congenital adrenal hyperplasia ( cah ) is caused by deficiency of 21-hydroxylase in the 
 adrenal glands .
cortisone acetate ( ca ) is used worldwide as an equivalent to hydrocortisone 
 ( hc ) , as the glucocorticoid component of substitution therapy for cah .
hc is identical to cortisol , while ca is 
 nearly equivalent to cortisone apart from the presence of an acetate group at the c21 
 position .
cortisol represents active glucocorticoid , while cortisone is an inactive form . 
 the hepatic enzyme 11-hydroxysteroid dehydrogenase 
 ( 11-hsd ) type 1 catalyzes the conversion of cortisone to cortisol by 
 reducing the keto group at the c11 position to a hydroxyl group
accordingly , orally 
 administered ca must be converted to cortisol by 11-hsd in order to be 
 bioactive .
the overall bioactivity of ca given orally has been reported to be 80% of that of hc ( 1 ) .
furthermore , a patient with 21-hydroxylase deficiency has been reported as 
 a poor responder to ca treatment ( 2 ) .
we converted 10 
 of our cah patients from ca to hc substitution therapy , compared clinical and laboratory 
 findings before and after the change .
ten patients with cah caused by 21-hydroxylase deficiency were studied ( 6 male , 4 female ; 
 ages , 4 to 35 yr ) .
of the 10 patients , 8 were salt 
 losers , who required fludrocortisone in addition to glucocorticoids .
for all subjects , hc 
 was administered instead of ca , initially at 80% of the previous ca dose .
the dose of hc 
 then was increased or decreased according to circulating concentrations of 
 17-hydroxyprogesterone ( ohp ) and/or adrenocorticotropin ( acth ) .
target concentrations were 
 below 10 ng / ml for 17-ohp and below 50 pg / ml for acth .
doses of fludrocortisone were not 
 changed . to compare required doses of ca and hc ,
the ca requirement was calculated as the 
 average of the several months preceding the change of drug , while the hc requirement was the 
 dose found to provide stable control of cah after several months .
these doses were 
 calculated as milligrams per square meter of body - surface area . before and after the drug change , we measured concentrations of 17-ohp and acth , as well as 
 patients height and weight . the mean observation period after the drug change was 10 mo ( 6 
 to 14 mo ) .
a radioimmunoassay was used to measure 17-ohp , while acth was measured by 
 immunoradiometric assay .
genomic dna of a patient who responded poorly to treatment with ca was obtained from 
 peripheral leukocytes .
all exons , exon - intron boundary regions and 2.4 kb of the promoter 
 region of 11-hsd were amplified by pcr .
then the dna sequence was 
 determined using an abi prism 310 genetic analyzer . for bone age determination ,
the 
 tanner - whitehouse 2 rus method according to the japanese standard was used .
the mean 17-ohp concentration during treatment of our patients with ca was 48.6 ng / ml . this 
 decreased to 10.1 ng / ml when the treatment was changed to hc ( table 1table 1 demographic , pharmacologic , and endocrinologic data for individual 
 subjects , fig .
1 serum concentrations of 17-hydroxyprogesterone ( ohp ) during treatment were 
 significantly lowered by changing from cortisone acetate ( ca ) to hydrocortisone ( hc ) . 

each data point represents the mean concentration of 17-ohp of an individual during 
 treatment with ca or hc . ) .
the mean concentration of acth was 198.0 pg / ml during treatment with ca , decreasing 
 to 35.1 pg / ml during treatment with hc .
we compared the dose of ca preceding the change of 
 drug with that of hc after dose adjustment , when disease control was stable .
the average 
 drug requirement for ca was 33.9 mg / m , while it was 20.3 mg / m for 
 hc . the relationship can be expressed as an equation , hc = 0.58  ca , and the coefficient is 
 substantially lower than the conventionally reported dose ratio of 0.8 ( 1 ) .
in addition , 
 older patients required more ca per square meter of body - surface than younger patients .
the 
 relationship between the ca dose shortly before the change of drug and the final hc dose is 
 shown in fig .
. 2 relationship between the dose requirements of cortisone acetate ( ca ) and 
 hydrocortisone ( hc ) . the solid regression line can be expressed as : hc = 0.58  
 ca .. no significant change in the obesity index occurred in any subject in association 
 with the change of drug . among subjects who already had attained their adult height , all 
 male patients ( cases 5 , 8 , and 9 ) showed short stature attributable to precocious puberty . 
 in case 5 ,
four patients ( cases 1 to 4 ) who had been diagnosed by 
 neonatal screening were at a prepubertal age . in cases 1 to 3 , no change of height sd score 
 was recognized before or after the drug change .
case 4 showed some auxological change 
 related to medication , described below .   serum concentrations of 17-hydroxyprogesterone ( ohp ) during treatment were 
 significantly lowered by changing from cortisone acetate ( ca ) to hydrocortisone ( hc ) . 

each data point represents the mean concentration of 17-ohp of an individual during 
 treatment with ca or hc .  
relationship between the dose requirements of cortisone acetate ( ca ) and 
 hydrocortisone ( hc ) .
the solid regression line can be expressed as : hc = 0.58  
 ca .
case 4 : a 10-yr - old boy was found to have an increased concentration of 17-ohp at 6 yr of 
 age , and was treated with ca .
the ca dose was increased from 20 mg / m at 6 yr to 
 35 mg / m at 8.2 yr . during this period ,
height velocity increased , as did height 
 sd score ( 0.1 to 0.8 ) . the bone age ( ba ) / chronological age ( ca ) ratio also increased ( 0.9 
 to 1.2 ) .
after conversion to hc at 9.4 yr of age , control of disease improved as evidenced 
 by a decrease in 17-ohp . at 10.1 yr of age ,
the height sd score had decreased to 0.6 , and 
 the ba / ca ratio had decreased to 1.1 . the hc requirement was 20.9 mg / m . in case 5 , we performed dna sequence analysis for 11-hsd type 1 because 
 treatment with ca had no effect at all .
case 5 : a 13 -yr - old boy was referred from another hospital where he had been treated with 
 28 mg / m of hc . in our outpatient clinic , treatment was changed to 36 
 mg / m of ca . soon afterwards 17-ohp
increased abruptly to 260 ng / ml from 5.3 
 ng / ml . the plasma level of acth increased to 1038 pg / ml from 8.3 pg / ml . since this patient 
 appeared to be a poor responder to ca , 28 mg / m of hc
inability to respond to ca initially was thought to result from impaired 
 low conversion of cortisone to cortisol , because of low activity of 11-hsd 
 type 1 . however , dna sequence determination in the gene encoding this enzyme detected no 
 changes from the reported normal sequence in any of the six exons , exon - intron boundary 
 regions , or the promoter region ( 2.4 kb ) ( 3 ) .
in 10 patients with 21-hydroxylase deficiency , we changed the glucocorticoid for the 
 substitution therapy from ca to hc .
indices of control of cah such as 17-ohp , and acth 
 decreased , indicating improvement . on average , the final requirement for hc based on these 
 indicators , was only 0.58 times the previous dose of ca , which was smaller than previously 
 reported ( 1 ) .
whorwood and warne ( 4 ) determined urinary tetrahydrocortisone ( the ) / 
 tetrahydrocortisol ( thf ) ratios for 14 cah patients treated with ca , and found that better 
 control of the disease was associated with lower the / thf ratios .
the pharmacologic effect of ca depends on conversion of cortisone to cortisol by 
 11-hsd .
however , when we performed gene sequencing in one of our poor ca 
 responders , we found no mutation in the 11-hsd gene including the promoter 
 region .
( 2 ) 
 similarly reported failure to detect a mutation in the 11-hsd gene .
up to 
 the present , no 11-hsd gene mutation has been detected in poor responders . 

even single - nucleotide polymorphism has not been common , apart from the recently reported 
 intronic gene polymorphism ( 5 ) .
as described for case 
 4 , an individual patient s response to ca can vary with age or other factors .
in addition , 
 blood concentrations of cortisone have been reported to be higher than those of cortisol in 
 the neonatal period and early infancy ( 6 ) .
accordingly 
 steroid metabolism in young children may differ from that in school - age or older children . 
 in our study ,
a poor response 
 to ca , therefore , may involve variability of 11-hsd activity rather than 
 genetic changes .
jamieson et al . ( 7 ) reported a 36-yr - old woman who had clinical features of hypercortisolemia 
 associated with a normal plasma cortisol concentration and an elevated urinary the / thf 
 ratio , possibly caused by a defect in hepatic 11-hsd . in another case of 6 

yr old boy with precocious pubarche had an elevated urinary the / thf ratio ( decreased thf / the 
 ratio ) attributed to low activity of 11-hsd ( 8) . this enzyme has attracted considerable attention in studies concerning obesity and other 
 endocrinological disorders .
an agonist at the peroxisome proliferator - activated receptor is 
 suspected to regulate 11-hsd , decreasing its activity ( 9 ) . among patients with cah , good responders
however , we found no relationship between 
 response to ca and obesity . among our subjects who attained adult height ,
male patients were shorter than previously 
 reported adult patients with cah ( 10 ) .
our findings provided no definitive 
 indication of whether or not hc is superior to ca in achieving a desirable height .
however , 
 in one growing child ( case 4 ) , changing the drug from ca to hc decreased the ba / ca ratio . 

final height in patients treated with hc might prove to be greater than that in patients 
 treated with ca .
as a therapeutic agent , ca shows considerably greater inter- and intra - individual 
 variations in efficacy than hc .
in addition , we found greater difference in pharmacological 
 activity between ca and hc than has been previously reported .
ca would seem inadequate for substitution 
 therapy not only in patients with cah , but also those with other forms of adrenal 
 insufficiency such as adrenal hypoplasia or hypofunction caused by pituitary disorders . 

treatment with hc is recommended for these patients as well . however , since hc has been 
 reported to be too bioavailable to maintain cortisol concentrations within physiologic 
 limits ( 11 ) , careful evaluation of physiologic 
 aspects of hc - based substitution regimens may be needed .
 although cortisone acetate is approved worldwide as corticosteroid substitution 
 therapy in congenital adrenal hyperplasia ( 21-hydroxylase deficiency ) , its effectiveness 
 is uncertain since its biologic activity depends on activation by 
 11-hydroxysteroid dehydrogenase ( 11-hsd ) . 
 we sought to 
 compare the effect of cortisone acetate with that of hydrocortisone . in 10 patients with 
 congenital adrenal hyperplasia , 
 cortisone acetate was replaced with hydrocortisone in 
 substitution therapy . during this change , 
 blood concentrations of 17-hydroxy - progesterone , 
 adrenocorticotropin ( acth ) , and requirements for each drug were monitored . 
 concentrations 
 of 17-hydroxyprogesterone decreased ( mean 10.1 vs. 48.6 ng / ml ) , as did those of acth . 
 
 cortisone acetate dose requirements averaged 33.9 mg / m2 , while hydrocortisone 
 dose requirements averaged only 20.3 mg / m2 . 
 in one of the patients resistant to 
 cortisone acetate therapy , dna sequences in the coding regions and promoter of the 
 11-hsd gene were analyzed , detecting no genetic abnormalities . 
 
 cortisone acetate is inferior to hydrocortisone as substitution therapy in patients with 
 congenital adrenal hyperplasia . 