11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY IN CUSHINGS-SYNDROME - EXPLAINING THE MINERALOCORTICOID EXCESS STATE OF THE ECTOPIC ADRENOCORTICOTROPIN SYNDROME

A characteristic feature of the ectopic ACTH syndrome is a state of mi neralocorticoid excess, although the etiology remains obscure. Some fo rms of endocrine hypertension, such as licorice ingestion, have been e xplained by cortisol acting as a mineralocorticoid in the setting of i nhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 be ta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inf erred from the ratio of the urinary excretion of tetrahydrocortisol (T HF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two pa tients with Gushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to control s, Gushing's patients had a significant increase (P < 0.001) in the ex cretion of all principal metabolites of F, secondary to a 5- to B-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-32 7) mg/day in Gushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly i ncreased in Gushing's syndrome regardless of etiology [mean, 1.81 (ran ge, 1.09-9.99) in Gushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Gushing's, this ratio wa s significantly higher in patients with the ectopic ACTH syndrome (4.1 2 vs. 1.49; P < 0.01) and was inversely correlated with serum potassiu m levels (r = -0.57; P = 0.01; n = 22). One explanation for the minera locorticoid excess state of the ectopic ACTH syndrome appears to be th at cortisol gains inappropriate access to the mineralocorticoid recept or through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be seco ndary to substrate saturation, inhibition by other adrenal steroids, o r product inhibition.