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

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.

Figures

Figure 1.

Steroidogenic pathways and disruption in 21OHD. Deficiency of CYP21A2 (black bar) impairs mineralocorticoid (aldosterone) and glucocorticoid (cortisol) production. Precursors accumulate and divert to pathways involving CYP17A1 to 19-carbon steroids dehydroepiandrosterone, androstenedione, and T (androgens). Addition of abiraterone acetate blocks CYP17A1-mediated pathways and lowers androgen production. AKR1C3, aldo-keto reductase family 1, member C3; Ang II, angiotensin II; 3βHSD2, 3β-hydroxysteroid dehydrogenase/isomerase type II; StAR, steroidogenic acute regulatory protein; SULT2A1, sulfotransferase family 2A, member 1.

Figure 2.

Serum androstenedione (A and D), serum T (B and E), and the sum of urine androsterone + etiocholanolone glucuronides (C and F; Andro + Etio, micrograms per gram creatinine) during 100 mg/d (A–C) and 250 mg/d (D–F) abiraterone acetate treatment periods. Concentrations are shown at left and percentage changes at right. Dotted line in left graph of panels A and D indicate upper limit of normal (230 ng/dL = 8 nmol/L). To convert to SI units, multiply androstenedione by 0.0349 (nanomoles per liter), T by 0.0347 (nanomoles per liter), and androsterone + etiocholanolone glucuronides by 0.000242 (nanomoles per micromole of creatinine). Each participant is consistently shown by the same color and symbol in all figures.

Figure 3.

Serum 17-hydroxyprogesterone (17OHProgesterone) concentrations during 100 mg/d (A) or 250 mg/d (B) abiraterone acetate treatment periods. To convert to SI units, multiply by 0.0303 (nanomoles per liter).

Figure 4.

Pharmacokinetic/pharmacodynamic correlation during abiraterone acetate therapy. Mean serum concentrations of androstenedione (left panel) and T (right panel) are graphed as a function of area under the curve (AUC) over 24 hours (AUC24) for plasma abiraterone concentration on day 6 of treatment periods (squares, 100 mg/d; circles, 250 mg/d treatment periods). Lines are least squares fits to the data, with curve-fitting statistics shown in insets. AA, abiraterone acetate.

Figure 5.

Comparison of androstenedione and T changes for participants taking three divided doses of hydrocortisone 20 mg/d (ie, three times a day, 10–5–5) (left) or two divided doses of hydrocortisone 20 mg/d (ie, twice a day, 10–0–10) (right) plus abiraterone acetate at 100 mg/d (A and B) or 250 mg/d (C and D). Two participants changed from three times a day to twice a day therapy between the 100 and 250 mg/d abiraterone acetate treatment periods. AA, abiraterone acetate.