Effects and mechanism of cyclophosphamide on the ovarian structure and function of rats with premature ovarian failure

Effects and mechanism of cyclophosphamide on the ovarian structure and function of rats with premature ovarian failure WEI Tian-qin, LING Li, FENG Xiu-shan, ZHANG Wen-qian, XIONG Zheng-ai Department of Gynecology and Obstetrics, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China Corresponding author, E-mail: docxza@163.com This work was supported by the National Natural Science Foundation of China (81671415) [Abstract] Objective To establish the premature ovarian insufficiency (POI) rat model with cyclophosphamide (CTX), and investigate the effects and mechanism of CTX on the ovarian structure and function. Methods Fifty female Sprague-Dawley (SD) rats were randomly divided into model group and control group. Rats in model group received intraperitoneal injection of loading dose CTX (50mg/kg), and maintenance dose of 8mg/(kg·d) for 14 days. Rats in the control group were given the same amount of saline during the same period. The modeling effects were judged by observation and comparison of estrous cycle, levels of sex hormone and morphological changes of organs between the two groups; the apoptosis of follicular granulose cell were detected by TUNEL, the contents of inflammatory cytokines in tissue homogenates were detected by ELISA, and the expressions of apoptosis related proteins were measured by Western blotting. Results Compared with control group, the estrous cycle in model group was disordered; the levels of serum anti-mullerian hormone (AMH) and estrogen (E2) decreased significantly (P<0.01) and those of follicle stimulating hormone (FSH) increased markedly (P<0.01); the quantity of follicles decreased obviously (P<0.05); the endometrium atrophied, the uterine wall thinned and the glands decreased in number. Compared with the control group, the apoptosis of follicular granulose cells increased in model group; the contents of TNF, IL-1 and IL-6 in the tissue homogenate increased significantly (P<0.01), the contents of vascular endothelial growth factor(VEGF) decreased markedly (P<0.01); the expression of apoptosis related protein Bax was up-regulated remarkably (P<0.01), while of Bcl-2 was down-regulated obviously (P<0.01). Conclusion CTX may induce the changes of ovary structure and endocrine function, and the mechanism may be related to the local microenvironment changes and the imbalance of Bax/Bcl-2 expression in regulating the apoptosis of granulose cells. [Keywords] cyclophosphamide; premature ovarian insufficiency; estrous cycle; Bax; Bcl-2