Transsphenoidal surgery (TSS) is the established first-line intervention for Cushing's disease. When surgery — even when performed by an experienced pituitary neurosurgeon at a specialised centre — does not achieve the defined remission threshold, a structured next-line approach is required.
Initial management: transsphenoidal surgery (TSS) as first-line therapy, performed by an experienced pituitary neurosurgeon, preferably at a Pituitary Tumor Centers of Excellence (PTCOE).
Escalation is triggered when the remission target is not reached: postoperative serum cortisol <55 nmol/L (<2 μg/dL) not achieved.
The primary objective is normalisation of urinary free cortisol (UFC). Treatment adequacy is reassessed if cortisol levels remain persistently elevated after 2–3 months on maximum tolerated doses.
If there are no contraindications for surgery, we suggest repeat TSS in patients with biochemical evidence of recurrent CD if tumor is evident on MRI, especially if the first surgery was not done in a PTCOE.
They may be used to treat hypercortisolism in patients with persistent or recurrent CD and those who are not candidates or refuse surgery, and to control cortisol levels in patients undergoing radiation therapy (RT).
Adrenal steroidogenesis inhibitors are usually used first given their reliable effectiveness.
For patients with mild disease and no visible tumor on MRI, ketoconazole, osilodrostat, or metyrapone are typically preferred.
For patients with mild-to-moderate disease and some residual tumor, there may be a preference for cabergoline or pasireotide because of the potential for tumor shrinkage.
RT is most commonly used in cases of persistent hypercortisolism after incomplete corticotroph tumor resection, particularly if the tumor is aggressive or invasive and/or considered unresectable.
Change in treatment should be considered if cortisol levels are persistently elevated after 2–3 months on maximum tolerated doses.
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