Humanin alone and in Combination with GnRHa therapy attenuates ovarian dysfunction induced by prepubertal cyclophosphamide chemotherapy in female mice

Liu Liu; Huawei Wang; Wen Wen; Shunqing Wang; Liqin Zuo; Yulin Cheng; Meng Rao; Yuru Ma; Li Tang

doi:10.1016/j.reprotox.2024.108824

Humanin alone and in Combination with GnRHa therapy attenuates ovarian dysfunction induced by prepubertal cyclophosphamide chemotherapy in female mice

Reprod Toxicol. 2025 Jan 8:108824. doi: 10.1016/j.reprotox.2024.108824. Online ahead of print.

Authors

Liu Liu¹, Huawei Wang¹, Wen Wen¹, Shunqing Wang¹, Liqin Zuo¹, Yulin Cheng¹, Meng Rao¹, Yuru Ma¹, Li Tang¹

Affiliation

¹ Reproductive Genetics Department, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.

PMID: 39793741
DOI: 10.1016/j.reprotox.2024.108824

Abstract

Prepubertal chemotherapy induced ovarian damage poses a significant threat to female fertility, particularly following cyclophosphamide (CP) treatment. Humanin (HNG), a small molecule polypeptide encoded by mitochondrial DNA, has a variety of effects, this study aimed to investigate the protective effects of HNG and its combination with conventional Gonadotropin Releasing Hormone Agonist (GnRHa) on ovarian function in a CP-induced damage model. The 21-day-old C57BL/6J female mice were randomly assigned to six groups: Control, CP model, HNG, HNG+CP, GnRHa+CP, and HNG+GnRHa+CP. Ovarian function was assessed through histopathological examination, follicle counts, serum sex hormone levels, estrous cycle monitoring, and oxidative stress evaluation. Results indicated that CP treatment led to significant reproductive dysfunction especially ovarian dysfunction, evidenced by reduced follicles, hormonal imbalances, prolonged estrous cycles, reduced body weight, and diminished ovarian and uterine weights, alongside pathological alterations. Notably, HNG treatment, both alone and in conjunction with GnRHa, significantly mitigated these adverse effects, however the combination did not provide additional benefits over HNG alone regarding follicles preservation and antioxidant capacity. Transcriptomic analysis revealed significant enrichment in inflammation and immune response pathways following HNG treatment. In conclusion, HNG demonstrates potential as a therapeutic agent to protect against CP-induced ovarian damage, offering insights for future strategies aimed at preserving female fertility during chemotherapy.

Keywords: GnRHa; Humanin; Prepubertal chemotherapy; fertility preservation; ovarian dysfunction.