GnRH antagonist cetrorelix inhibits mitochondria-dependent apoptosis triggered by chemotherapy in granulosa cells of rats.
OBJECTIVE
Exposure to chemotherapy causes various adverse effects on the ovaries including premature ovarian failure and infertility. GnRH antagonist cetrorelix could reverse the ovarian damage during chemotherapy, but the mechanism remains unclear. The objectives of this study were to examine the role of the cetrorelix for prevention of mitochondria-dependent apoptosis in granulosa cells of rats during the treatment with cyclophosphamide(Cy), if the mitochondria-dependent apoptotic process was involved.


METHODS
Female SD rats were injected with cetrorelix before and after administration of saline, or Cy. Main outcome measures were the apoptotic indexes, serum hormones, ultrastructure of granulosa cells, mitochondrial membrane potential, the kinetics of cytochrome c (Cyt-c) processing in cells, and apoptotic markers.


RESULTS
The ovarian apoptotic indexes as shown by TUNEL assay were reduced by cetrorelix pretreatment and the rats regained normal hormonal profile. The ultrastructure and JC-1 fluorescence intensity assessments showed cetrorelix pretreatment inhibited mitochondrial dysfunction in granulosa cells induced by chemotherapy. Western blot analysis showed that cetrorelix suppressed the release of Cyt-c from mitochondria to cytoplasm. Meanwhile, cetrorelix pretreatment expressed less Bax, caspase-3 and Cyt-c in granulosa cells compared with chemotherapy alone.


CONCLUSIONS
Cetrorelix could reduce the apoptosis in granulosa cells through inhibiting mitochondria-dependent apoptosis triggered by chemotherapy.
Zhao
Xue-Jing
XJ
Department of Obstetrics and Gynecology, Xi'jing Hospital, 4th Military Medical University, Xi'an, Shaanxi 710033, PR China.
Huang
Yan-Hong
YH
Yu
Yue-Cheng
YC
Xin
Xiao-Yan
XY
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000096:biosynthesis; D003520:Cyclophosphamide / Q000494:pharmacology*; D045304:Cytochromes c / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D006727:Hormone Antagonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011374:Progesterone / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D018906:Antineoplastic Agents, Alkylating; C494828:Bax protein, rat; D006727:Hormone Antagonists; D051028:bcl-2-Associated X Protein; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D003520:Cyclophosphamide; D045304:Cytochromes c; D053148:Caspase 3; C062876:cetrorelix