Methotrexate (MTX) an antifolate drug and leucovorin its antidote, are used in the treatment of both neoplastic and non-neoplastic diseases in young women. We hypothesize that MTX treatment might comprise a deleterious effect on fast proliferating reproductive cells, an unavoidable and unwanted side effect. MTX given dose dependently to rats for 20 days prevented vaginal cyclicity and caused a reduction in serum progesterone and estradiol. External morphology of reproductive tract displayed thinning of organs and reduction in their weights. To reveal mechanism of MTX action, we examined the histology of ovary, oviduct, uterus, cervix and vagina. Results suggested that in a dose-dependent fashion MTX restrained preantral and antral follicular growth in ovary. Epithelium and stroma of oviduct, uterus, cervix and vagina were disrupted and lost their normal structures. Such alterations in ovarian function raised serum follicle stimulating hormone, luteinizing hormonal profiles. Expression of steroidogenic acute regulatory protein and P450 cholesterol side chain cleavage gene, which are both essential for steroidogenesis, markedly decreased in ovary upon MTX treatment. Total RNA, DNA and protein concentrations, glucose 6 phosphate dehydrogenase, lactate dehydrogenase and alkaline phosphatase enzyme activities in ovary were distinctly altered. Leucovorin supplementation and withdrawal of the treatment, improved MTX caused effects partially. These results for the first time indicate that the malfunction of female reproductive organs by MTX treatment in young women is not only correlated to the disrupted circulating levels of hormones and histoarchitecture of tissues but also discrepancies in steroidogenic genes and hormone regulated enzyme activities in ovary.
The effects of single dose, 4 consecutive days, 4 and 8 weekly doses of methotrexate (MTX) treatment (3 mg/kg body weight, intramuscularly) with and without leucovorin (LCN) supplementation (0.3 mg/kg body weight, intramuscularly) on serum testosterone titres, total, free and esterified cholesterol concentrations and steroidogenic enzymes, viz. 3beta- and 17beta-hydroxy steroid dehydrogenase activities were studied in adult albino rats. MTX treatment caused a marked reduction in serum testosterone titres in all the treatment groups in a duration-dependent manner. LCN supplementation did not restore serum testosterone titres to normalcy. Total and free cholesterol concentrations remained unaltered in both MTX and MTX + LCN treated groups. On the other hand, a marked increase in esterified cholesterol concentration was evident only in weekly dose treatment groups. The specific activities of 3beta- and 17beta-hydroxy steroid dehydrogenase were markedly diminished in both MTX and MTX + LCN treated groups. The results suggest the inhibitory effect of MTX on steroidogenesis.
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