24-Hour Profiles of 11-Oxygenated C(19) Steroids and Δ(5)-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency.

Optimal management of androgen excess in 21-hydroxylase deficiency (21OHD) remains challenging. 11-oxygenated-C19 steroids (11-oxyandrogens) have emerged as promising biomarkers of disease control, but data regarding their response to treatment are lacking. To compare the dynamic response of a broad set of steroids to both conventional oral glucocorticoids (OG) and circadian cortisol replacement via continuous subcutaneous hydrocortisone infusion (CSHI) in patients with 21OHD based on 24-hour serial sampling. We studied 8 adults (5 women), ages 19-43 years, with poorly controlled classic 21OHD who participated in a single-center open-label phase I-II study comparing OG with CSHI. We used mass spectrometry to measure 15 steroids (including 11-oxyandrogens and Δ5 steroid sulfates) in serum samples obtained every 2 h for 24 h after 3 months of stable OG, and 6 months into ongoing CSHI. In response to OG therapy, androstenedione, testosterone (T), and their four 11-oxyandrogen metabolites:11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone (11KT) demonstrated a delayed decline in serum concentrations, and they achieved a nadir between 0100-0300. Unlike DHEAS, which had little diurnal variation, pregnenolone sulfate (PregS) and 17-hydoxypregnenolone sulfate peaked in early morning and declined progressively throughout the day. CSHI dampened the early ACTH and androgen rise, allowing the ACTH-driven adrenal steroids to return closer to baseline before mid-day. 11KT concentrations displayed the most consistent difference between OG and CSHI across all time segments. While T was lowered by CSHI as compared with OG in women, T increased in men, suggesting an improvement of the testicular function in parallel with 21OHD control in men. 11-oxyandrogens and PregS could serve as biomarkers of disease control in 21OHD. The development of normative data for these promising novel biomarkers must consider their diurnal variability.

Turcu AF ，Mallappa A ，Nella AA ，Chen X ，Zhao L ，Nanba AT ，Byrd JB ，Auchus RJ ，Merke DP ... -  《Frontiers in Endocrinology》

A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia.

Nella AA ，Mallappa A ，Perritt AF ，Gounden V ，Kumar P ，Sinaii N ，Daley LA ，Ling A ，Liu CY ，Soldin SJ ，Merke DP ... -  《-》

Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men.

Turcu AF ，Zhao L ，Chen X ，Yang R ，Rege J ，Rainey WE ，Veldhuis JD ，Auchus RJ ... -  《-》

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

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. To identify biomarkers of disease control and long-term complications in 21OHD. Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. 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. 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). 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

Turcu AF ，Mallappa A ，Elman MS ，Avila NA ，Marko J ，Rao H ，Tsodikov A ，Auchus RJ ，Merke DP ... -  《-》

Salivary Profiles of 11-oxygenated Androgens Follow a Diurnal Rhythm in Patients With Congenital Adrenal Hyperplasia.

Several studies have highlighted the importance of the 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as potential biomarkers for monitoring patients with 21-hydroxylase deficiency (21OHD). To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD. Cross-sectional single-center study including 59 patients with classic 21OHD (men = 30; women = 29) and 49 body mass index- and age-matched controls (men = 19; women = 30). Salivary concentrations of the following steroids were analyzed by liquid chromatography-tandem mass spectrometry: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11β-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: mean reduction of hormone concentrations between timepoint 1 and 5 (Δ mean) in male patients = 66%; male controls Δ mean = 83%; female patients Δ mean = 47%; female controls Δ mean = 86%; 11KT: male patients Δ mean = 57%; male controls Δ mean = 63%; female patients Δ mean = 50%; female controls Δ mean = 76%). Significant correlations between the area under the curve for 17OHP and 11KT (rpmale = 0.773<0.0001; rpfemale = 0.737<0.0001), and 11OHA4 (rpmale = 0.6330.0002; rpfemale = 0.5640.0014) were observed in patients but not present or reduced in controls. Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

Nowotny HF ，Auer MK ，Lottspeich C ，Schmidt H ，Dubinski I ，Bidlingmaier M ，Adaway J ，Hawley J ，Keevil B ，Reisch N ... -  《-》