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Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

Abstract:

Context: Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done. Objective: We aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Methods: Using liquid chromatography-Tandem mass spectrometry, steroids were measured in left (n=7) and right (n=4) spermatic vein and simultaneously drawn peripheral blood (n=7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age-and BMI-matched controls. Additionally, steroids were quantified in TART cell-and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. Results: Compared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11β-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11β-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART. Conclusion: In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.