The Study On Using Gonadotropin-Releasing Hormone Antagonist Combination With Estrogen In Preventing The Ovarian Damage Induced By Cisplatin In Mouse Model

In the last two decades, the survival rates for many of the malignancies that affect young adults have markedly improved as a result of advances in supportive care and changes in cancer therapies. For many of these malignancies, survival rates exceed 80-90%. However, with these advancements cancer survivors now face the long-term consequences of treatment with intensive, multimodality therapies. Young women exposed to various forms of cancer therapy, particularly high-dose chemotherapy, can potentially suffer the loss of reproductive function, with damage ranging from minimal to complete ovarian failure. According to some epidemiological studies, damage to ovarian function with subsequent sterility and premature ovarian failure (POF) has been observed in 70-80% of cases after successful antitumour therapy. Furthermore,in these women, ovarian failure does not imply onlya loss of fertility (reproductive function) but also the loss of estrogen production (endocrine function) by the ovaries, including vasomotor symptoms, vaginal dryness, body weight gain, rapid bone loss and risk of subsequent fracture. Since many of these patients are young, with expectations of a normal reproductive life-span, premature menopause and sterilization can impact their quality of life and self-esteem dramatically.Cisplatin(CDDP) a commonly used chemotherapeutic agent used to treat a wide range of cancers, including testicular,ovarian, bladder, cervical, head and neck, and smallcell and non-small-cell lung cancers. But it is associated with a variety of side effects. In rats, cisplatin has been shown to cause ovarian funtion damage,increased follicular apoptosis, decreased expression of anti-mullerian hormone (AMH) alterations in the estrous cycle, and a decrease in the number of AMH-producing follicles. In humans, cisplatin has been demonstrated to cause increased incidences of premature ovarian failure.Thus, protection against iatrogenic premature ovarian failure caused by chemotherapy currently is of high priority.Because dividing cells are known to be more sensitive to the cytotoxic effects of chemotherapeutic agents than are cells at rest, it has been suggested that inhibition of the pituitary-gonadal axis would reduce the rate of oogenesis and thereby render the germinal epithelium less susceptible to the effects of chemotherapy. Several investigators have demonstrated that GnRH analogues(GnRH agonists and GnRH antagonists) can inhibit the pituitary-gonadal axis in order to inhibit chemotherapy-induced ovarian follicular depletion.GnRH agonists causes a " flare-up " period of 1-2 weeks, during which the stimulated ovaries may be more vulnerable to the gonadotoxic effect of chemotherapy before pituitary-ovarian desensitization is accomplished. Several investigators may examine GnRH-antagonists instead of agonists, eliminating the waiting period of 7-14 days needed by the GnRH agonists to achieve down regulation. Indeed, Meirow et al have previously demonstrated that in mice a GnRH antagonist significantly reduced the number of primordial follicles loss after exposure to different doses of cyclophophamide.GnRH antagonist have side effects such as hot flashes and decreased bone density. It is accepted that the loss of bone mineral density in this situation may be reduced significantly by using low doses of hormone replacement therapy or tibolone. A report about add-back therapy with tibolone can alleviate the undesirable hypoestrogenic effectsof the GnRH antagonist, including vasomotor symptoms and loss in bone mineral content, thus making long-term treatment with GnRH antagonist safer and more acceptable.ObjectiveTo investigate the effect of using gonadotropin-releasing hormone antagonist (GnRH Antagonist) combination with estrogen in preventing cisplatin-induced ovarian failure in mice model.Materials and Methods1 MethodsForty young female BALB/c mice of 5-6 weeks were randomly divided into four groups:the control group, cisplatin(DDP) group,GnRHant(cetrorelix)+estrogen (progynova) group, cetrorelix+progynova+DDP group.Mouse weight change, ovary and uterus wet weight, the numbers of the follicle and histomorphological features of ovary were observed. Radioimmunoassay was used to analyze serum level of follicle-stimulating hormone (FSH) and estradiol (E2) among the four groups.2 Statistical treatmentData were recorded and analyzed by using the Statistical Package for Social Sciences software, version 13.0 One-way ANOVAs were used for statistical analysis of the different treatment groups. LSD was used for comparison between any two groups. Statistical significance was set at a=0.05.Results1. The average ovarian and uterine weight and mouse weightof DDP group were lower than that of the other group(P<0.05). The weight changes in the rest of the three groups, there is no statistical significance differences (P<0.05).2. As compared with the other group,FSH levels of DDP group significantly increased and E2 level of DDP group significantly decreased(P<0.05).That level in the other group,there is no statistical significance. 3. As compared with the control group, DDP treatments produced a significant reduction in the total number of follicle, especially the growth and maturation follicle (P<0.05). Cetrorelix significantly reduced the number of medium-large follicles and increased the number of small one, the total number of follicles did not decrease(P>0.05).Conclusions1. Cisplatin can cause a certain degree of ovarian funtion damage.2. GnRHant combination with estrogen could reduce the chemotherapy-induced ovarian damage in mice.