Our study provides novel data about molecular mechanisms by which estradiol alone or together with GPER agonists and GPER and PPAR antagonists may modulate the expression of TGF-β, inflammation factor COX-2, and two factors implicated in vascularization and angiogenesis (VEGF and HIF-1α) via the MAPK and PI3K/Akt signaling in mouse testicular explants and mouse tumor Leydig cells. This evidence concerns the gene HIF1A and neoplasm.