Towards non-surgical therapy for uterine fibroids: Catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model

M. H. Hassan, H. Fouad, S. Bahashwan, A. Al-Hendy

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background Uterine leiomyomas (fibroids) are the most common pelvic tumors in women. We assessed the potential therapeutic utility of Ro 41-0960, a synthetic catechol-O-methyl transferase inhibitor (COMTI), in the Eker rat. Methods We randomized uterine fibroid-bearing Eker rats for treatment with Ro 41-0960 (150 mg/kg/12 h) versus vehicle for 2 and 4 weeks. The fibroids were measured by caliper and subjected to histological evaluation. Urinary levels of 2-hydroxy estrogen (E2), 16-hydroxy E2 and DPD (osteoporosis marker) and serum liver enzymes were evaluated. Expressions of Cyclin D1, proliferating cell nuclear antigen (PCNA), Poly [ADP-ribose] polymerase1 (PARP1), tumor suppressor gene (P53) and transforming growth factor (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RTPCR. Apoptosis was confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL). Results Ro 41-0960-treated rats exhibited fibroid volumes of 86 ± 7 and 105 ± 12 of initial burden, at 2 and 4 weeks post-treatment, respectively, significantly lower than control group (240 ± 15 and 300 ± 18; P< 0.01). Ro 41-0960 increased the urinary 2-hydroxy E2/16-hydroxy E2 ratio, level of p53 mRNA and TUNEL positivity (P< 0.05) and decreased PARP1, PCNA and cyclin D1 proteins and TGFβ3 mRNA (P< 0.05). Ro 41-0960 did not change normal tissue histology, liver functions or urinary DPD level. Conclusions Ro 41-0960 (COMTI) arrested growth/shrunk uterine fibroids in Eker rats. This result may be related to modulation of estrogen-dependent genes involved in apoptosis, proliferation and extracellular matrix deposition via accumulation of 2-hydroxy estrogen. The efficacy and safety of Ro 41-0960 in rats suggest its candidacy for treatment of uterine fibroids.

Original languageEnglish (US)
Pages (from-to)3008-3018
Number of pages11
JournalHuman Reproduction
Volume26
Issue number11
DOIs
StatePublished - Nov 2011

Keywords

  • Eker rats
  • catechol estrogen
  • catechol-O-methyl transferase inhibitor
  • estradiol
  • uterine leiomyomas

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

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