403
IV. Evaluation of a Standard ACTH-17-Hydroxycorticosteroid
Response Test in Children
By ROBERT S. ELY, M.D., RICHARD B. RAILE, M.D.,* PATRICK F. BRAY, M.D.,f AND VINCENT C. KELLEY, M.D., PH.D.
Salt Lake City
C
LINICAL evaluation of the functional status of the adrenal cortex has beendependent upon indirect technics. The
criteria of function which have been
em-ployed have included hematologic
re-sponses, urinary excretion of steroids and
water and electrolyte regulation. A more
direct measurement of this function is
pro-vided by the response of circulating
17-hydroxycorticosteroids to the intramuscular
injection of 25 lU. ACTH.’ The purpose
of the present communication is to evaluate this response test as a measure of adrenal
cortical function.
MATERIALS AND METhoDs
The patients included in this study were 80
children ranging in age from 2% to 16 yr. The sick children were suffering with a variety of
illnesses as indicated in the tables. The “well control” subjects consisted of a group of
chil-dren satisfying the clinical criteria previously
outlined.2
Blood specimens of 30 cc. volume were ob-tained by venipuncture before and 2 hr. after
the intramuscular injection of 25 LU. ACTH.t
Plasma was separated by centrifugation and
stored in the frozen state until used for
deter-mination of plasma concentrations of
17-From tile Lockhart Memorial Laboratory of the Department of Pediatrics, University of Utah Col-lege of Medicine, Salt Lake City.
Supported by grants-in-aid from the Life Insur-ance Medical Research Fund and the Helen Hay \Vhitney Foundation.
(Received for publication Nov. 25, 1953.)
* Present address: Department of Pediatrics, University of Minnesota Medical School, Minne-apolis.
f Present address: Lt. Patrick F. Bray, 427 \Vaskow, Killeen, Texas.
ACTHAR#{174}, supplied through the courtesy of the Armour Laboratories.
hydroxycorticosteroids by the method of
Nd-son and Samuels.3 In each individual counts of
absolute number of eosinophils (by the method of Randolph4) were made prior to and 1, 2 and 4 hr. after the administration of ACTH.
OBSERVATiONS
In the control group of 40 children (table 1) the mean plasma 17-hydroxycorticosteroid
con-centration was 12.0 tg./100 cc. and the S.E.M.
th 1.29 ,.g./100 cc. Individual values ranged from 0 to 28.7 p.g./lOO cc. Two hours after the intramuscular injection of 25 I.U. ACTH the mean plasma 17-hydroxycorticosteroid
con-centration in this same group of children was 29.8 2.50 g./100 cc. Statistical comparison of the pre- and post- ACTH steroid values
re-veals a highly significant difference. In general there was a considerable rise in the steroid
level in each individual 2 hr. after the
ACTH injection, the mean increase being 17.8
th 1.76 p.g./100 cc. Because of the excessive or extremely small responses of occasional
indi-viduals, the standard deviation is large, being 11.1 g./100 cc. When these response data
were analyzed according to the log dose of ACTH administered/unit weight, a lambda value of 0.38 resulted. Thus, if the weight of the subject is considered, the variation in
steroid responses is decreased somewhat. Table 2 gives a comparison of the magnitude of responses to 25 lU. and to 100 I.U. ACTH in 13 subjects (performed on different days). The mean change in plasma
17-hydroxycorti-costeroid concentration following the intramus-cular injection of 25 I.U. ACTH was 13_i 4.50 &g./100 cc.; following the intramuscular
injection of 100 I.U. ACTH it was 30.1 4.43
Lg./lOO cc. The difference between the 2
mean changes is statistically significant. In this group of patients the mean steroid response to
25 I.U. ACTH approximated 50% of the mean
PLASMA 17-ITYDRoxYcoRTIcosTERoID RESPONSE TO ACTH: RESPONSE TO 25 lU. ACTII (I.M.) IN CONTROL GROUP OF CHILDREN
Pt. No.
1 7-Hydroxycorticosteroids
gig. % Pt.
No.
1 7-Hydroxycorticosteroids Mg. %
0 Hr. 2 Hr. Change 0 Hr. 2 Hr. Change
1 17.5 37.4 19.9 21 11.2 48.4 37.2
1 10.1 30.4 20.3 2-2 1-2.7 26.7 14.0
3 5.0 24.3 19.3 23 17.3 56.5 39.1
4 7.3 30.1 21.8 24 10.1 18.1 18.1
5 0 19.1 19.1 15 1.3 26.3 14.0
6 0 35.9 35.9 26 14.9 40.7 15.8
7 6.6 25.0 18.4 27 11.6 39.0 16.4
8 12.7 472 34.5 28 2.0 14.1 12.1
9 13.6 29.7 16.1 29 10.6 15.1 4.5
10 28.7 62.5 33.8 30 . 7.3 19.8 12.5
11 15.6 43.2 276 31 10.4 23.7 13.3
12 17.4 34.1 16.8 32 9.2 15.1 5.9
13 25.3 52.4 27.1 33 0 13.7 13.7
14 27.6 68.8 41.2 34 4.6 15.5 10.9
15 21.2 33.7 11.5 35 8.1 15.4 7 .3
16 27.4 34.5 7.1 36 4.4 4.8 04
17 13.6 14.4 0.8 37 11.5 15.6 4.1
18 4.0 15.8 11.8 38 20.4 38.7 18.3
19 27.0 59.5 31.5 39 4.0 14.6 10.6
20 7.6 10.0 2.4 40 9.0 136 4.6
0 Hr. I Hr. Change
Mean - 12.0 29.8 17.8
S.E.M.- ± 1.19 ± 2.50 ± 1.76
S.D. - ± 8.2 ±15.8 ±11.1
TABLE 1
log dose/unit weight response technic reveals
a lambda value of 0.58. Thus, while there is
a greater steroid release in response to the larger dose of ACTH, there is not a close cor-relation between size of dose and magnitude of response in this group.
Although the mean pre-ACTH plasma
con-centration of 17-hydroxycorticosteroids was
120 tg./100 cc., the levels of these steroids in the plasmas of several children, who presum-ably had normal adrenal cortical function, were
either zero or quite low. However, as shown by the data in table 3, a low initial steroid
value does not necessarily indicate inadequate adrenal cortical responsiveness. In this table
the 17-hydroxycorticosteroid responses to
ACTH in one group of children, whose initial plasma steroid concentrations were more than
one standard deviation below the mean for the control group, are compared with those in an-other group whose initial steroid levels were more than one standard deviation above that
mean. In the group with low initial steroid levels the mean increase in steroid concentration
was 16.5 2.41 p.g./100 cc. whereas in the
other group it was 27.2 7.04 p.g./100 cc.
The difference between these absolute mean
responses is suggestive but not statistically
sig-nificant (p > 0.10). From these data it is con-eluded that a single low initial plasma steroid value may be entirely consistent with adequate adrenal cortical function as measured by the response of 17-hydroxycorticosteroids to an injection of ACTH. Although the absolute re-sponses in the 2 groups did not differ signifi-cantly, the mean per cent change in the group with low initial steroid levels was + 1270%
whereas in the other group it was only + 91%. Therefore, the per cent increase in steroid
con-centration is not a reasonable manner in which to describe the adrenal cortical response to ACTH because it may be influenced so greatly by the initial steroid value.
nor-TABLE 2
I’LASMA 17-HYDR0KYc0RTIc0sTER0ID RESPONSE TO ACTH: COMPARISON OF RESPONSES
TO 25 lU. VS. 100 lU. ACTH (I.M.) IN GROUP OF 13 CHILDREN
25 lU. ACTH
1 7-Ilydroxycorticosteroids Mg. %
No.
0 Hr. Hr. Change
100 lU. ACTH
17-Hydroxycorticosteroids g- %
No. -______________________________
0 hr. Hr. Change
1 9.6 40.6 31.0
2 16.9 5.4 -11.5
3 6.3 14.4 8.1
4 16.6 31.2 14.6
5 13.5 50.5 37.0
6 11.8 18.8 7.0
7 17.3 56.5 39.2
8 15.4 16.7 1.3
9 13.3 ‘28.8 15.5
10 8.7 ‘27.6 18.9
11 6.4 8.8 2.4
12 33.4 22.4 -11.0
13 25.4 43.8 18.4
Mean Absolute Change 13.1±4.50
1 0 33.1 33.1
2 12.8 393 26.5
3 0 14.1 14.1
4 13.9 49.3 354
5 8.1 74.5 66.4
6 2.6 ‘22.2 19.6
7 34.1 90.2 56.1
8 14.8 28.7 13.9
9 20.9 50.1 29.2
10 7.4 37.4 30.0
11 15.6 43.2 ‘27.6
12 1.3 28.0 26.7
13 21.2 33.7 12.5
30.1 ±4.43
Mean Difference = 17.0±6.30
T = 2.70
p ==<0.01
mally functioning adrenal cortex to the intra-muscular injection of ACTH, data are shown in
table 4 comparing this response in the control
group and in a group of children with
congeni-tal adrenal hyperplasia. In the latter group adrenal cortical function is inadequate, at least with respect to 17-hydroxycorticosteroid
pro-duction.5 Table 4 shows that the mean initial plasma steroid concentration in the group of
children with congenital adrenal hyperplasia
(2.6 tg./100 cc.) is significantly lower (p =
.01) than that in the control group (12.0 tg./
100 cc.). In addition, repeated determinations consistently demonstrate low concentrations of
these steroids in the former group. Moreover, whereas the mean steroid increase in response
to ACTH administration in the control group
is 17.8%, there is no significant increase in the group of patients with congenital adrenal
hy-perplasia.
Inasmuch as the injection of ACTH produces an eosinopenia as well as the demonstrated
in-crease in plasma 17-hydroxycorticosteroid
con-centrations it was of interest to see whether a
correlation exists between the degree of
eosino-phil depletion and the magnitude of steroid
increase following ACTH administration, If the eosinopenia produced by ACTH stimulation
of the adrenal cortex is mediated by the 17
hydroxycorticosteroids secreted one might
e-pect the degree of eosinopenia to be correlated with the observed increase in plasma steroid
concentration, With regard to this relationship, data concerning eosinophil and
17-hydroxy-corticosteroid responses to ACTH injection in 50 children were analysed. Chart 1 expresses
these data as a scattergram. For each subject
the change in steroid concentration observed
2 hr. after the administration of ACTH
is plotted against the maximum per cent
de-crease in eosinophils. If perfect correlation existed the quantitative increase in steroid con-centration would be directly proportional to the per cent decrease in eosinophils, and “r” would be 1.0. The correlation value “r” ob-tained here is 0.167, whereas the minimum value of “r” which would represent a significant positive correlation between the 2 variables in this series would be 0.279. Therefore, it is apparent from these data that no significant
correlation exists. The regression lines indicate
an almost complete lack of predictability of the magnitude of one variable on the basis of
the magnitude of the other, i.e., knowing the
.
.
regression line
.
.
.
ra +0.167
Regression lines:
V. O.22X + 10.7
(,ia 19.7) X’O.127Y+49.2
(5( ‘2&0)
line U,
o
o
Eosinophi I Depletion - 0/0 (X)
. .
.
.
.
S
5..
#{149} S #{149} S
#{149}#{149}
S #{149}
S 406
CHART 1. Plasma 17-hydroxycorticosteroid response to ACTH: Comparison with eosinophil response.
DIscussIoN
The data presented suggest that the
change in plasma 17-hydroxycorticosteroid
concentration induced by ACTH
adminis-tration can be used as a measure of adrenal
cortical function. In its present stage of
development this response test is capable of
identifying those individuals in whom
ad-renal cortical function is absent or consider-ably limited. This is illustrated by the poor
individual responses in the group of
chil-dren with congenital adrenal hyperplasia, as compared with those in the control group
(table 4). However, rigid interpretation of
the result of a single test as it is now
em-ployed is hazardous, especially if the results
indicate inadequate function. This is
il-lustrated by the poor response of steroid
levels to intramuscular ACTH in some
chil-dren in the control group, all of whom
pre-sumably have normal adrenal function. On
tile other hand, if a satisfactory i7-hydroxy-corticosteroid response is observed, it can
be assumed that the individual has
ade-quate adrenal function. At the present time
data concerning the response to an ACTH
dosage based on weight, although
suggest-ing that this approach gives somewhat more
uniform results, are inadequate to warrant
changing from a standard ACTH (lose to a
dose/unit weight.
Certain factors which contribute to
oc-casional falsely low responses to ACTH are
understood. Diurnal variation in plasma
17-hydroxycorticosteroid concentrations
gen-erally results in some progressive reduction of these levels during the morning6 at a time when most of the response tests in this
series were performed. Hence, a small
ob-served increase in steroid concentration
after injection of ACTH might actually
in-dicate a potentially greater response which was modified by the influence of diurnal
variation. Also, occasionally, the peak
steroid elevation does not occur at two
hours after ACTH injection, probably
be-cause of a variable rate of ACTH release
from its intramuscular site or Perhaps
be-cause of some variation in the speed of
re-sponse of tile adrenal cortex to the ACTH
LOW STEROID LEVELS
Pt. I 7-Ilydroxycorticosteroids Mg- %
No.
0 hr. ‘2hr.
Pt.
No.
Change
HIGH STEROII) LEVELS 17-Hydroxycorticosteroids Mg. %
0 Hr. Hr. Change
1 2.6 28.1
‘2 0 40.2
3 0 18.9
4 1.4 5.9
.5 3.2 15.1
6 2.1 18.7
7 ‘2.3 26.3
8 0.9 5.2
9 (1 19.1
10 (1 35.9
11 (1 8.3
II 2.0 14.1
13 0 5.1
14 3.0 6.1
15 ‘2.6 15.3
16 0 13.6
17 1) 13.7
18 3.1 21.5
19 1.2 4.6
20 0 ‘20.5
Meaii Absolute Change Mean Per Cent Change
‘25.5 40.2 ‘28.9 3.5 2L9 16.6 24.0 4.3 19.1 35.9 8.3 1’2.1 5.1 3.1 12.7 13.6 13.7 18.4 3-4 ‘20.5 16.5±2.41 + 1270%
1 31.8 77.8 36.0
‘2 44.0 68.7 24.7
3 35.2 53.4 18.1
4 33.4 119.0 85.6
5 ‘29.3 36.9 7.6
6 27.() 59.5 31.5
7 30.8 42.5 11.7
8 30.0 47.1 17.1
9 22.6 39.0 16.4
10 ‘23.2 11.3 -11.9
11 34.1 139.7 105.6
12 28.7 66.5 37.8
13 25.3 52.4 ‘27.1
14 28.1 117.5 89.4
15 23.9 48.2 -24.3
16 17.4 34.5 7.1
17 14.2 31.3 7.1
18 17.6 68.8 41.2
19 ‘27.8 19.7 - 8.1
‘20 39.6 ‘22.0 -17(1
‘21 35.3 441 8.8
172± 7.04 +91%
Mean Difference= 10.7±7.44
T = 1.44
p =>0.10
* Low concentrations refer to those >1 Si). below the control group meaii (12.0 g. %). High concentrations are >1. S.D. above tile mean.
TABLE 3
PLASMA 17-HYDROXYCORTICOSTEROID RESPONSE TO ACTH: EFFECT OF INITIAL STEROID CONCENTRATION*
ACTH dosage to be employed in a test of
this type has not been determined. It may
be that the test dose employed in this study does not stimulate the adrenal cortex
suffi-ciently in certain subjects to serve as a
valid test of adrenal function. That the test dose of 25 lU. ACTH given intramuscularly is not producing a maximal stimulation of
the adrenal cortex is indicated by the
ob-servation of a greater response to 100 I.U.
than to 25 lU. ACTH. Finally, the ACTH
administered has been standardized by the
adrenal ascorbic acid depletion response
technic. It is possible that potency with
regard to adrenal cortical steroid
produc-tion may not correspond to the adrenal
ascorbic acid response. It is believed that
these factors all may contribute toward
causing the inadequate or absent
17-hy-droxycorticosteroid response to ACTH
which is observed occasionally in subjects
with apparently normal adrenal cortical
function. When a second steroid response
test is performed on such subjects a
satis-factory response generally is seen. These
limitations in sensitivity of the test also probably account for the present inability to
assess quantitatively adrenal cortical
func-tion. Modification of this plasma steroid
response test in children to employ
intra-venous administration of ACTH, such as has
sen-TABLE 4
PLASMA 17-HYDR0xYc0RTIc05TER0ID RESPONSE TO ACTIL: RESPONSE IN ChILDREN WITH
CON-GENITAL ADRENAL IIYPERPLASIA
Pt. No.
17-Hydrox ycorticostero ids g- %
0 Hr. Hr. Change
1 4.1* 5.1 1.0
2 2.5* 3.1 0.6
3 1.8 2.0 0.2
0 2.5 2.5
2.0* ‘2.5 0.5
0* 0 0
4 5.2 6.3 1.1
5 0 0 0
0* 0 0
6 8.3 1.9 -6.4
Mean
4.6* 5.1 0.5
11 2.6±0.82 2.6±0.67 0.0±0.68
Control
Children 40 12.0±1.29 29.8±2.50 17.8±1.76
* 100 lU. ACTH given.
sitivity, and thus permit a more quantitative measurement of adrenal function,
It should be emphasized that the observa-tion of a low plasma
17-hydroxycorticos-teroid concentration in an individual does
not necessarily indicate inadequate adrenal cortical function, since this plasma con-centration reflects not only the rate of re-lease of these steroids by the adrenal cortex but the rate of their removal from the blood
by metabolic processes which may include
utilization, destruction, conjugation and
urinary excretion. However, the repeated
observation of low circulating
concentra-tions of these steroids suggests more
strongly such inadequacy. If, in addition,
the patient has no response or an
inade-quate response of plasma
17-hydroxycorti-costeroid concentration to the injection of
ACTH, the diagnosis of adrenal cortical
in-sufficiency becomes reasonably certain.
Of the procedures which have been
pro-posed for the evaluation of adrenal cortical
function several have had considerable
clinical use. Among these are included:
the water-load test;8#{176} the salt-deprivation test;1’ the urinary excretion of (1) 17-keto-steroids, (2) “corticoids” and (3)
17-hydroxy-corticosteroids; the response of urinary
excretion of these steroids to the adminis-tration of ACTH;13’T and the eosinophil
re-sponse tests.’82’ All these procedures are
based upon measurement of variables which
only indirectly reflect adrenal cortical
func-tion. Consequently, they have the
disad-vantage either of being nonspecffic or of
being influenced by nonadrenal factors. The
most direct test of this group is that
em-ploying the urinary excretion of
17-hy-droxycorticosteroids in response to ACTH.
Among these tests by far the most widely used clinically are the eosinophil response tests. These generally have been accepted as providing a simple means of evaluating
adrenal cortical function, It has been
as-sumed, since 17-hydroxycorticosterone is
the principal adrenal hormone in man,15’ 22
since eosinopenia follows the administration of 17-hydroxycorticosterone or cortisone,2325 since the administration of ACTH in
gen-eral produces simultaneously a decrease in
circulating eosinophils and an increase in
circulating xyrti26 and
since in vitro incubation of blood with
cortisone results in an eosinopenia,27 that
the eosinopenia resulting from ACTH or
epinephrine administration is affected by an increased secretion of
17-hydroxycorti-costeroids by the adrenal cortex. It now
has been demonstrated adequately that the
eosinopenia following epinephrine
stimula-tion is not mediated by an increased
cir-culating concentration of
17-hydroxycorti-26, 25 This test is no longer ac-cepted as a valid measure of adrenal corti-cal function IS, 20, 29, #{176}It has been suggested
previously2 that tile eosinopenia induced
by
ACTH
administration need not bemediated by increased circulating
concen-trations of i7-hydroxycorticosteroids
al-though commonly both occur in response to
correla-tion between the magnitude of response of
eosinophils and that of circulating
17-hydroxycorticosteroids demonstrated by the
data of chart 1 strongly suggests that the
eosinopenia induced by ACTH is not
en-tirely dependent upon an increase in
cir-culating 17-hydroxycorticosteroid
concen-tration.
The urinary excretion of
17-hydroxycorti-costeroids in response to ACTH has been
considered a more direct and reliable test than the eosinophil response test,3’ since
this urinary response test measures the
ex-cretion of products of adrenal cortical
secre-tion. The plasma 17-hydroxycorticosteroid response test measures directly the change
in circulating concentrations of the
pre-dominant hormone produced by the adrenal
cortex in response to
ACTH
administrationand thus represents an even more direct
test. It therefore seems logical to attribute
greater validity to the plasma steroid
re-sponse test as an indicator of the status of adrenal cortical function. In its present
form this test is generally, but not
uni-formly, reliable. Modification of the test to
employ intravenous administration of
ACTH
might considerably improve itsre-liability, since the effect of certain variables
would thus be minimized.
SUMMARY
An ACTH-17-hydroxycorticosteroid
re-sponse test is described as a measure of ad-renal cortical function in which the change
in plasma concentrations of 17-hydroxycorti-costeroids in response to the intramuscular injection of 25 I.U. ACTH is determined.
The limitations of this test are discussed and it is compared with other tests of ad-renal cortical function.
No correlation is seen between the
mag-nitude of steroid elevation and of
eosin-openia in response to ACTH. These data
suggest that the ACTH-induced eosinopenia
is not mediated by elevations in the cir-eulating concentrations of
17-hydroxycorti-costeroids.
Although this test might be improved by
modifying the ACTH dose or route of
ACTH
administration, the direct measure-ment of alterations in circulating concentra-tions of 17-hydroxycorticosteroids probablyrepresents the most practical approach to
evaluation of adrenal cortical responsive-ness.
ACKNOWLEDGMENT
The authors wish to express their
ap-preciation for technical assistance to Doris
F. Tippit, Mary C. O’Brien and H. Beth
Dowding.
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SPANISH ABSTRACT
Estudios
Sobre
los
17-Hidroxicorti-costeroides
IV.
Valoraci#{243}n de una Prueba en Ni#{241}os Sobre la Respuesta al A.C.T.H. de losl7-Hidroxicorticosterojdes
Los autores describen una prueba de la
de las concentraciones plasm#{225}ticas de los
17-hidroxicorticosteroides al H.A.C.T. Los
esteroides se determinan antes y dos horas
despu#{233}s de hacer una aplicaci#{243}n intramuscular
de 25 unidades de H.A.C.T. La prueba
pre-senta actualmente algunas limitaciones, como
las variaciones en tiempo de la respuesta, pero
se considera m#{225}sdirecta que cualquier otra prueba clInica usada. En su estado actual de
desarrollo, esta prueba es capaz de identificar
a los individuos con funci#{243}n adrenoc#{243}rtica con-siderablemente limitada o ausente. Reconocen
los autores e peligro de llegar a
interpreta-ciones rigidas con ci valor de tin solo nivel
bajo de esteroides 6 bien de una sola respuesta pobre de esteroidea al H.A.C.T., como sucede ocasionaimente en pacientes con funci#{243}nnor-mal adrenoc#{243}rtica.
No hay correlaci#{243}n entre la elevaci#{243}nde los niveles de esteroides y el grado de eosinopenia
como respuesta al H.A.C.T.; por lo tanto,
parece ser que la eosinopenia consecutiva a su administraci#{243}n no est#{225}determinada por las elevaciones de estos esteroides adrenales par-ticulares.
