Dopamine agonist-associated fibrosis in prolactinomas: clinical challenges, impacts on the tumor microenvironment, and future directions

Prolactinomas account for approximately 30% to 50% of pituitary adenomas. Dopamine agonists (DAs) are the first-line treatment and effectively induce tumor regression while normalizing prolactin levels. However, DA therapy not only inhibits tumor growth but also is associated with fibrosis within the tumor. This fibrotic transformation remodels the tumor microenvironment (TME), altering cellular interactions, vascular structures, and extracellular matrix (ECM) composition. We hypothesize that this fibrotic response may not be a mere side effect; emerging, though largely indirect, evidence suggests it could potentially protect residual tumor cells by impeding drug penetration and facilitating immune evasion. Despite extensive clinical use of DAs, the mechanisms underlying DA-associated fibrosis and its implications for tumor behavior as well as patient outcomes remain poorly understood. This review integrates current knowledge regarding the pathophysiological processes leading to DA-associated fibrosis in prolactinomas, explores alterations in the TME, and assesses the clinical implications of these alterations. By integrating recent experimental and clinical studies, we aim to provide a comprehensive overview that elucidates the challenges posed by this fibrotic change in DA therapy and to propose actionable avenues for future research aimed at overcoming these obstacles.