Case: A 41-year-old man presented with a two-year history of proximal myopathy, back pain, height loss and easy bruising. His background included type 2 diabetes mellitus and hypertension requiring multiple agents, and examination demonstrated florid Cushingoid features.

Biochemical evaluation confirmed severe ACTH-dependent Cushing syndrome with 24-hour urinary free cortisol (UFC) 2997 nmol/day (reference range 54–319), morning cortisol 1181 nmol/L and ACTH 38.2 pmol/L. IPSS was consistent with a pituitary source of ACTH, and MRI demonstrated a 6mm left-sided pituitary lesion. Two transsphenoidal operations failed to identify an adenoma, with histopathology demonstrating non-neoplastic pituitary tissue. Hypercortisolism persisted despite otherwise complete panhypopituitarism, and post-operative MRI scan showed no convincing residual tumour. Ga68-DOTATATE PET-CT demonstrated no ectopic ACTH source. During ongoing hypercortisolism, he sustained progressive vertebral fragility fractures despite only moderately reduced bone mineral density.

Osilodrostat (a novel steroidogenesis inhibitor) was commenced as bridging therapy, resulting in normalisation of UFC and marked clinical improvement, including resolution of diabetes and resistant hypertension. After two years of treatment, serial MRI demonstrated an 11mm pituitary adenoma arising from the cavernous sinus. A third transsphenoidal resection confirmed a Grade 2b invasive corticotroph tumour with Ki67 5.1% and mitotic count 11/10 HPF.

Discussion: This case highlights the challenges of managing persistent Cushing disease despite biochemical and radiological evidence of pituitary source. Osilodrostat is an established steroidogenesis inhibitor for controlling hypercortisolism while awaiting definitive treatment [2]. Emerging reports describe corticotroph tumour enlargement during prolonged therapy, possibly reflecting loss of cortisol-mediated negative feedback analogous to Nelson syndrome [1,3]. In our patient, prolonged treatment was associated with enlargement of a previously identified but surgically elusive pituitary lesion. Although causality cannot be established, this case adds to emerging evidence that prolonged steroidogenesis inhibition may influence corticotroph tumour biology and supports serial ACTH measurement and pituitary MRI during long-term osilodrostat therapy.