Table of Contents 21-4

Effectiveness of Hydrocortisone and Cortisone Acetate for the Treatment of CAH

Although cortisone acetate (CA) is used worldwide as corticosteroid substitution therapy in congenital adrenal hyperplasia (CAH), its effectiveness is uncertain since CA must be converted to cortisol to be biologically active. Its biologic activity depends on the activation by 11 ß-hydroxysteroid dehydrogenase (11 ß-HSD) reductase. Inada et al reported that hydrocortisone (HC) is more effective than CA for the treatment of CAH. The authors compared the effect of CA with that of HC in 10 patients (aged 4–35 years) with 21-hydoxylase deficiency (21-OHD). Of the 10 patients, 8 were salt losers who required fludrocortisone in addition to glucocorticoids. HC was administered to all subjects instead of CA; the initial dose was 80% of the previous CA dose, since the overall bioactivity of oral CA has been reported to be 80% of that of HC. The dose of HC was subsequently changed in accordance with the circulating levels of serum 17-hydroxyprogesterone (17-OHP) and/or plasma adrenocorticotropin (ACTH). Doses of fludrocortisone were not changed. Target concentrations were below 10 ng/ml for 17-OHP and below 50 pg/ml for plasma ACTH. The mean observation period after the drug changes was 10 months. Mean concentrations of serum 17-OHP decreased from 48.6 ng/ml to 10.1 ng/ml, as did those of plasma ACTH from 198.0 pg/ml to 35.1 pg/ml. The average drug requirement for CA was 33.9 mg/m², while it was 20.3 mg/m² for HC when disease control was stable. The relationship can be expressed as an equation, HC = 0.58 × CA; the coefficient was substantially lower than the conventionally reported dose ratio of 0.8. The authors concluded that CA is inferior to HC as the substitution therapy in patients with CAH.

Inada H, Imamura T, Nakajima R, Yamano T. Poor response to substitution therapy with cortisone acetate in patients with congenital adrenal hyperplasia. Clin Pediatr Endocrinol. 2004;13:11−15.

Editor’s Comment: CA may be used as the glucocorticoid component of substitution therapy for CAH. However, the paper by Inada and a previous paper by Jinno 1 indicate that oral administration of CA was inappropriate as glucocorticoid replacement therapy in patients with 21-OHD. The Jinno group compared the effect of CA with that of HC in 7 neonates with 21-OHD. From the time of diagnosis, CA was administered to 4 subjects, while HC was given to the other 3 subjects. The serum cortisol (F), cortisone (E), and 17-OHP in these 7 neonates with 21-OHD were compared with 118 normal subjects. In the normal subjects, serum E concentrations were greater than F during the first 2 months after birth, whereas F concentrations exceeded E after 2 months of age (Table). Infants with 21-OHD who received high CA doses had extremely low serum F concentrations, while 17-OHP concentrations were high until about 2 months of age. Thereafter, the serum F exceeded E, and 17-OHP became fully suppressed even though infants received moderate doses of CA. In contrast, HC administration successfully normalized serum 17-OHP in the neonatal period. With temporary switching from HC to CA, serum F concentrations immediately decreased and 17-OHP concentrations increased. Thus, conversion of E to F may be limited during early infancy, adversely affecting the treatment with CA. Jinno and colleagues also noted that CA was inappropriate as a glucocorticoid replacement during early infancy in patients with 21-OHD.

To this author’s knowledge, no comparative studies of CA and HC treatment during the neonatal period or infancy have been published. In the Jinno et al study, serum E concentration exceeded that of F in normal subjects until the age of 2 months. Conversion of E to F by CA may be difficult, as production of E is greater than that of F in the adrenal cortex from the fetal period to approximately 2 months of age. The predominant E production may reflect age-related morphologic findings of the neonatal adrenal. The human fetus extensively converted F to E (an oxidation reaction), but was unable to convert E to F (a reduction reaction).

At term, in normal infants, each adrenal gland weighs 4 to 5 g, more than 80% of which consists of an inner, hyperemic fetal zone. In this zone, conversion of F to E overshadows conversion of E to F. One-half of the adrenal weight is lost by 1 month of age, and by the age of 1 year the average gland weighs only about 1 g. This postnatal involution of the adrenal cortex involves gradual remodeling of fetal zone cells into the zona fasciculate during the first weeks and months of life. As the fetal zone is associated with a predominance of E, its involution was associated with the age-related changes of serum concentrations of E and F shown in normal subjects.¹

Activity of 11 ß-HSD is high in human tissues, especially the inner fetal zone of the adrenal cortex. Results suggest the occurrence of a physiologic inability to respond to treatment with CA during early infancy in patients with 21-OHD, because oxidation by 11 ß-HSD predominates in the residual fetal cortex.¹ In contrast to cortisone, HC possesses an 11 b-hydroxyl group and does not require activation by the enzyme 11 ß-HSD.

HC should be the drug of choice for substitution therapy in children with CAH. The Japanese Society of Pediatric Endocrinology recommends HC for the maintenance therapy of CAH.

Yoshikazu Nishi, MD

Reference - (linked to )

1. Jinno K, Sakura N, Nomura S, Fujitaka M, Ueda K, Kihara M. Pediatr Int. 2001;43:478–482.