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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  )
- Jinno K, Sakura N, Nomura S, Fujitaka M, Ueda K, Kihara M. Pediatr Int. 2001;43:478–482.
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Current GGH - Vol. 24 No. 1
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