A characteristic feature of the
ectopic ACTH syndrome is a state of
mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine
hypertension, such as licorice ingestion, have been explained by
cortisol acting as a
mineralocorticoid in the setting of inhibition or deficiency of
11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This
enzyme is responsible for the conversion of
cortisol (F) to hormonally inactive
cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of
tetrahydrocortisol (THF) and its isomer (5 alpha THF) to
tetrahydrocortisone. Twenty-two patients with
Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal
adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the
cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/
tetrahydrocortisone ratio was significantly increased in
Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing'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 Cushing's, this ratio was significantly higher in patients with the
ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum
potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the
mineralocorticoid excess state of the
ectopic ACTH syndrome appears to be that
cortisol gains inappropriate access to the
mineralocorticoid receptor 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 secondary to substrate saturation, inhibition by other adrenal
steroids, or product inhibition.