Comparison of Adrenocorticotropin (ACTH) Stimulation Tests and Insulin Hypoglycemia in Normal Humans: Low Dose, Standard High Dose, and 8-Hour ACTH-(1–24) Infusion Tests1
Elisabeth J. Nye2,
Jeffrey E. Grice,
Gregory I. Hockings,
Christopher R. Strakosch,
Georgina V. Crosbie,
Margaret M. Walters and
Richard V. Jackson
Neuroendocrine Research Unit, Department of Medicine, The
University of Queensland, Brisbane, Queensland 4120, Australia
The efficacy of the standard high dose ACTH stimulation test(HDT),
using a pharmacological 250-µg dose of syntheticACTH-(1–24), in the
diagnosis of central hypoadrenalismis controversial. The insulin
hypoglycemia test is widely regardedas the gold standard dynamic
stimulation test of the hypothalamo-pituitary-adrenal(HPA) axis that
provides the most reliable assessment of HPAaxis integrity and
reserve. Alternatively, a prolonged infusionof ACTH causes a
continuing rise in plasma cortisol levels thatmay predict the
adrenals’ capacity to respond to severeongoing stress.
In nine normal subjects, we compared plasma ACTH and cortisollevels
produced by three iv bolus low doses of ACTH-(1–24)(0.1, 0.5, and 1.0
µg/1.73 m2; LDTs) with those stimulatedby hypoglycemia
(0.15 U/kg insulin) and with the cortisol responseto a standard
250-µg dose of ACTH-(1–24). The normalcortisol response to an 8-h
ACTH-(1–24) infusion (250µg at a constant rate over 8 h) was
determined using threemodern cortisol assays: a high pressure liquid
chromatographymethod (HPLC), a fluorescence polarization immunoassay
(FPIA),and a standard RIA.
In the LDTs, stepwise increases in mean peak plasma ACTH wereobserved
(12.4 ± 2.0, 48.2 ± 7.2, 120.2 ±15.5 pmol/L for the
0.1-, 0.5-, and 1.0-µg LDTs, respectively;P values
all <0.0022 when comparing peak values between tests).The peak plasma
ACTH level after insulin-induced hypoglycemiawas significantly lower
than that produced in the 1.0-µgLDT (69.6 ± 9.3
vs. 120.2 ± 15.5 pmol/L; P <
0.0002),but was higher than that obtained during the 0.5-µg LDT
(69.6± 9.3 vs. 48.2 ± 7.2 pmol/L;
P < 0.02). Inthe LDTs, statistically different,
dose-dependent increasesin peak cortisol concentration occurred
(355 ± 16, 432± 13, and 482 ± 23 nmol/L; greatest
P value is0.0283 for comparisons between all tests).
The peak cortisollevels achieved during the LDTs were very different
from thoseduring the HDT (mean peak cortisol, 580 ± 27 nmol/L;
allP values <0.00009. However, the mean 30 min
response in the1.0-µg LDT did not differ from that in the HDT
(471 ±22 vs. 492 ± 22 nmol/L;
P = 0.2). In the 8-h ACTH infusiontest, plasma
cortisol concentrations progressively increased,reaching peak levels
much higher than those in the HDT [995± 50 vs.
580 ± 27 nmol/L (HPLC) and 1326 ±100 vs 759 ± 31
nmol/L (FPIA)]. Significant differencesin the basal, 1 h, and
peak cortisol levels as determined bythe three different assay methods
(HPLC, FPIA, and RIA) wereobserved in the 8-h infusion tests.
Similarly, in the HDTs therewere significant differences in the mean
30 and 60 min cortisollevels as measured by HPLC compared with those
determined byFPIA.
We conclude that up to 30 min postinjection, 1.0 µg/1.73
m2ACTH-(1–24) stimulates maximal adrenocortical
secretion.Similar lower normal limits at 30 min may be applied in the
1.0-µgLDT and the HDT, but not when lower doses of ACTH-(1–24)are
administered. The peak plasma ACTH level produced in the1.0-µg LDT
is higher than in the insulin hypoglycemiatest, but is of the same
order of magnitude. The peak cortisolconcentration obtained during an
8-h synthetic ACTH-(1–24)infusion is considerably higher than that
stimulated by a standardbolus 250-µg dose, potentially providing a
means of evaluatingthe adrenocortical capacity to maintain maximal
cortisol secretion.Appropriate interpretation of any of these tests of
HPA axisfunction relies on the accurate determination of normal
responseranges, which may vary significantly depending on the cortisol
assayused.
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