Metabolism of glucocorticoids and mineralocorticoids in patients with adrenal incidentalomas

Background Adrenal incidentalomas are mostly nonfunctioning adrenocortical adenomas (NFI). However, in 5%-12% of the patients a preclinical Cushing's syndrome (PCS) with autonomous cortisol production by the tumour is present. Since urinary free cortisol excretion is not sensitive enough to determine subclinical hypercortisolism, in the present study more sensitive indicators of daily cortisol production were measured. Design (1) Tetrahydrocortisol, tetrahydrocortisone, urinary free cortisone together with urinary free cortisol were measured in 35 patients with adrenal incidentalomas (29 NFI and six PCS) and in 35 healthy controls. (2) Since little is known about daily aldosterone production, aldosterone metabolite excretions were measured. (3) As recently reported, ACTH stimulation revealed an increased response of precursors of the glucocorticoid and mineralocorticoid pathway. To find out which steroidogenic enzymes have altered activities, a 1-24 ACTH stimulation test (250 mug i.v.) was carried out in 25 patients and 18 healthy controls with determination of multiple steroids. (4) Finally, since it was assumed that 21-hydroxylase deficiency or even 11b-hydroxylase deficiency may be involved in adrenal tumourigenesis, the prevalence of germline CYP21B and CYP11B1 mutations were studied in the same patients, who had underwent the ACTH stimulation test. Results (1) Glucocorticoid metabolites were within the normal range in all but three patients with NFI. As a group, the patients had subtle alterations in cortisol metabolism Tetrahydrocortisol excretion was elevated in NFI and PCS compared with normal subjects (2.1 +/- 0.2 and 2.5 +/- 0.5 vs. 1.5 +/- 0.1 mg 24 h(-1); P < 0.05). Accordingly, the twofold elevation of the tetrahydrocortisol/free cortisol ratio indicates an increased 5-beta-reduction of cortisol in the liver. (2) Tetrahydroaldosterone and aldosterone-18-glucuronide excretions were not different to controls. (3) In patients with incidentalomas an increased response to ACTH was seen for 17-hydroxyprogesterone (595 +/- 133 vs. 160 +/- 25 ng dL(-1)), 21-desoxycortisol (105 +/- 25 vs. 29 +/- 9 ng dL(-1)) and 11-desoxycortisol (401 +/- 40 vs. 293 +/- 17 ng dL(-1)). (4) In only one of 25 patients, a heterozygous deletion in exon 3 of the CYP21B gene was detected. Conclusions (1) In conclusion, even thr excretion of the main glucocorticoid metabolites is not a marker sensitive enough to distinguish between NFI and PCS. However, it is also possible that alterations in cortisol secretion are qualitative rather than quantitative. (2) Zona glomerulosa function is not influenced. (3) The elevation of 21-desoxycortisol argues against an impairment of 11 beta-hydroxylase and favours a decreased activity of 21-hydroxylase. All others had wild-type sequences of both genes. (4) In conclusion, neither 21-hydroxylase deficiency nor 11 beta-hydroxylase deficiency are predisposing factors for adrenal tumourigenesis.