A possible defect in the inter-conversion between cortisone and cortisol in prepubertal patients with congenital...

Oral administration of cortisone acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient 'first pass' hepatic conversion of the biologically inactive cortisone (E) to cortisol (F) by the 11-reductase component of the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) system is required for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. 11-beta-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving cortisone acetate therapy. In this paper, we describe THE and THF concentration in 24 h urine samples collected every 3-6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving cortisone acetate and 9 alpha-fluorohydrocortisone since diagnosis and were investigated for 2-4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5 beta, 17 alpha-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime-trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean +/- SD) was significantly higher in patients during periods of poor control (6.56 +/- 2.51, P less than 0.001) compared with periods of good control (3.73 +/- 0.96) in the same patients. THE/THF levels were also significantly (P less than 0.001) higher in CAH patients, irrespective of the level of control, than those for the normal subjects (1.79 +/- 0.20). Furthermore, THE excretion was significantly higher during periods of poor control compared with good control at all doses of cortisone acetate administered (10-50 mg/day). There were no significant differences in THF excretion. THE levels also rose significantly (P less than 0.001) in response to increasing total dose during periods of poor control. The increase in THF excretion was slight and significant only at doses greater than 40 mg/day compared with doses less than 15 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)