MODULATION OF THE TGF-β SIGNALING PATHWAY IN THE TREATMENT OF ENDOMETRIAL HYPERPLASIA WITH GESTAGENS

R.M. Sarkisyan
In: Laboratornaya i klinicheskaya meditsina. Farmatsiya · 2025 · pp. 23–33 · doi:10.14489/lcmp.2025.03.pp.023-033 · W4415527356
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⚙ AI-generated summary by claude@2026-06, 2026-06-12 ⓘ

Progestogen treatment suppressed upregulated TGF-β and modulated SMAD proteins in endometrial hyperplasia, restoring them to normal levels and confirming pathway sensitivity to therapy.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-12 · read from full text ⓘ

This corpus set examines how gestagens (progestin therapies) modulate the transforming growth factor-β (TGF-β) signaling pathway in the uterine endometrium, relating these effects to apoptosis, epithelial-to-mesenchymal transition, and endometrial hyperplasia or cancer-related processes, using a mix of mechanistic studies and narrative/background reviews, including reported experimental and clinical observations (e.g., measuring TGF-β isoforms after progestin exposure). Across included works, progestin treatment is described as inducing apoptosis and altering TGF-β-related signaling dynamics in uterine tissues, while additional mechanistic studies emphasize how extracellular matrix context can switch TGF-β responses such as apoptosis versus EMT. A key caveat is that the materials provided span multiple different study designs and endpoints (some focused on hyperplasia/cancer, others on broader TGF-β biology), limiting direct synthesis into a single unified causal conclusion about “optimal” gestagen-mediated TGF-β modulation. Relevance to endometriosis: the corpus includes studies that explicitly assess TGF-β1/SMAD3 expression in ectopic versus eutopic endometrium in endometriosis and compare EMT marker staining in endometriosis, though the main emphasis here is on endometrial hyperplasia and progestin effects via TGF-β signaling rather than adenomyosis or endometriosis specifically.

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Abstract

Objective. This study aimed to investigate the effect of progestogens on key components of the transforming growth factor beta (TGF-β) signaling pathway in the endometrial mucosa in cases of non-atypical endometrial hyperplasia, in order to determine the pathogenetic role of this pathway and to predict treatment outcomes. Materials and Methods. A comprehensive examination was conducted on 19 patients with non-atypical endometrial hyperplasia before and after 3 months of conservative treatment with progestogens. Endometrial samples were obtained by dilatation and curettage or Pipelle biopsy. Results. The study revealed that progestogens suppress the upregulated expression of TGF-β observed in endometrial hyperplasia and modulate the altered expression of other components of the TGF-β-dependent signaling pathway, particularly SMAD proteins ( From the name of the Drosophila MAD gene (mothers against decapentaplegic) and the Caenorhabditis elegans SMA gene (small worm phenotype), restoring them to levels typical of normal endometrium. Conclusion. These findings confirm that components of the TGF-β signaling pathway are altered in endometrial hyperplasia and are sensitive to modulation by progestogen therapy. This opens new perspectives for the treatment of this condition and for the prevention of malignant transformation of the endometrial lining leading to endometrial carcinoma.
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Comparative analysis of immunohistochemical staining intensity determined by light microscopy, ImageJ and QuPath in placental Hofbauer cells. Acta Histochem Cytochem. 2021;54(1):21-9. DOI: 10.1267/ahc.20-00032 11. Omelchenko VP, Demidova AA. Informatics, medical informatics, statistics. Moscow: GEOTAR-Media; 2021. 608 p. DOI: 10.33029/9704-5921-8-MIS-2021-1-608 12. Rodriguez GC, Rimel BJ, Watkin W, et al. Progestin treatment induces apoptosis and modulates transforming growth factor-? in the uterine endometrium. Cancer Epidemiol Biomarkers Prev. 2008;17(3):578-84. DOI: 10.1158/1055-9965 13.Delbandi AA, Mahmoudi M, Shervin A, et al. Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls. BMC Womens Health. 2020;20(1):3. DOI: 10.1186/s12905-019-0865-4 14. Wang F, Qualls AE, Marques-Fernandez L, et al. Biology and pathology of the uterine microenvironment and its natural killer cells. Cell Mol Immunol. 2021;18:2101-13. DOI: 10.1038/s41423-021-00739-z 15. Chemerinski A, Garcia de Paredes J, Blackledge K, et al. Mechanisms of endometrial aging: lessons from natural conceptions and assisted reproductive technology cycles. Front Physiol. 2024;28(15):1332946. DOI: 10.3389/fphys.2024.1332946 16. Mandelbaum RS, Ciccone MA, Nusbaum DJ, et al. Progestin therapy for obese women with complex atypical hyperplasia: levonorgestrel-releasing intrauterine device vs systemic therapy. Am J Obstet Gynecol. 2020;223(1):103. DOI: 10.1016/j.ajog.2019.12.273 17. Yu HF, Yang ZQ, Xu MY, et al. Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2. Int J Biol Sci. 2022;18(6):2261-76. DOI: 10.7150/ijbs.67756 18. Yang B, Hu M, Fu Y, et al. LASS2 mediates Nrf2-driven progestin resistance in endometrial cancer. Am J Transl Res. 2021;15(13):1280-9. 19. Reis FM, Ribeiro MF, Maia AL, et al. Regulation of human endometrial transforming growth factor ?1 and ?3 isoforms through menstrual cycle and medroxyprogesterone acetate treatment. Histol Histopathol. 2002;17:739-45. DOI: 10.14670/HH-17.739 20. Kumari A, Shonibare Z, Monavarian M, et al. TGF? signaling networks in ovarian cancer progression and plasticity. Clin Exp Metastasis. 2021;38(2):139-61. DOI: 10.1007/s10585-021-10077-z 21. Zubrzycka A, Migdalska-Sek M, Jedrzejczyk S, et al. The expression of TGF-?1, SMAD3, ILK and miRNA-21 in the ectopic and eutopic endometrium of women with endometriosis. Int J Mol Sci. 2023;24(3):2453. DOI: 10.3390/ijms24032453 22. Kriseman ML, Tang S, Liao Z, et al. SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration. Commun Biol. 2023;6(1):261. DOI: 10.1038/s42003-023-04619-2 23. Kriseman M, Monsivais D, Agno J, et al. Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer. Proc Natl Acad Sci U S A. 2019;116(9):3873-82. DOI: 10.1073/pnas.1806862116 24. Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology. 1990;1(1):43-6. PMID: 2081237. 25. Clinical guidelines. Endometrial hyperplasia. Moscow: Ministry of Health of the Russian Federation; 2023. 56 p. (In Russ).

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