Pirfenidone reduces ovarian fibrosis and improves PCOS in letrozole-induced rat model

Authors

  • Ayşe Çakır Gündoğdu Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye https://orcid.org/0000-0002-2466-9417
  • Neziha Senem Arı Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml
  • Ahmet Koçak Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml
  • Gülnihal Şenol Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml https://orcid.org/0000-0002-9553-6021
  • Asiye Höbel Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml
  • Ömer Eldiven Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml
  • Fatih Kar Department of Medical Biochemistry, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml
  • Orhan Özatik Department of Histology and Embryology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Türkiye image/svg+xml

DOI:

https://doi.org/10.17305/bb.2025.12676

Keywords:

Polycystic ovary syndrome, PCOS, ovarian fibrosis, pirfenidone, combined oral contraceptives, COC, TGF-β1

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by cystic ovarian morphology, anovulation, and infertility. Ovarian fibrosis has recently emerged as a key pathological feature of PCOS. This study investigated whether pirfenidone (PFD), an antifibrotic agent, could improve ovarian dysfunction in a letrozole-induced PCOS rat model. Forty-two female Wistar albino rats were divided into six groups (n=7 each): control, PFD, PCOS, PCOS/PFD, PCOS/combined oral contraceptives (COC), and PCOS/PFD/COC. PCOS was induced using letrozole (1 mg/kg/day orally for 21 days). PFD (200 mg/kg/day) and/or COC (0.18 mg/kg cyproterone acetate and 0.00315 mg/kg ethinyl estradiol) were administered for 21 days. Compared to controls, PCOS rats exhibited significant disruptions in estrous cyclicity, ovarian morphology, and fibrosis-related markers (all p<0.0001), despite no significant changes in testosterone (p=0.058) or estrogen (p=0.896) levels. PFD treatment significantly improved estrous cyclicity, follicular profile, and corpora lutea count (all p<0.0001), reduced ovarian fibrosis (p<0.0001), downregulated TGF-β1, CTGF, and MMP-9 (all p<0.0001), and upregulated PPAR-γ and MMP-2 (both p<0.0001), without affecting hormone levels (p=0.945 and p=0.479, respectively). COC treatment also improved estrous cyclicity and ovarian histology (all p<0.0001), reduced fibrosis (p=0.005), and modulated TGF-β1, CTGF, MMP-9, and PPAR-γ expression (p=0.0001 to <0.0001), but had no effect on MMP-2 (p=0.868). Combination therapy (PCOS/PFD/COC) provided additional improvement in corpora lutea count (p<0.0001 vs. PCOS/PFD) and collagen deposition (p=0.002 vs. PCOS/PFD) but did not confer further benefits in fibrosis-related marker expression or folliculogenesis (all p>0.05). These findings suggest that pirfenidone mitigates PCOS pathology by targeting ovarian fibrosis, supporting antifibrotic therapy as a novel and promising approach.

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Pirfenidone reduces ovarian fibrosis and improves PCOS in letrozole-induced rat model

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Published

30-06-2025

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Research article

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How to Cite

1.
Pirfenidone reduces ovarian fibrosis and improves PCOS in letrozole-induced rat model. Biomol Biomed [Internet]. 2025 Jun. 30 [cited 2025 Aug. 18];. Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12676