Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency

Richard J. Auchus, Elizabeth O. Buschur, Alice Y Chang, Gary D. Hammer, Carole Ramm, David Madrigal, George Wang, Martha Gonzalez, Xu Steven Xu, Johan W. Smit, James Jiao, Margaret K. Yu

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2763-2770
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number8
DOIs
StatePublished - 2014

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Steroid 21-Hydroxylase
Androstenedione
Androgens
Hydrocortisone
Hypokalemia
Serum
Hypertension
17-alpha-Hydroxyprogesterone
Glucose Intolerance
Prodrugs
Metabolites
Congenital adrenal hyperplasia due to 21 hydroxylase deficiency
Abiraterone Acetate
Renin
Electrolytes
Glucocorticoids
Testosterone
Prostatic Neoplasms
Bone
Obesity

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. / Auchus, Richard J.; Buschur, Elizabeth O.; Chang, Alice Y; Hammer, Gary D.; Ramm, Carole; Madrigal, David; Wang, George; Gonzalez, Martha; Xu, Xu Steven; Smit, Johan W.; Jiao, James; Yu, Margaret K.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 8, 2014, p. 2763-2770.

Research output: Contribution to journalArticle

Auchus, RJ, Buschur, EO, Chang, AY, Hammer, GD, Ramm, C, Madrigal, D, Wang, G, Gonzalez, M, Xu, XS, Smit, JW, Jiao, J & Yu, MK 2014, 'Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency', Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 8, pp. 2763-2770. https://doi.org/10.1210/jc.2014-1258
Auchus, Richard J. ; Buschur, Elizabeth O. ; Chang, Alice Y ; Hammer, Gary D. ; Ramm, Carole ; Madrigal, David ; Wang, George ; Gonzalez, Martha ; Xu, Xu Steven ; Smit, Johan W. ; Jiao, James ; Yu, Margaret K. / Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 8. pp. 2763-2770.
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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

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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.

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