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Effects of PD-1 inhibitors on ovarian function-based on two-sample mendelian randomization and visualization
Jiaxin Zheng1, Na Zhu2, Chang Liu3
1Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, China; Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Faculty of Medicine, Dalian University of Technology, Dalian, China.
Immune checkpoint inhibitors (ICIs) targeting PD-1 do not appear to cause acute ovarian toxicity. This study found no evidence of harm to ovarian function or follicular health from PD-1 inhibitors in preclinical models, supporting their use in fertility-sparing cancer treatments.
Area of Science:
- Oncology
- Immunology
- Reproductive Biology
Background:
- Immune checkpoint inhibitors (ICIs) have improved cancer survival.
- Ovarian safety of ICIs, particularly PD-1 inhibitors, requires further investigation.
- Understanding ICI impact on ovarian function is crucial for fertility-sparing treatments.
Purpose of the Study:
- To assess the impact of PD-1 inhibitors on ovarian function using both Mendelian randomization (MR) and in vitro experimental validation.
- To determine if PD-1 inhibition affects ovarian morphology, endocrine function, or cellular stress.
- To evaluate the acute ovarian toxicity of PD-1 inhibitors at clinically relevant concentrations.
Main Methods:
- Combined Mendelian randomization (MR) with genome-wide association studies (GWAS) data.
- Conducted in vitro experiments using mouse follicles treated with a PD-1 inhibitor, doxorubicin (DOX), or PBS.
- Assessed follicular morphology, estradiol (E2) secretion via ELISA, and cytoplasmic Ca2+ dynamics using FRET-based probes.
Main Results:
- MR analysis revealed no significant genetic association between PD-1 levels and risks of premature ovarian insufficiency or infertility.
- In vitro experiments showed PD-1 inhibitor treatment did not alter follicular size or E2 secretion.
- Doxorubicin induced significant Ca2+ elevation, while PD-1 inhibitors had no effect on Ca2+ dynamics, indicating no acute cellular stress.
Conclusions:
- PD-1 inhibitors at clinically relevant concentrations demonstrate no acute ovarian toxicity.
- These findings support the safety of standard anti-PD-1 immunotherapy in fertility-sparing oncology protocols.
- Further research is warranted to evaluate the long-term effects of PD-1 inhibitors on ovarian function.
