CDK4/6 inhibitörlerinin insan overinde dormant foliküller ve steroidogenez üzerine etkileri

CDK4/6 inhibitors, including palbociclib and ribociclib, are established therapies for hormone receptor–positive breast cancer, yet their potential effects on ovarian physiology remain largely unexplored. The human ovary contains a finite pool of dormant follicles and relies on granulosa cell function for coordinated endocrine activity, raising the question of whether pharmacologic CDK4/6 inhibition could alter ovarian function. This study investigated the effects of CDK4/6 inhibition in human ovarian models using a multilayered approach that incorporated proliferative non-luteinized granulosa cell lines (HGrC1, COV434), primary luteinized granulosa cells (HLGCs), and ovarian cortical explants. CDK4/6 inhibitors consistently enforced G1 arrest by preventing Rb phosphorylation and activating the pRb–E2F1–p21 cascade, confirming a cytostatic rather than cytotoxic mechanism. In HLGCs, modest dose and inhibitor specific reductions in CYP19A1 and 3β-HSD expression were detected, but estradiol and progesterone secretion remained stable. In ovarian explants, estradiol and AMH secretion were preserved for up to 72 hours with steroidogenic enzyme expression remaining stable in the short term. Apoptotic activation was not observed with palbociclib, whereas ribociclib produced a compound-specific reduction in total PARP without loss of viability. Taken together, these findings provide the first integrated preclinical evidence in human ovarian models that CDK4/6 inhibition may not acutely compromise endocrine function or reserve markers. While ovarian steroidogenesis appears resilient to short-term pharmacologic CDK4/6 inhibition, further long-term and in vivo studies are required to clarify the consequences of longer exposure on ovarian function.