TY - JOUR
T1 - Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency
AU - Auchus, Richard J.
AU - Buschur, Elizabeth O.
AU - Chang, Alice Y.
AU - Hammer, Gary D.
AU - Ramm, Carole
AU - Madrigal, David
AU - Wang, George
AU - Gonzalez, Martha
AU - Xu, Xu Steven
AU - Smit, Johan W.
AU - Jiao, James
AU - Yu, Margaret K.
PY - 2014/8
Y1 - 2014/8
N2 - Context: Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer. Objective: The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia. Design: This was a phase 1 dose-escalation study. Setting: The study was conducted at university clinical research centers. Participants: We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L). Intervention: AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate. Main Outcome Measure: The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (- 230 ng/dL [-8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides. Results: With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7- 8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2- 4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed. Conclusion: AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.
AB - Context: Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer. Objective: The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia. Design: This was a phase 1 dose-escalation study. Setting: The study was conducted at university clinical research centers. Participants: We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L). Intervention: AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate. Main Outcome Measure: The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (- 230 ng/dL [-8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides. Results: With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7- 8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2- 4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed. Conclusion: AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.
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U2 - 10.1210/jc.2014-1258
DO - 10.1210/jc.2014-1258
M3 - Article
C2 - 24780050
AN - SCOPUS:84905825222
SN - 0021-972X
VL - 99
SP - 2763
EP - 2770
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 8
ER -