title: Bilateral Testicular Tumors Resulting in Recurrent Cushing Disease After Bilateral Adrenalectomy.
abstract: BACKGROUND
  Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing disease is extremely rare.
  
  
  METHODS
  We present a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing disease with complete clinical resolution. Cushingoid features recurred 12 years later, with bilateral testicular enlargement. Hormonal tests confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing disease. Surgical resection of the testicular tumors led to clinical and biochemical remission.
  
  
  RESULTS
  Gene expression analysis of the tumor tissue by quantitative polymerase chain reaction showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 × 105 (CYP11B1), 1.8 × 102 (CYP11B2), and 6.3 × 104 (MC2R) times higher than nonsteroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2 fivefold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol, and total glucocorticoids. Leydig-specific genes were 4.3 × 101 (LHCGR) and 9.3 × 100 (HSD17B3) times higher than control, and urinary steroid profiling showed twofold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone but unresponsive to human chorionic gonadotropin stimulation, supporting the role of ACTH, but not luteinizing hormone, in regulating tumor-specific steroid excess.
  
  
  CONCLUSIONS
  We report bilateral testicular tumors occurring in a patient with recurrent Cushing 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, suggesting the presence of pluripotent cells even in patients without congenital adrenal hyperplasia.
authors.affiliation: Departments of Medicine.|Department of Endocrinology, Changi General Hospital, Singapore 529889, Singapore.
authors.forename: Troy
authors.initials: T
authors.lastname: Puar
authors.affiliation: Paediatrics, Division of Endocrinology.|Laboratory Medicine.
authors.forename: Manon
authors.initials: M
authors.lastname: Engels
authors.affiliation: Laboratory Medicine.
authors.forename: Antonius E
authors.initials: AE
authors.lastname: van Herwaarden
authors.affiliation: Laboratory Medicine.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Pathology, and.
authors.forename: Christina
authors.initials: C
authors.lastname: Hulsbergen-van de Kaa
authors.affiliation: Radiology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Kamphuis-van Ulzen
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham N15 2TT, United Kingdom; and.|Centre for Endocrinology, Diabetes, and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Chortis
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham N15 2TT, United Kingdom; and.|Centre for Endocrinology, Diabetes, and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.affiliation: Departments of Medicine.
authors.forename: Nike
authors.initials: N
authors.lastname: Stikkelbroeck
authors.affiliation: Paediatrics, Division of Endocrinology.
authors.forename: Hedi L
authors.initials: HL
authors.lastname: Claahsen-van der Grinten
authors.affiliation: Departments of Medicine.
authors.forename: Ad R M M
authors.initials: AR
authors.lastname: Hermus
mesh_terms: D000315:Adrenalectomy; D000328:Adult; D001800:Blood Specimen Collection / Q000379:methods; D002648:Child; D003480:Cushing Syndrome / Q000209:etiology / Q000601:surgery*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006728:Hormones / Q000097:blood; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D055432:Metabolomics / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D013256:Steroids / Q000097:blood / Q000652:urine; D013736:Testicular Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000601:surgery
chemical_list: D006728:Hormones; D012333:RNA, Messenger; D013256:Steroids