11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency

Abstract

Context:Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes.Objective:To identify biomarkers of disease control and long-term complications in 21OHD.Setting and Participants:Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center.Methods:We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones.Results:Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11β-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = −0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001).Conclusion:11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

Gonadal function in adult male patients with congenital adrenal hyperplasia

“…We recommend to include the evaluation of the AD/TS ratio in the regular follow-up of male patients with CAH and interpret this ratio in combination with gonadotropin concentrations in order to detect a disturbance of the HPG axis. Our study does not include data on 11-oxygenated androgens, that are generated through conversion of androstenedione and are reported to be elevated in patients with CAH (29,30). Recent studies indicate that 11-oxygenated androgens are almost entirely derived from the 11beta-hydroxylation of androstenedione in the adrenal, and as they are potent androgens, they can contribute to suppression of the HPG axis (31).…”

Transcriptional comparison of Testicular Adrenal Rest Tumors with fetal and adult tissues

“…Functional analysis and KEGG pathway analysis highlight the adrenal steroidogenic properties of TART. Previous research indicated that TART produces adrenal-specific steroids (26,29), as blood of CAH patients with TART present higher levels of adrenal specific 11-oxygenated androgens compared to blood of patients without TART (29). Furthermore, higher levels of adrenal-specific steroid hormones have been detected in spermatic vein sampling compared to peripheral blood samples in CAH patients (16,26,30).…”

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

“…At least annual physical examination and hormone measurements (morning 17OHP and androstenedione) are recommended by the Endocrine Society, but no guidance is given about specific targets (9). Recently, metabolites such as 11-oxygenated-C 19 and pregnenolone sulphate have been suggested as useful biomarkers in classic CAH for disease control and long-term complications (92). However, these are not available in clinical practice and their use in NCAH has not been investigated.…”