Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic-pituitary-adrenal axis

Objective: Assessment of the hypothalamic-pituitary-adrenal (HPA) axis relies on the interpretation of serum (total) cortisol in response to dynamic tests of the HPA axis. Most cortisol is bound to cortisol-binding globulin (CBG) and serum total cortisol levels are significantly affected by variation in CBG. We hypothesised that CBG variation significantly affects interpretation of dynamic tests of the HPA axis. Design: We investigated the effect of CBG variation on the outcome of the 250 mug short Synacthen test (SST) in 30 healthy adults. Methods: Blood was sampled at time -30, 0 (at which point Synacthen was given) and +30min. CBG and total cortisol were measured at each time-point. Integrity of the HPA axis was confirmed by measurement of urine cortisol. Results: We found that CBG varied significantly within individuals, falling from 51 +/- 3.4 to 43 +/- 3.2 mug/ml (P < 0.0001) on changing from standing to lying. Total cortisol levels strongly correlated with CBG (r = 0.88, P < 0.0001). Thirteen subjects had a +30 min total cortisol <550 nmol/l. In these subjects, the CBG levels at each time-point were significantly lower compared with subjects who had a +30 min total cortisol of >550 nmol/l (P < 0.05). To correct for variation in CBG we calculated the total cortisol:CBG ratio and found no significant difference in the +30min ratio between these two groups. Conclusion: CBG varies significantly within and between individuals. This is accompanied by changes in serum total cortisol large enough to affect the outcome of an SST and, by implication, other tests of the HPA axis.