A POSSIBLE DEFECT IN THE INTERCONVERSION BETWEEN CORTISONE AND CORTISOL IN PREPUBERTAL PATIENTS WITH CONGENITAL ADRENAL-HYPERPLASIA RECEIVING CORTISONE-ACETATE THERAPY

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 concentrations 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 < 0.001) compared with periods of good control (3.73 +/- 0.96) in the same patients. THE/THF levels were also significantly (P < 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 < 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 > 40 mg/day compared with doses < 15 mg/day. A significant linear correlation could be drawn between THE excretion and total daily dose during periods of both poor (r = 0.67, P < 0.05) and good (r = 0.68, P < 0.005) control. Excretion of 5-alpha-THF, cortols and the cortolones, unlike that for normal subjects, was very low in cortisone acetate treated CAH patients. In contrast, the ratios of 5-alpha/5-beta C19 steroid metabolites were no different from normal. The results from this study suggest that poor therapeutic control is unlikely to be due to: (i) failure of compliance with therapy; (ii) inefficient absorption from the intestine; or (iii) inefficient acetate group removal. The data are consistent with a hypothesis of rapid tetrahydroderivitization of E, present in excess of the capacity of 11-beta-HSD to form F; i.e. a preferential reduction of the A ring rather than the 11-keto group as a consequence of hepatic 'first pass' uptake of the exogenously administered E. The ability of prednisolone and dexamethasone, both of which are bioactive and not subject to significant A ring reduction, to suppress the HPA axis of patients poorly suppressed by cortisone acetate, lends support to this hypothesis.