Studies on the Metabolic Abnormality of Cortisol and Corticosterone in a Case of Dexamethasone Responsive Mineralocorticoid Excess

In a case of dexamethasone responsive mineralocorticoid excess, we found a peculiar phenomenon; namely, that the administration of cortisol or cortisone in a replacement dose produced apparent hypokalemia even under dexamethasone suppression. The clinical course of this Japanese girl is described in Table 1. At the age of three years, a laparotomy was performed under the diagnosis of Conn's syndrome, but no adrenal tumor was found on either side, and subtotal adrenalectomy was done bilaterally. Microscopic findings of both adrenals showed a disarrangement of adrenocortical zonation, and the initial stage of adrenal hyperplasia was suspected. One month after surgery, hypertension and hypokalemia reappeared. The administration of dexamethasone was dramatically effective in suppressing the symptoms of mineralocorticoid excess. At the age of 13 years, sexual maturation and ovarial estrogen secretion were normal and a regular menstrual cycle was observed. From these clinical pictures and the results of steroid secretion studies, the 17-alpha-hydroxylase deficiency syndrome was ruled out. In an attempt to alter the therapeutic agent from dexamethasone to natural glucocorticoid, it was found that a single injection of cortisone acetate (25mg) produced a hypertensive crisis and the administration of cortisol 30mg daily for six days produced apparent hypokalemia (Fig. 1). From these findings, some abnormalities of cortisol metabolism or hypersensitiveness to cortisol with regard to mineralocorticoid activity were suggested. Tracer doses of cortisol-1.2-3H and corticosterone-4-14C were injected simultaneously, and the urinary metabolites were analyzed on successive 24-hour urine collections. After ethyl acetate washing to remove free steroids, washed urine was subjected to beta-glucuronidase hydrolysis, and liberated steroids were extracted by dichloromethane. The extract was purified by solvents partition and paper chromatography. Finally tetrahydrometabolites of cortisol and corticosterone were isolated by the Bush B-5 and modified B-5 systems respectively. Each paper strip was scanned using a gas-flow strip scanner, and a radioactinogram was obtained. The results were as follows : 1. In this patient, the peak of tetrahydrocortisone (THE) was not observed, while a relative increase of allotetrahydrocortisol (allo-THF, 5a-THF) was observed (Fig. 4). 2. The major peak of corticosterone metabolite was located less polarly than tetrahydrocorticosterone (THB). This substance was suspected to be allotetrahydrocorticosterone (allo-THB, 5α-THB) from its RF value. The peak corresponding to 11-dehydro-tetrahydrocorticosterone (THA) was not observed clearly (Fig. 5). 3. After a three day administration of Zinc-corticotropin (Cortrosyn-z) this pattern of metabolism was unaltered (Fig. 6 & 7). From these results, it is very likely that this patient suffers from abnormalities of steroid metabolism especially on reduced 11-beta-hydroxy-dehydrogenation and elevated 5-alpha-reduction. The pattern of metabolic abnormality resembled closely cortisol 11-beta-ketoreductase deficiency (11-beta-hydroxy-dehydrogenase deficiency) which was recently reported by New and collaborators. (Pediat. Research 12 : 416, 1978) But the clinical pictures are somewhat different. In their case amelioration of the symptoms of mineralocorticoid excess was introduced by salt restriction rather than by dexamethasone.