Divergent Effects of GnRH Agonist and GnRH Antagonist Treatment on Platelet Activity and Transcriptome

Prostate cancer is associated with increased cardiovascular risk. Among androgen deprivation therapy (ADT) modalities, the gonadotropin-releasing hormone (GnRH) antagonist relugolix appears to confer a lower risk for cardiovascular events than the GnRH agonist leuprolide.

The aim of this prospective study was to investigate the impact of relugolix and leuprolide on platelet phenotype.

Patients with prostate cancer initiating first-line ADT were prospectively enrolled. Blood samples were collected at baseline and 8 ± 4 weeks after treatment initiation. Platelet activation was assessed using flow cytometry (P-selectin, PAC-1, CD40, CD40L, and monocyte-platelet aggregates). Platelet RNA sequencing was performed to characterize treatment-associated transcriptomic changes.

Compared with healthy control subjects, patients (n = 69) exhibited elevated P-selectin expression and enrichment of thromboinflammatory pathways. During leuprolide treatment (n = 40), PAC-1 expression increased compared with baseline in response to epinephrine, thrombin, adenosine diphosphate (ADP) and arachidonic acid (AA), while P-selectin increased in response to epinephrine and was higher with ADP and AA, though not statistically different. In contrast, during relugolix treatment (n = 29), AA-induced P-selectin expression and CD40 decreased. Platelet RNA sequencing in relugolix-treated patients demonstrated down-regulation of pathways associated with platelet activation and aggregation. Finally, leuprolide-treated patients on aspirin (n = 6) did not exhibit increased AA-induced platelet activation and in vitro P2Y₁₂ inhibition of patient-derived platelets attenuated activation induced by epinephrine, ADP, and AA.

Prostate cancer is associated with heightened platelet activation and thromboinflammatory signaling. Treatment with leuprolide, but not relugolix, was associated with further augmented platelet activity. These findings support further studies to clarify links with platelet-mediated cardiovascular risk and the potential role of platelet-targeted strategies.