Examination of the effects of methotrexate on histological and steroid receptor changes in the endosalpinx of the rat.
OBJECTIVE
Methotrexate (MTX) has been a prevalent drug in conservative treatment of unruptured tubal pregnancy for many years. However, few researchers have performed morphological and protein analysis simultaneously to evaluate the specific toxic effects of MTX on the fallopian tubes. The aim of this study was to investigate acute and long-term toxic effects of increasing doses of MTX on the fallopian tubes and a possible dose-effect relationship. We also discuss the potential implications for subsequent pregnancies.


METHODS
At the 10th day and the 2nd and 3rd months after MTX treatment, a total of 108 females SD rats in estrus stage (27 rats in each group) were collected according to the dose of MTX i.p.: 1, 2, 5mg/kg body weight in groups I, II and III respectively and physiological saline i.p. in group IV for control. Nine rats in each group were killed at each time point and tissues close to the ampulla of the fallopian tubes were dissected for HE staining and routine histological observation. Estrogen receptor (ER) and progesterone receptor (PR) expression was detected by immunohistochemistry and Western blot.


RESULTS
Morphological observation showed acute endosalpingitis in group I, becoming more intense with increasing doses of MTX in groups II and III in a reversible mode. Expression of ER in the endosalpinx significantly decreased in parallel with increasing doses of MTX in a dose-effect manner, which was reversible in groups I and II and irreversible in group III. Furthermore, ER and PR could recover close to normal levels in groups I and II after the 3rd month, while they could not restore to normal in group III.


CONCLUSIONS
These results provide the first evidence that MTX (>or=5mg/kg) can induce long-term, irreversible damage to steroid hormone receptors in the fallopian tubes in a dose-dependent manner. We tentatively suggest that MTX should be used in a relatively small and safe range of dosage in order to avoid impairment and potential risk of subsequent tubal pregnancy or infertility.
Yang
Xiao-Jun
XJ
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang Province 325000, PR China. laoyangxiao@yahoo.com.cn
Wang
Han-Chu
HC
Chen
Yan-Ping
YP
Zhao
Jing
J
Zheng
Fei-Yun
FY
D000020:Abortifacient Agents, Nonsteroidal / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005187:Fallopian Tubes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007247:Infertility, Female / Q000453:epidemiology; D008727:Methotrexate / Q000009:adverse effects / Q000494:pharmacology*; D023421:Models, Animal; D011247:Pregnancy; D011274:Pregnancy, Tubal / Q000453:epidemiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012307:Risk Factors
D000020:Abortifacient Agents, Nonsteroidal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D008727:Methotrexate