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-C ₁₉ (11oxC19) steroids: 11 β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11 β-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.

Abstract

Using LC-MS/MS, we show 11-oxygenated 19-carbon steroids and pregnenolone sulfate are biomarkers of disease control and long-term complications in adults and children with 21-hydroxylase deficiency.