The effects of immune checkpoint inhibitors and targeted therapies on female fertility and ovarian function: a systematic review.

OBJECTIVE

Advances in cancer survival have made fertility preservation an essential clinical need for young female patients. While traditional chemotherapy's gonadotoxicity is well established, the effects of newer systemic therapies (immune checkpoint inhibitors, poly [adenosine diphosphate-ribose] polymerase inhibitors, and cyclin-dependent kinase 4/6 inhibitors) on female fertility remain unclear. This systematic review aims to compare the impact of these agents on ovarian function and fertility outcomes.

METHODS

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed/MEDLINE and Cochrane Library for studies published between January 2020 and December 2025. We included clinical and pre-clinical original research articles examining the effects of immune checkpoint inhibitors or targeted therapies on fertility in women of reproductive age or suitable pre-clinical models. Clinical studies were assessed using the Newcastle-Ottawa Scale and pre-clinical studies using Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool.

RESULTS

Eleven studies met the inclusion criteria, including 6 pre-clinical studies and 5 clinical investigations. Pre-clinical studies evaluating poly (adenosine diphosphate-ribose) polymerase inhibitors consistently reported reductions in primordial follicle counts and increased markers of DNA damage in ovarian tissue, suggesting potential impairment of ovarian reserve. Clinical and pharmacovigilance data on immune checkpoint inhibitors indicate possible immune-mediated ovarian dysfunction, including menstrual irregularities and cases of ovarian insufficiency reported in small observational cohorts. In contrast, available clinical data on cyclin-dependent kinase 4/6 inhibitors did not demonstrate clear additional gonadotoxic effects beyond those associated with prior systemic therapies. Most available evidence is derived from pre-clinical studies and small observational clinical cohorts, which limits the strength of conclusions regarding fertility outcomes.

CONCLUSIONS

Current evidence suggests potential gonadotoxic effects of poly (adenosine diphosphate-ribose) polymerase inhibitors, primarily based on pre-clinical findings. In contrast, available clinical data do not demonstrate clear additional gonadotoxicity associated with immune checkpoint inhibitors or cyclin-dependent kinase 4/6 inhibitors, although evidence remains limited. As most data derive from pre-clinical models and small observational cohorts, findings should be interpreted cautiously, highlighting the need for prospective studies with standardized fertility end points.