Pituitary adenomas (PitNETs): molecular pathophysiology, targeted drug delivery strategies and clinical therapeutic...

Pituitary neuroendocrine tumors (PitNETs), historically referred to as pituitary adenomas, comprise a heterogeneous group of neuroendocrine tumors with diverse hormonal phenotypes, molecular characteristics, and clinical behavior. Their management includes surgery, pharmacological therapy, radiotherapy, and, in selected refractory cases, systemic or molecularly targeted approaches. Advances in molecular endocrinology have identified recurrent alterations and dysregulated signaling networks, including GNAS, USP8, PI3K/AKT/mTOR, and MAPK-associated pathways, that contribute to the biological heterogeneity of PitNETs. This review summarizes the molecular mechanisms underlying PitNET development and examines established pharmacological therapies, including dopamine agonists, somatostatin receptor ligands, growth hormone receptor antagonists, and temozolomide, with emphasis on their mechanisms and clinical evidence. Emerging molecularly targeted approaches, including mTOR inhibition, EGFR-associated targeting, anti-angiogenic therapy, and immune checkpoint inhibition, are discussed according to their current level of experimental and clinical evidence. The review also evaluates advanced drug-delivery strategies relevant to pituitary disease, including intranasal delivery, nanoparticle-based systems, liposomal carriers, receptor-targeted platforms, and sustained-release formulations. Particular attention is given to the distinction between clinically established delivery technologies and approaches that remain experimental or are supported primarily by evidence extrapolated from other therapeutic areas. Clinical trial evidence is further summarized to contextualize the efficacy, limitations, and translational status of current and emerging therapies. Together, these perspectives highlight the opportunities and remaining challenges in developing more precise pharmacological and drug-delivery strategies for the management of PitNETs.