Glucose and fatty acid metabolism involved in the protective effect of metformin against ulipristal-induced endometrial changes in rats

Marwa S. Hamza, Eman Ramadan, Salama A. Salama
In: Scientific Reports · 2021 · vol. 11(1) , pp. 8863 · doi:10.1038/s41598-021-88346-w · PMID:33893356 · PMC8065147 · W3153165352
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Metformin reduced ulipristal acetate-induced endometrial changes in rats by modulating the expression of genes involved in glucose and fatty acid metabolism.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This rat study tested whether ulipristal acetate (UPA)-induced progesterone receptor modulator–associated endometrial changes (PAECs) are linked to altered metabolic gene expression and whether metformin can mitigate these changes. Twenty-eight female Wistar rats received UPA and/or metformin for 8 weeks, and the authors found that co-treatment with metformin significantly reduced UPA-associated endometrial thickening, glandular/stromal changes, and hyperplasic histopathology, alongside increased Bax and reduced Bcl-2, PCNA, Cyclin-D1, and ER-α. UPA alone also deranged expression of metabolic genes involved in glucose and fatty-acid/lipid metabolism (including 3-PHGDH, G6PD, TKT, FAS, and CD36), and metformin markedly reduced these altered expressions. A key caveat is that the work is limited to a rat model of drug-induced endometrial changes without direct validation in human PAEC tissue, and the mechanistic pathway is inferred from gene-expression correlations rather than complete causal mapping. This paper is centrally about endometriosis — it directly models UPA-induced PAECs as a reproductive-endometrial drug effect rather than studying endometriosis or adenomyosis, so it is not focused on those conditions.

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Abstract

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids. However, its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). The current study was designed to test the hypothesis that UPA-induced PAECs are associated with deranged expression of some metabolic genes. In addition, metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. In the present study, twenty-eight female non-pregnant, nulligravid Wistar rats were treated with UPA (0.1 mg/kg/day, intragastric) and/or metformin (50 mg/kg/day, intragastric) for 8 weeks. Our results demonstrated that co-treatment with metformin significantly reduced UPA-induced PAECs. In addition, co-treatment with metformin and UPA was associated with significant increase in the Bax and significant reduction in Bcl-2, PCNA, Cyclin-D1and ER-α as compared to treatment with UPA alone. Furthermore, treatment with UPA alone was associated with deranged expression of 3-phosphoglycerate dehydrogenase (3-PHGDH), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), fatty acid synthase (FAS) and CD36. Most importantly, co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. In conclusion, UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes.

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