Original Articles

Synergistic Role of Fisetin and Dapagliflozin in Ameliorating Oxidative Damage & Insulin Resistance in Dehydroepiandrosterone Induced Polycystic Ovarian Syndrome in Rats

Abstract

Objective: This study aims to test how fisetin and dapagliflozin—alone and combined—affect reproductive cycles, blood markers, hormones, oxidative stress, and tissue changes in DHEA-induced PCOS rats.
Materials and methods: This study used 30 female rats split into five groups of six animals each: normal controls, PCOS disease controls, fisetin treatment, dapagliflozin treatment, and combination treatment. PCOS was created by giving the rats DHEA injections under the skin for 21 days, followed by 28 days of treatment. The researchers measured body weight, reproductive cycles, organ weights, hormone levels (LH, FSH, testosterone, insulin), cholesterol profiles, oxidative stress markers (MDA, SOD), inflammation markers (TNF-α, IL-6), and examined tissue samples under a microscope.
Results: PCOS induction in rats caused estrous cycle disruption (shown through vaginal cytology), weight gain, elevated LH/testosterone/insulin levels, and compromised antioxidant status. Individual fisetin and dapagliflozin treatments significantly ameliorated these abnormalities, but their combination demonstrated the most comprehensive therapeutic benefits, effectively restoring reproductive cycles, hormonal balance, and metabolic parameters while reducing oxidative damage.
Conclusion: Fisetin and dapagliflozin, particularly when used together, helped reduce PCOS-related problems by fighting inflammation, protecting against cellular damage, and improving insulin function. This likely works by influencing the PI3K/AKT cellular signaling pathway.

1. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602-18.
2. Chang S, Dunaif A. Diagnosis of polycystic ovary syndrome: which criteria to use and when? Endocrinol Metab Clin North Am. 2021;50(1):11-23.
3. Huddleston HG, Dokras A. Diagnosis and treatment of polycystic ovary syndrome. JAMA. 2022;327(3):274-5.
4. Dapas M, Lin FT, Nadkarni GN, Sisk R, Legro RS, Urbanek M, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. PLoS Med. 2020;17(6):e1003132.
5. Wang K, Li Y. Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome. Front Endocrinol (Lausanne). 2023;14:1191759.
6. Moghetti P, Tosi F. Insulin resistance and PCOS: chicken or egg? J Endocrinol Invest. 2021;44(2):233-44.
7. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum Reprod. 2013;28(3):777-84.
8. Liu Q, Tang B, Zhu Z, Kraft P, Deng Q, Stener-Victorin E, et al. A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome. Diabetologia. 2022;65(9):1483-94.
9. Persson S, Elenis E, Turkmen S, Kramer MS, Yong EL, Poromaa IS. Higher risk of type 2 diabetes in women with hyperandrogenic polycystic ovary syndrome. Fertil Steril. 2021;116(3):862-71.
10. Herman R, Sikonja J, Jensterle M, Janez A, Dolzan V. Insulin metabolism in polycystic ovary syndrome: secretion, signaling, and clearance. Int J Mol Sci. 2023;24(4):3140.
11. Hansen SL, Svendsen PF, Jeppesen JF, Hoeg LD, Andersen NR, Kristensen JM, et al. Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean with polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104(5):1841-54.
12. Armanini D, Boscaro M, Bordin L, Sabbadin C. Controversies in the pathogenesis, diagnosis and treatment of PCOS: focus on insulin resistance, inflammation, and hyperandrogenism. Int J Mol Sci. 2022;23(8):4110.
13. Ye W, Xie T, Song Y, Zhou L. The role of androgen and its related signals in PCOS. J Cell Mol Med. 2021;25(4):1825-37.
14. Hu KL, Chen Z, Li X, Cai E, Yang H, Chen Y, et al. Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction. Reprod Biol Endocrinol. 2022;20(1):81.
15. Li T, Mo H, Chen W, Li L, Xiao Y, Zhang J, et al. Role of the PI3K-Akt signaling pathway in the pathogenesis of polycystic ovary syndrome. Reprod Sci. 2017;24(5):646-55.
16. Sadeghi HM, Adeli I, Calina D, Docea AO, Mousavi T, Daniali M, et al. Polycystic ovary syndrome: a comprehensive review of pathogenesis, management, and drug repurposing. Int J Mol Sci. 2022;23(2):583.
17. Zhang J, Xing C, He B. Sodium-glucose cotransporter-2 inhibitors for improving endocrine and metabolic profiles in overweight and obese individuals with polycystic ovary syndrome: a meta-analysis protocol. BMJ Open. 2022;12(4):e058260.
18. Wang K, Li Y. Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome. Front Endocrinol (Lausanne). 2023;14:1191759.
19. Zughaibi TA, Suhail M, Tarique M, Tabrez S. Targeting PI3K/Akt/mTOR pathway by different flavonoids: a cancer chemopreventive approach. Int J Mol Sci. 2021;22(22):12455.
20. Chahal SK, Kabra A. Fisetin ameliorates polycystic ovary syndrome in rats via a mechanistic modulation of AMP-activated protein kinase and SIRT1 molecular pathway. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(12):10017-29.
21. Moustafa PE, Abo El Nasr NM, Shabana ME, Saleh DO. Fisetin mitigates letrozole-induced polycystic ovarian syndrome in rats: crosstalk of AMPK/PI3K/AKT-mediated-Nrf2 antioxidant defense mechanism and the inflammasome NLRP3/NF-κB P65/IL-1β signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(10):8077-88.
22. Mihanfar A, Nouri M, Roshangar L, Khadem-Ansari MH. Ameliorative effects of fisetin in letrozole-induced rat model of polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2021;213:105954.
23. Choi JH, Jang M, Kim EJ, Lee MJ, Park KS, Kim SH, et al. Korean Red Ginseng alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats via its anti-inflammatory and antioxidant activities. J Ginseng Res. 2020;44(6):790-8.
24. Tosi F, Bonora E, Moghetti P. Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes. Hum Reprod. 2017;32(12):2515-21.
25. Lin B, Guo X, Lu W, Niu R, Zeng X, Chen Z, et al. Dapagliflozin attenuates fat accumulation and insulin resistance in obese mice with polycystic ovary syndrome. Eur J Pharmacol. 2024;977:176742.
26. Kafali H, Iriadam M, Ozardalı I, Demir N. Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch Med Res. 2004;35(2):103-8.
Files
IssueVol 19, No 4 (December 2025) QRcode
SectionOriginal Articles
Keywords
Polycystic Ovary Syndrome (PCOS) Fisetin Dapagliflozin PI3K/AKT Pathway SGLT2 Inhibitor Insulin Resistance Metabolic Syndrome Dyslipidaemia
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Ramachandran V, Naarayanan S, Kumar K, Murugan G, Mohanty B. Synergistic Role of Fisetin and Dapagliflozin in Ameliorating Oxidative Damage & Insulin Resistance in Dehydroepiandrosterone Induced Polycystic Ovarian Syndrome in Rats. J Family Reprod Health. 2025;19(4):265-271.