Antiestrogenic and antiprogestational activity of methotrexate and its effect on uterine histoarchitecture of ovariectomized albino rats

Background: Methotrexate (MTX) is used as an antineoplastic drug in the treatment of various cancers and non -cancerous diseases. Ovarian ablation is considered to be effective in delaying recurrence of cancer and increasing survival in young women. When added to chemotherapy, it is less clear that this technique is effective. Uniqueness of the present study is that we used ovariectomized (OVX) rats as an experimental model to investigate the action of MTX and leucovorin (LCN) a universal antidote on uterus without or with estrogen and progesterone replacement therapy. Results: The present study describes the drug effects on body and organ weights, histopathology of uterus and steroidogenic acute regulatory protein (StAR) expression in the uterus. MTX treatment decreased body and organ (oviduct, uterus, cervix and vagina) weights in OVX rats. Histopathological studies revealed that MTX treatment regressed uterine epithelium and stroma revealing its anti-uterotrophic property. Considerable increase in body and uterus weights and improvement in histology of uterus were observed after estradiol and progesterone replacement. However, such changes were significantly decreased when MTX was treated in combination with LCN, estradiol and progesterone. Conclusion: Our results unambiguously revealed that steroidogenic marker StAR protein expression in OVX uterus was enhanced by steroids supplementation. Additionally, MTX treatment alone or in combination with LCN, E2 and P treatment inhibited StAR protein expression in uterus thereby affecting steroid hormones replacement. LCN supplementation did not bring about a rescue of uterus and the side effects were profound. These results for the first time indicate antiestrogenic and antiprogestational action of MTX.