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KMID : 0378019680110060067
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New Medical Journal
1968 Volume.11 No. 6 p.67 ~ p.77
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The Effects of Methotrexate on the Gonads and Other Organs in Rats
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Abstract
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Since the report of a dramatic effect of folic acid antagonist on acute leukemia of children in 1 year Farber et al. methotrexate has been used widely for the treatment of various types of malignancy. Li et al. (1963), Li et al. 0966), Mertz (1961, 1963) and Solomon et al. (1967) reported that methotrexate can not only arrest but also cure choriocarcinoma. In view of the fact that choriocarcinoma is originated from embryonal tissue element, methotrexate has been tried to treat tumors of germ cell origin in the testis and ovary (Mackenzie 1966, Solomon et al. 1967).
Mechanism of the action of methotrexate is attributed to its antagonistic effect against folic acid which is necessary for the synthesis of DNA and RNA as well as for cell maturation (Werkheizer, 19963, Bertino et al. 1964). By virtue of this effect methotrexate inhibit the growth of any types of cells which grow -rapidly, as well as neoplastic cells. Most frequently and markedly affected non-neoplastic tissues include hematopoietic tissue, liver and the mucosa of gastrointestinal tract.
The ovary and testis contain relatively rapidly growing tissue elements, such as germ cells and follicular cell components. Therefore, it, is thought that methotrexate may affect these continuously growing tissue elements in the gonads. Present investigation is designed to investigate the effects of methotrexate on the gonadal tissue in comparison with the previously proved effects on other tissues.
Materials and Methods
Albino rats; young and adult females, young and adult males, were divided into four major groups and treated as follows.
Group I : Young femxale rats
A. Normal untreated control(12 rats)
B. Methotrexate administration for 1-course(12 rats)
C. Methotrexate administration for 2 courses(12 rats)
Group I : Adult female rats
A. Normal untreated control(12 rats)
B. Methotrexate administration for 1 course(12 rats)
C. Methotrexate administration for 2 courses(12 rats)
Group IQ : Young male rats
A. Normal untreated control(12 rats)
B. Methotrexate administration for 1 course(12 rats)
C. Methotrexate administration for 2 courses(12 rats)
Group IV Adult male rats
A. Normal untreated control(12 rats)
B. Methotrexate administration for 1 course(12 rats)
C. Methotrexate administration for 2 courses(12 rats)
Body weight of around 100 gms were used for young group while the body weight of adult group was around 180 gms. Methotrexate was given orally in a dose of 0.4 mg per kg of body weight once a day for 5 consecutive days for 1 course, and the 2nd course of 5 days with same dose are given
20 days after the end of the 1st course. 141
From each group, 4 animals were killed at the Ist, 10th and 20th day after the ending of methop~ ;
trexate administration. The changes of body and organ weight following the treatment of
methotrexate were checked, and histological examinations of the ovary, testes, liver, bone marrow,
spleen,and other organs are made. Tissues for histologic examinations were fixed in 10% neutral
formalin, and cut in 6p. thickness after paraffin embedding, and stained with hematoxylin and eosin.
Results and Summary
a´
There was no notable changes of body weight increase in young animal groups, but the adult groups shoved slight depression on the body weight increase after the 2nd course of methotrexate administration. The weight of the ovary and testis did not alter notably in all groups, but the weight of the liver and spleen showed marked fluctuation following the administration of methotrexate in all groups. Immediately after the methotrexate administration, the weight of the liver and spleen diminished, and it was followed by rapid and marked rebound increase at the 10th day after the cessation of methotrexate treatment, thereafter returning to normal level.
Histologic alterations in the ovary consisted of maturation arrest of the developing follicles and depression of luteinization of corpus luteum with occasional focal necrosis in the corpus luteum, and marked increase of interstitial cell mass. Histologic alteration of the testis consisted of depression of spermatogenesis, as evidenced by the decrease of spermatocytes, spermatids and spermatozoa. Associated with the decrease of cell population, a tendency of nuclear enlargment was noted, but no multinucleated giant cell formation or frank necrosis of the cells were found. The most markedly affected cells were spermatocytes and the least affected were spermatogoma.
The bone. marrow showed marked hypoplastic picture with congestion and even hemorrhage immediately after the cessation of methotrexate treatment, but it regenerated promptly to normal or even hyperplastic state at the 10th day. The spleen showed a marked degree of extramedullary hematopoiesis at the 10th day after the cessation of methotrexate treatment.
Histologic alterations in the Liver were a mild degree of cloudy swelling and fltty degeneration, and the histologic alterations in the kidney and adrenals were not remarkable.
In summary, administration of methotrexate in a dose of 0.4 mg/kg of body weight produced rather marked depression on the bone marrow, but induced relatively little effect on the ovary and testes, indicating that the gonads will not be effected greatly as long as the dose of methotrexate is tolerable to the bone marrow.
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KEYWORD
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