A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment for Cushing’s Disease

Ticiana Paes, Rob van der Pas, Peter M van Koetsveld, Fadime Dogan, Kees K A van den Berge, Romana T Netea-Maier, Peter H Bisschop, Leo J Hofland, Richard A Feelders
Journal of the Endocrine Society, Volume 9, Issue 7, July 2025, bvaf089
https://doi.org/10.1210/jendso/bvaf089

Abstract

Context and Objective

The lack of efficacy of somatostatin receptor subtype 2 (SST2) preferring somatostatin analogs in patients with Cushing’s disease (CD) results from a downregulating effect of hypercortisolism on SST2 expression. Our objective is to evaluate the efficacy of a strategy with sequential treatment of ketoconazole to reduce cortisol levels and potentially restore SST2 expression followed by octreotide as maintenance therapy in patients with CD.

Patients and Design

Fourteen adult patients with CD were prospectively enrolled. Patients started with ketoconazole. Once cortisol levels were normalized, octreotide was initiated. After 2 months of combination therapy, patients were maintained on octreotide monotherapy until the end of the study period (9 months). Treatment success was defined by normalization of urinary free cortisol (UFC) levels.

Results

Ketoconazole was able to normalize UFC levels in 11 (79%) patients. Octreotide effectively sustained normal levels of UFC in 3 patients (27%) (responders). Four patients (36%) showed a partial response. The remaining 4 (36%) patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders). Octreotide responders had lower UFC levels at baseline when compared to partial responders and nonresponders (1.40 ± 0.07 vs 2.05 ± 0.20 UNL, P = 0.083). SST2 mRNA was highly expressed in adenomas of 2 responder patients (0.803 and 0.216 copies per hprt).

Conclusion

Sequential treatment with ketoconazole to lower cortisol levels followed by octreotide to maintain biochemical remission according to UFC may be effective in a subset of patients with mild CD, suggesting that cortisol-mediated suppression of SST2 expression is a reversible process.

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