Comparative Effects of Metformin and Dienogest on PI3K/AKT Signaling in Experimental Endometriosis

Tabatabaei S, Seyedmahdi Tabatabaei, Nazlı Çil, Çil N, Önder E, Elif Önder, İsmail Kubilay Baykan, Baykan İK, Hande Şenol, Şenol H, Abdullah Coğuplugil, Coğuplugil A, Mete GA, Gulcin Abban Mete
In: Research Square · 2026 · doi:10.21203/rs.3.rs-10557372/v1 · W7202182668
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Abstract

Abstract This study investigates the therapeutic effects of Metformin and Dienogest on the PI3K/AKT signaling pathway in a rat model of induced endometriosis, aiming to enhance treatment strategies. Experimental groups included untreated control rats, rats with surgically induced endometriosis, and treatment groups receiving Dienogest (0.3 mg/kg/day) and Metformin (100 mg/kg/day) for 28 days. Treatments began on the 21st day post-induction and continued until sacrifice on day 49. Uterine cycle was monitored via vaginal smears, and endometrial lesion areas were reassessed pre- and post-treatment. Blood estradiol (E2), progesterone, and VEGF levels were evaluated using enzyme-linked immunosorbent assay (ELISA). The endometriotic implants and uterus were assessed using histopathological analysis. The expression of PI3K/AKT pathway proteins was evaluated in endometriosis lesions and uterine tissue using immunohistochemical and RT-PCR methods. Metformin significantly reduced lesion diameter compared with untreated and dienogest-treated groups (p = 0.002). Serum E2 levels were significantly higher in the metformin group (p = 0.05). Histological examination showed reduced inflammatory infiltration and tissue degeneration in both treatment groups. RT-PCR demonstrated that PI3K, p-PI3K, and AKT expression were increased in the treatment groups within the endometriosis lesions. However, PI3K and p-PI3K expression were found to be reduced in uterine tissue. AKT expression was statistically significantly higher in the metformin group (p = 0.05). These findings confirm Metformin and Dienogest as effective agents for endometriosis regression, with molecular-level differences suggesting distinct mechanisms of action. Metformin's comprehensive effects on macroscopic, biochemical, microscopic, and molecular levels underscore its therapeutic potential. Further research is essential to unravel its mechanisms fully and explore clinical applications.

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