Introduction: Consensus regarding the diagnostic cutoff values for cortisol responses to low-dose cosyntropin testing (LDT) and its specific advantages over standard high-dose test (HDT) in assessing the pituitary-adrenal axis in children is lacking. Methods: In a retrospective study, patients who underwent sequential LDT and HDT were classified into two groups depending on the reason for testing: prolonged systemic glucocorticoid exposure (group 1) or suspected hypothalamic-pituitary dysfunction (group 2). Sensitivity and specificity analysis of varying cortisol levels during LDT in diagnosing adrenocorticotropic hormone (ACTH) deficiency (ACTHD) were calculated via the receiver operating characteristic curve analysis against the reference diagnostic test HDT. ACTHD was defined as peak cortisol level <18 μg/dL (500 nmol/L) in HDT. Results: This analysis included 112 patients, of whom 20 were diagnosed with ACTHD. There was a strong correlation between peak cortisol levels during LDT and HDT (r = 0.93, p < 0.001). A cortisol peak of 13.5 μg/dL (372 nmol/L) during the LDT had the best diagnostic accuracy (Sensitivity 90%, Specificity 90%: area under the curve 0.973 [95% CI: 0.945–1, p < 0.001]) in the entire cohort. A higher cortisol level was needed for group 1 to achieve comparable performance to group 2 (14.5 vs. 11.5 μg/dL [317 nmol/L], respectively). Conclusions: The strong correlation between cortisol responses in the LDT and HDT suggests that, when appropriately lower cutoff values are applied, the LDT provides results comparable to the HDT.

1.
Husebye
ES
,
Pearce
SH
,
Krone
NP
,
Kämpe
O
.
Adrenal insufficiency
.
Lancet
.
2021
;
397
(
10274
):
613
29
.
2.
Beun
JG
,
Burman
P
,
Kämpe
O
,
Husebye
ES
,
Hahner
S
,
Kristensen
J
, et al
.
Doctors, teach your adrenal insufficiency patients well: provide them with a European Emergency Card
.
Endocr Connect
.
2023
;
12
(
1
):
e220345
.
3.
Birtolo
MF
,
Antonini
S
,
Saladino
A
,
Zampetti
B
,
Lavezzi
E
,
Chiodini
I
, et al
.
ACTH stimulation test for the diagnosis of secondary adrenal insufficiency: light and shadow
.
Biomedicines
.
2023
;
11
(
3
):
904
.
4.
Hurel
SJ
,
Thompson
CJ
,
Watson
MJ
,
Harris
MM
,
Baylis
PH
,
Kendall-Taylor
P
.
The short synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis
.
Clin Endocrinol
.
1996
;
44
(
2
):
141
6
.
5.
Fleseriu
M
,
Gassner
M
,
Yedinak
C
,
Chicea
L
,
Delashaw
JB
,
Loriaux
DL
.
Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review
.
Endocr Pract
.
2010
;
16
(
1
):
64
70
.
6.
Cho
HY
,
Kim
JH
,
Kim
SW
,
Shin
CS
,
Park
KS
,
Kim
SW
, et al
.
Different cut-off values of the insulin tolerance test, the high-dose short Synacthen test (250 μg) and the low-dose short Synacthen test (1 μg) in assessing central adrenal insufficiency
.
Clin Endocrinol
.
2014
;
81
(
1
):
77
84
.
7.
Nye
EJ
,
Grice
JE
,
Hockings
GI
,
Strakosch
CR
,
Crosbie
GV
,
Walters
MM
, et al
.
Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests
.
J Clin Endocrinol Metab
.
1999
;
84
(
10
):
3648
55
.
8.
Ospina
NS
,
Al Nofal
A
,
Bancos
I
,
Javed
A
,
Benkhadra
K
,
Kapoor
E
, et al
.
ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis
.
J Clin Endocrinol Metab
.
2016
;
101
(
2
):
427
34
.
9.
Cortez
S
,
Arbeláez
AM
,
Wallendorf
M
,
McNerney
K
.
Peak serum cortisol cutoffs to diagnose adrenal insufficiency across different cortisol assays in children
.
J Clin Res Pediatr Endocrinol
.
2023
;
15
(
4
):
375
9
.
10.
Javorsky
BR
,
Raff
H
,
Carroll
TB
,
Algeciras-Schimnich
A
,
Singh
RJ
,
Colón-Franco
JM
, et al
.
New cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation using specific cortisol assays
.
J Endocr Soc
.
2021
;
5
(
4
):
bvab022
.
11.
Dickstein
G
,
Shechner
C
,
Nicholson
WE
,
Rosner
I
,
Shen-Orr
Z
,
Adawi
F
, et al
.
Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test
.
J Clin Endocrinol Metab
.
1991
;
72
(
4
):
773
8
.
12.
Murphy
H
,
Livesey
J
,
Espiner
EA
,
Donald
RA
.
The low dose ACTH test: a further word of caution
.
J Clin Endocrinol Metab
.
1998
;
83
(
2
):
712
3
.
13.
Fleseriu
M
,
Hashim
IA
,
Karavitaki
N
,
Melmed
S
,
Murad
MH
,
Salvatori
R
, et al
.
Hormonal replacement in hypopituitarism in adults: an endocrine Society clinical practice guideline
.
J Clin Endocrinol Metab
.
2016
;
101
(
11
):
3888
921
.
14.
Elder
CJ
,
Sachdev
P
,
Wright
NP
.
The short Synacthen test: a questionnaire survey of current usage
.
Arch Dis Child
.
2012
;
97
(
10
):
870
3
.
15.
Beuschlein
F
,
Else
T
,
Bancos
I
,
Hahner
S
,
Hamidi
O
,
van Hulsteijn
L
, et al
.
European Society of Endocrinology and Endocrine Society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency
.
Eur J Endocrinol
.
2024
;
190
(
5
):
G25
51
.
16.
El-Farhan
N
,
Pickett
A
,
Ducroq
D
,
Bailey
C
,
Mitchem
K
,
Morgan
N
, et al
.
Method-specific serum cortisol responses to the adrenocorticotrophin test: comparison of gas chromatography-mass spectrometry and five automated immunoassays
.
Clin Endocrinol
.
2013
;
78
(
5
):
673
80
.
17.
Cemeroglu
AP
,
Kleis
L
,
Postellon
DC
,
Wood
MA
.
Comparison of low-dose and high-dose cosyntropin stimulation testing in children
.
Pediatr Int
.
2011
;
53
(
2
):
175
80
.
18.
Cartaya
J
,
Misra
M
.
The low-dose ACTH stimulation test: is 30 minutes long enough
.
Endocr Pract
.
2015
;
21
(
5
):
508
13
.
19.
Gill
H
,
Barrowman
N
,
Webster
R
,
Ahmet
A
.
Evaluating the low-dose ACTH stimulation test in children: ideal times for cortisol measurement
.
J Clin Endocrinol Metab
.
2019
;
104
(
10
):
4587
93
.
20.
Bridges
NA
,
Hindmarsh
PC
,
Pringle
PJ
,
Honour
JW
,
Brook
CG
.
Cortisol, androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS) and 17 hydroxyprogesterone (17OHP) responses to low doses of (1-24)ACTH
.
J Clin Endocrinol Metab
.
1998
;
83
(
10
):
3750
3
.
21.
Crowley
S
,
Hindmarsh
PC
,
Honour
JW
,
Brook
CG
.
Reproducibility of the cortisol response to stimulation with a low dose of ACTH(1-24): the effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics
.
J Endocrinol
.
1993
;
136
(
1
):
167
72
.
22.
Alía
P
,
Villabona
C
,
Giménez
O
,
Sospedra
E
,
Soler
J
,
Navarro
MA
.
Profile, mean residence time of ACTH and cortisol responses after low and standard ACTH tests in healthy volunteers
.
Clin Endocrinol
.
2006
;
65
(
3
):
346
51
.
23.
Jeffcoate
WJ
,
Phenekos
C
,
Ratcliffe
JG
,
Williams
S
,
Rees
L
,
Besser
GM
.
Comparison of the pharmacokinetics in man of two synthetic ACTH analogues: alpha1-24 and substituted alpha1-18 ACTH
.
Clin Endocrinol
.
1977
;
7
(
1
):
1
11
.
24.
Moncloa
F
,
Velazco
I
,
Beteta
L
.
Biological half-life of a synthetic corticotrophin in men
.
Acta Endocrinol
.
1966
;
52
(
3
):
337
40
.
25.
Clarke
SA
,
Eng
PC
,
Comninos
AN
,
Lazarus
K
,
Choudhury
S
,
Tsang
C
, et al
.
Current challenges and future directions in the assessment of glucocorticoid status
.
Endocr Rev
.
2024
;
45
(
6
):
795
817
.
You do not currently have access to this content.