The Gonadotoxic Effects of Conditioning Chemotherapy Regimens Prior to Hematopoietic Stem Cell Transplantation [ID: 1376168

Abstract

INTRODUCTION: Primary ovarian insufficiency secondary to high-dose chemotherapy in females undergoing the conditioning regimen before hematopoietic stem cell transplantation is a challenging late complication. Limited studies have investigated the ovarian toxicity of various conditioning regimens. This study aimed to explore the gonadotoxic effects of cyclophosphamide (CY) and busulfan (BU) in CD-1 mice strain. METHODS: Sixteen 1-month-old female CD-1 mice (n=4/group) were subcutaneously injected with solvent, BU, CY, or BU+CY, respectively. The doses (144 mg/kg BU and 300 mg/kg CY) and injection plan were adjusted to human doses. The ovaries and female reproductive tracts were harvested 1 week after the last administration. Follicle counting was performed. The levels of serum antimüllerian hormone (AMH) and 17-beta-estradiol were measured. Animal use approval was obtained from the Institutional Animal Care and Use Committee at the University of Nebraska Medical Center. RESULTS: All mice survived the injections and grossly appeared normal. The average ovary weight was significantly lower in BU (P=.0007) and BU+CY (P<.0001) groups than in the control and CY groups. The primordial (P<.0001) and primary follicles (P=.01) in treatment groups were decreased compared to the control group. The serum AMH level in the BU group was also significantly lower than the control and CY group (P=.003). CONCLUSION: We show that conditioning chemotherapy with CY and BU can reduce the ovarian reserve in CD-1 mice strain and may have a synergic effect. Future studies to investigate the mechanism of chemotherapy-related ovarian follicle death are needed to improve fertility outcomes in patients receiving conditioning chemotherapy.