Fisetin Plus Dapagliflozin Synergistically Reverses PCOS Markers in Rat Model
Combining the flavonoid fisetin with SGLT2 inhibitor dapagliflozin outperformed either drug alone in restoring hormones, reducing oxidative stress, and normalizing reproductive cycles in PCOS rats.
Summary
Researchers induced PCOS in female rats using DHEA injections, then treated animals for 28 days with fisetin (20 mg/kg), dapagliflozin (1 mg/kg), or both combined. The combination therapy produced the strongest improvements across all measured outcomes: 83% of combination-treated rats regained normal estrous cyclicity, body weight and ovarian weight returned near baseline, and oxidative stress markers (MDA/TBARS) fell while antioxidant enzyme SOD rose. Hormonal disruptions—elevated LH, testosterone, and insulin with suppressed FSH—were most effectively corrected by the combination. Lipid profiles also improved most with dual treatment. The authors propose synergy operates through the PI3K/AKT signaling pathway, with fisetin's senolytic and anti-inflammatory flavonoid properties complementing dapagliflozin's insulin-independent glucose excretion and NF-κB/NLRP3 modulation.
Detailed Summary
Polycystic ovary syndrome (PCOS) affects an estimated 5–15% of reproductive-age women worldwide, yet up to 70% remain undiagnosed. The condition is driven by insulin resistance, chronic low-grade inflammation, oxidative stress, and androgen excess—making single-target therapies inadequate. This study asked whether pairing the natural flavonoid fisetin with the SGLT2 inhibitor dapagliflozin could produce synergistic benefits beyond what either agent achieves alone in a well-established rodent PCOS model.
Thirty female Sprague–Dawley rats were divided into five groups: normal control, DHEA-induced PCOS control, fisetin monotherapy (20 mg/kg/day oral), dapagliflozin monotherapy (1 mg/kg/day oral), and combination therapy. PCOS was induced by subcutaneous DHEA (6 mg/100 g) for 21 days, confirmed by persistent diestrus on vaginal cytology and significant weight gain. Treatment lasted 28 days. Endpoints included body and organ weights, estrous cyclicity, serum LH, FSH, testosterone, estradiol, fasting blood glucose, fasting insulin, full lipid panel, oxidative stress markers (SOD, catalase, TBARS/MDA), inflammatory cytokines (TNF-α, IL-6), and ovarian histopathology.
DHEA-induced PCOS rats showed the expected phenotype: weight gain, persistent diestrus, elevated LH and testosterone, reduced FSH, hyperinsulinemia, dyslipidemia (raised LDL and triglycerides, reduced HDL), increased TBARS/MDA, suppressed SOD and catalase, and elevated TNF-α and IL-6. Ovarian histology confirmed cystic follicles and reduced corpora lutea. Both monotherapies produced statistically significant but partial improvements across most parameters. The combination group, however, achieved the most comprehensive restoration: 83% of animals regained normal cyclic patterns, body weight fell below PCOS controls (109.5 ± 0.71 g vs. 124.4 ± 0.89 g), ovarian weight normalized, testosterone approached control values, and lipid and oxidative stress parameters showed the greatest correction (all p < 0.001 vs. PCOS control for key endpoints).
The proposed mechanism centers on complementary pathway engagement. Fisetin, a plant polyphenol with senolytic, antioxidant, and anti-inflammatory properties, is thought to activate PI3K/AKT signaling to improve insulin receptor sensitivity and suppress NF-κB-driven cytokine production. Dapagliflozin promotes urinary glucose excretion independent of insulin, reducing hyperglycemia and hyperinsulinemia while also attenuating NLRP3 inflammasome activation and lipotoxicity. Together, these mechanisms address the metabolic, inflammatory, and oxidative dimensions of PCOS simultaneously, explaining the superior outcomes of combination therapy.
Caveats are notable. The study used only six animals per group, limiting statistical power. Numerical data in Table 2 show surprisingly small differences between groups for hormonal parameters, raising questions about biological effect size versus statistical significance. The DHEA rat model, while widely used, does not fully recapitulate human PCOS pathophysiology. No pharmacokinetic interaction data were reported, and long-term safety of the combination was not assessed. Human translation remains speculative without clinical trials.
Key Findings
- Combination fisetin + dapagliflozin restored normal estrous cyclicity in 83% of PCOS rats vs. 0% in untreated PCOS controls.
- Combination therapy reduced body weight significantly (109.5 g) compared to PCOS controls (124.4 g), outperforming either monotherapy.
- Dual treatment produced the greatest reductions in LDL, triglycerides, TBARS/MDA and the largest increases in HDL and SOD antioxidant activity.
- Testosterone and LH levels were most effectively normalized by combination therapy, approaching values seen in healthy controls.
- Anti-inflammatory cytokines TNF-α and IL-6 were most suppressed in the combination group, suggesting additive anti-inflammatory action.
Methodology
PCOS was induced in female Sprague–Dawley rats via subcutaneous DHEA (6 mg/100 g) for 21 days, confirmed by vaginal cytology and weight gain. Five groups (n=6 each) received 28 days of oral fisetin (20 mg/kg), dapagliflozin (1 mg/kg), combination, or vehicle. Endpoints included hormonal ELISAs, enzymatic lipid assays, TBARS/pyrogallol oxidative stress assays, cytokine ELISAs, and H&E ovarian histopathology, analyzed by one-way ANOVA with Tukey's post hoc test.
Study Limitations
The study used only six animals per group, substantially limiting statistical power and generalizability. The DHEA-induced rat model incompletely mirrors human PCOS, particularly regarding metabolic and neuroendocrine complexity. Hormonal data in Table 2 show numerically small inter-group differences that may not be clinically meaningful, and no human pharmacokinetic, safety, or efficacy data exist for this combination.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.