Bilateral testicular tumors resulting in recurrent Cushing's syndrome after bilateral adrenalectomy

Troy Puar, Manon Engels, Antonius van Herwaarden, Fred Sweep, Christina Hulsbergen-van de Kaa, Karin Kamphuis-van Ulzen, Vasileios Chortis, Wiebke Arlt, Nike Stikkelbroeck, Hedi Claahsen-van der Grinten, Ad Hermus

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CONTEXT: Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing's disease is extremely rare.

PATIENT: We present a rare case of a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing's disease with complete clinical resolution. Cushingoid features recurred 12 years later, along with bilateral testicular enlargement. Hormonal tests confirmed ACTH-dependent Cushing's. Surgical resection of the testicular tumors led to clinical and biochemical remission.

DESIGN AND RESULTS: Gene expression analysis of the tumor tissue by qPCR showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 x 10(5) (CYP11B1), 1.8 x 10(2) (CYP11B2) and 6.3 x 10(4) (MC2R) times higher than non-steroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2-5 fold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol and total glucocorticoids. Leydig-specific genes were 4.3 x 10(1) (LHCGR) and 9.3 x 10(0) (HSD17B3) times higher than control and urinary steroid profiling showed 2-fold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone, but unresponsive to hCG stimulation, supporting the role of ACTH, but not LH, in regulating tumor-specific steroid excess.

CONCLUSION: We report bilateral testicular tumors occurring in a patient with recurrent Cushing's disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia. This suggests the presence of pluripotent cells even in patients without CAH.

Original languageEnglish
Pages (from-to)339-344
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
Early online date30 Nov 2016
Publication statusPublished - Feb 2017


  • Cushing's disease
  • bilateral adrenalectomy
  • Nelson's syndrome
  • Testicular-adrenal rest tumor
  • congenital adrenal hyperplasia


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