18-hydroxycortisol (18-OHF) and 18-oxocortisol (18oxo-F) are derivatives of cortisol whose origin and regulation are uncertain. 18-OHF is synthesised by zona fasciculata 11-beta hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase. Levels of both steroids are increased in patients with Primary Aldosteronism. However, the origin of these steroids in normal subjects is not known.8 normal subjects and 6 subjects with primary adrenal failure performed 24-hour urine collections for measurement of steroid excretion (by GCMS) on three occasions. On one occasion normal subjects took dexamethasone (DMX; 2mg for 3 days) and subsequently also took hydrocortisone (HC; 20mg twice daily on the third day of DMX).18-OHF and 18-oxoF excretion (micrograms/24 hours) was detected in normal subjects (means =25.9 & 4 respectively) and in patients with adrenal failure (3.42&17.3) during HC therapy. DMX suppressed 18-OHF and 18-oxoF in both groups; in normal subjects cortisol (F; 2.9) and cortisone (E; 0.6) excretion were also suppressed. During HC (+ DMX) excretion of F (52.6) and E (87.3) were higher than basal in normals. Importantly, in both groups, HC administration resulted in detectable levels of 18-OHF (10.9 in normals, 3.42 in patients) and raised levels of 18-oxoF (11.6 in normals, 17.3 in patients). There was a close correlation between 18-oxoF and cortisol excretion during HC in normal subjects (r=0.86, p<0.001).These data show, for the first time, that 18-OHF and 18oxoF can be synthesised from circulating cortisol. The correlation between 18-oxoF and cortisol in all circumstances suggests that 18-oxoF is normally produced by the action of aldosterone synthase utilising circulating cortisol as substrate. This may occur in zona glomerulosa or in extra-adrenal sites where aldosterone synthase is expressed. Although 18OHF can be synthesized from circulating cortisol, our data suggest that the steroid is normally produced in the zona fasciculata by 11beta-hydroxylase from locally available cortisol.
22 - 24 Mar 2004
British Endocrine Societies