. Lete I, Martínez A, Lasaga I, Centurión E, Vesga A. Update on the combination of myo-inositol/d-chiro-inositol for the treatment of polycystic ovary syndrome. Gynecol Endocrinol. 2024;40(1):2301554. https://doi.org/10.1080/09513590.2023.2301554
21. Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, Lanzone A. N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertil Steril. 2002;77(6):1128-1135. https://doi.org/10.1016/S0015-0282(02)03133-3
22. Genazzani AD, Battipaglia C, Foschi M, et al. Improved insulin sensitivity and reproductive profile in overweight/obese PCOS patients undergoing integrative treatment with carnitines, L-arginine, L-cysteine and myo-inositol. Gynecol Endocrinol. 2025;41(1):2458710. https://doi.org/10.1080/09513590.2025.2458710
23. Sacchi S, Marinaro F, Tondelli D, et al. Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol. Reprod Biol Endocrinol. 2016;14(1):52. https://doi.org/10.1186/s12958-016-0189-2
24. Madeira IR, Carvalho CNM, Gazolla FM, de Matos HJ, Borges MA, Bordallo MA. [Cut-off point for Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index established from Receiver Operating Characteristic (ROC) curve in the detection of metabolic syndrome in overweight pre-pubertal children]. Arq Bras Endocrinol Metabol. 2008;52(9):1466-1473. https://doi.org/10.1590/S0004-27302008000900010
25. Teede HJ, Tay CT, Laven JJE, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447-2469. https://doi.org/10.1210/clinem/dgad463
26. Genazzani AD, Santagni S, Rattighieri E, et al. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol. 2014;30(6):438-443. https://doi.org/10.3109/09513590.2014.897321
27. Genazzani AD, Prati A, Simoncini T, Napolitano A. Modulatory role of D-chiro-inositol and alpha lipoic acid combination on hormonal and metabolic parameters of overweight/obese PCOS patients. Eur Gynecol Obstet. 2019;1(1):29-33.
28. Benelli E, Del Ghianda S, Di Cosmo C, Tonacchera M. A Combined Therapy with Myo-Inositol and D-Chiro-Inositol Improves Endocrine Parameters and Insulin Resistance in PCOS Young Overweight Women. Int J Endocrinol. 2016;2016(1):3204083. https://doi.org/10.1155/2016/3204083
29. Bril F, Lomonaco R, Orsak B, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59(6):2178-2187. https://doi.org/10.1002/hep.26988
30. Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting Insulin-Degrading Enzyme in Insulin Clearance. Int J Mol Sci. 2021;22(5):2235. https://doi.org/10.3390/ijms22052235
31. Fosam A, Sikder S, Abel BS, et al. Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans. J Clin Endocrinol Metab. 2020;105(4):e1835-1846. https://doi.org/10.1210/clinem/dgaa070
32. Genazzani AD, Battipaglia C, Petrillo T, et al. HIE (hepatic insulin extraction) index in overweight/obese PCOS patients with or without familial diabetes. Gynecol Reprod Endocrinol Metab. 2022;3(1):57-68. https://doi.org/10.3390/endocrines3020024
33. Vidal-Cevallos P, Mijangos-Trejo A, Uribe M, Tapia NC. The Interlink Between Metabolic-Associated Fatty Liver Disease and Polycystic Ovary Syndrome. Endocrinol Metab Clin North Am. 2023;52(3):533-545. https://doi.org/10.1016/j.ecl.2023.01.005
34. Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C. Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Invest. 2015;38(12):1319-1326. https://doi.org/10.1007/s40618-015-0372-x
35. Genazzani AD, Battipaglia C, Rusce L, et al. Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients. Gynecol Endocrinol. 2024;40(1):2341701. https://doi.org/10.1080/09513590.2024.2341701
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Veronica Setti, Christian Battipaglia, Elena Maria Santini, Maria Laura Rusce, Alessandro Mondini, Peter Chedraui, Alessandro D. Genazzani