The GnRH antagonist reduces chemotherapy-induced ovarian damage in rats by suppressing the apoptosis

Abstract

Objective GnRH antagonist cetrorelix could reserve the ovarian follicles during chemotherapy, but the mechanism remains unclear. The objectives of this study were to examine the overall effect of cetrorelix against ovarian failure and to define if the apoptotic process was involved. Methods Female SD rats were injected with cetrorelix before and after administration of saline, or cyclophosphamide (Cy), or oral etoposide (VP). Main outcome measures were the number of ovarian follicles, serum hormones, ovary histology and apoptotic markers. Results The females exposed to Cy or VP had reduced body and ovary weights, which could be restored by cetrorelix pretreatment. Single cetrorelix treatment could increase the number of primordial follicles, but reduce the number of growing and mature follicles. As a consequence, the ovaries exposed to cetrorelix prior to Cy or VP showed significantly higher numbers of follicles at all developing stages than those exposed to Cy or VP alone. Meanwhile, the ovarian apoptotic indexes as shown by TUNEL assay were reduced by cetrorelix pretreatment and the ovary expressed less caspases-3 and more Bcl-2 compared with chemotherapy alone. Moreover, the rats regained normal hormonal profile after cetrorelix pretreatment without any alterations in ovarian expression of estrogen receptor (ER)α, ERβ, or progesterone receptor (PR). Conclusion Cetrorelix could reduce the chemotherapy-induced ovarian damage through regulating the expression of Bcl-2 and caspases-3 in the ovary, without any expressional alterations of nuclear receptors, suggesting the apoptosis pathway involved.