ESPE Abstracts

Background: Some patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) survive without glucocorticoid treatment, despite low total cortisol levels. This may be caused by accumulating precursor steroids such as 21-deoxycortisol (21DF), which could contribute to the glucocorticoid activity. In addition, these precursor steroids may decrease the cortisol-protein binding, thereby increasing the free (biologically active) glucocorticoid concentrations. Here, we set out to test both hypotheses.

Methods: An LC-MS/MS method for free cortisol and free 21DF was established and validated. Total and free concentrations of cortisol and 21DF were measured before and after Synacthen® administration in untreated patients with classic CAH (n = 29), non-classic CAH (NCCAH, n = 5), other forms of adrenal insufficiency (AI, n = 3), and controls (n = 11).

Results: The median unstimulated total morning cortisol concentration in serum was 106 nmol/L for CAH patients, which was, as expected, significantly lower than levels in NCCAH patients (249 nmol/L, P = 0.010) and controls (202 nmol/L, P = 0.016). Remarkably, the median free cortisol concentration of untreated CAH patients was 8.62 nmol/L, which was similar to NCCAH patients (9.84 nmol/L, P = 0.313) and controls (6.94 nmol/L, P = 0.573). In addition, the median total and free 21DF concentrations in 21OHD patients was respectively 67.5 and 5.32 nmol/L, which increased to respectively 94.5 and 7.34 nmol/L after Synacthen® administration. In AI patients and controls, 21DF concentrations were low (total <0.7 nmol/L; free <0.19 nmol/L) without noteworthy increase after Synacthen®.

Discussion: Patients with classic CAH have free cortisol concentrations that are similar to controls in unstimulated conditions. In addition, classic 21OHD patients produce high total and free levels of 21DF, that increase after Synacthen® administration. The increased percentage of free cortisol in CAH patients might be explained by increased concentrations of precursor steroids, such as 17-hydroxyprogesterone and 21DF, that displace cortisol from its binding proteins. In addition, increased androgen levels might increase free cortisol levels by decreasing 11-hydroxy steroid dehydrogenase type 2 activity or decreasing the levels of corticosteroid binding globulin. The presence of similar levels of free cortisol compared to healthy controls and the existence of elevated levels of 21DF with glucocorticoid activity might explain why some classic 21OHD patients with low total cortisol levels survive without overt signs of cortisol deficiency. Therefore, in the specific case of 21OHD, free cortisol and free 21DF levels should be considered in the clinical evaluation for the assessment of adrenal insufficiency.