Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease

OBJECTIVE The insulin hypoglycaemia test (IHT) is believed to be the most r eliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l, Reference levels for a normal pl asma ACTH response have not been reported recently. DESIGN AND PATIENTS We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measureme nts of serum or plasma cortisol and of plasma ACTH, in order to establish r eference levels and to study the dose-response relationship between ACTH an d cortisol in this test. In most patients, other pituitary hormonal axes we re evaluated in addition. RESULTS With the cortisol kit from Diagnostic Products Corporation (DPC), s erum cortisol was about 13% lower than plasma (EDTA) levels with an excelle nt correlation between serum and plasma (r = 0.976; P < 0.001). In the norm als, the lower limit of the cortisol response (mean cortisol peak level min us 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l), In no rmals, the cortisol response was independent of the magnitude of the ACTH r esponse. Seventeen out of 30 patients with ACTH responses to levels <8.8 pm ol/l (< 40 ng/l) had subnormal cortisol responses, However, 38 of the patie nts with pituitary disease had normal cortisol responses in spite of subnor mal ACTH responses (group 2), while 47 patients had completely normal IHT r esults (group 1), Patients in group 2 had more often additional pituitary h ormone deficiencies than those of group 1. The dose-response relationship b etween ACTH and cortisol in the patients resembled a dose-response curve th at had been set up previously in normal subjects who received incremental d oses of subcutaneous human ACTH (1-39), CONCLUSIONS The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels >500 nmol/l. Patients wi th a subnormal ACTH but normal cortisol response in the IHT have a decrease d ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situati ons unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp divi ding line between normality and disease, and whether a patient needs perman ent glucocorticoid substution is a discretionary decision.