Acromegaly: A Critical Narrative Review of Pathogenesis, Tumour Classification, Systemic Manifestations and Evolving Therapeutic Paradigms

Abstract

Acromegaly is a chronic disorder of growth hormone and insulin-like growth factor 1 excess, caused in almost all cases by a somatotroph pituitary neuroendocrine tumour. Three developments have changed the field within a single decade: the reclassification of pituitary neoplasms around transcription-factor lineage and tumour subtype, the accumulation of population-scale data on systemic morbidity and survival, and the arrival of orally administered and subcutaneously self-administered somatostatin receptor agonists alongside established injectable and receptor-antagonist therapies. These strands have largely been reviewed separately, and the practical question of whether tumour biology can be used to direct treatment selection remains unresolved. This critical narrative review synthesises evidence retrieved from scholarly databases and verified bibliographic sources, with searches completed on 21 July 2026, in order to examine how mechanistic understanding, histopathological and radiological classification, clinical phenotype and therapeutic choice relate to one another. Evidence indicates that somatic activating mutations of the stimulatory G protein alpha subunit, germline predisposition genes and chromatin-level dysregulation define partially distinct tumour subgroups, and that sparsely granulated morphology, low somatostatin receptor subtype 2 expression and hyperintense T2-weighted magnetic resonance signal converge on a phenotype that responds poorly to first-generation somatostatin receptor ligands. Support for acting on these markers rests largely on retrospective series and one prospective randomised protocol, so confidence in routine biomarker-directed prescribing remains moderate at best. Population studies show that mortality approaches that of the general population once biochemical control is achieved, yet arthropathy, vertebral fragility, sleep-disordered breathing and impaired quality of life frequently persist, indicating that current treatment targets are necessary but insufficient. Comparative efficacy estimates derived from network meta-analysis are internally inconsistent and sensitive to the evidence included. Priorities for research include prospective validation of predictive markers, trials powered for patient-reported and structural outcomes rather than hormone concentrations alone, and evidence generation in settings where access to surgical expertise and modern pharmacotherapy is constrained.