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 Define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Participants and methods Steroids were measured in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral blood (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. For comparison, we also measured the peripheral steroid concentrations in five adrenalectomized patients and twelve 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 to peripheral blood of 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 to 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- versus peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.

11-Oxygenated androgens are not secreted by the human ovary: in-vivo data from four different cases of hyperandrogenism

“…Although it has been shown that 11β-hydroxysteroid dehydrogenase types 1 and 2 are expressed in testicular Leydig and ovarian theca cells ( 15 ), our findings contradict the idea that gonadal 11-KT production significantly contributes to the systemic pool in females because CYP11B1 is usually only expressed in negligible amounts in the gonads ( 23 ). An exception to this are patients with CAH in which aberrant adrenal tissue can be found within the testicles or ovaries ( 24 , 25 ). The idea that 11-KT is produced in peripheral tissue from 11-OHA4 produced in the adrenal is supported by the observation that 11-KT levels did not differ between the sampling sites, considering the significantly higher 11-OHA4 levels in the adrenal vein samples, especially.…”

Interpretation of steroid biomarkers in 21-hydroxylase deficiency and their use in disease management

“…There is also evidence that TART tissue actively synthesizes steroids. Besides the production of 17OHP, 21dF, and progesterone, TART tissue can contribute to the production of adrenal androgens, including 11-oxygenated androgens (137)(138)(139).…”

11-Oxyandrogens from the viewpoint of pediatric endocrinology

“…Likewise, blood levels of 11-KT and other 11-oxyandrogens were increased in patients with 21-OHD and testicular adrenal rest tumors (TART) ( 27 ). Steroid measurement of spermatic vein blood samples suggested that TART can produce various 11-oxyandrogens ( 28 ). Particularly the high levels of 11-OHT in the spermatic vein blood samples of patients with TART ( 28 ) are indicative of high CYP11B1 activity in these tumors.…”

“…Steroid measurement of spermatic vein blood samples suggested that TART can produce various 11-oxyandrogens ( 28 ). Particularly the high levels of 11-OHT in the spermatic vein blood samples of patients with TART ( 28 ) are indicative of high CYP11B1 activity in these tumors.…”