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Original Studies |
Division of Endocrinology, Department of Medicine, Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany
Address all correspondence and requests for reprints to: W. Oelkers, M.D., Division of Endocrinology, Department of Medicine, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany.
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Abstract |
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We performed both the HDT and the LDT in 35 control subjects and in 44 patients with pituitary disease, mostly pituitary tumors. In these patients, more sensitive reference tests for evaluating the pituitary-adrenal axis (insulin-induced hypoglycemia, metyrapone, and CRH tests) were also performed. In the HDT, plasma cortisol was measured 30 and 60 min after tetracosactin injection; in the LDT (0.5 µg/m2 body surface area), plasma cortisol was measured 20, 30, 40, 50, and 60 min postinjection. In 6 control subjects, tetracosactin plasma levels were also measured after injection.
In the HDT, the correlation between 30 and 60 min cortisol levels was extremely high (r = 0.991; P < 0.0001), but the correlation of the LDT with the HDT at 30 min was also highly significant (r = 0.948; P < 0.0001). The lower normal limit of cortisol responses (means of controls minus 2 SD) at 30 min was lower in the LDT by 3.1 µg/dL (85 nmol/L) than in the HDT. Compared with the reference tests, the diagnostic sensitivities of the HDT and the LDT were almost identical. Both tests identified patients with moderately to severely pathological insulin and metyrapone tests, but not those with slightly pathological reference tests. In the HDT, plasma tetracosactin rose to more than 60,000 pg/mL shortly after injection. In the LDT, it rose to 1,900 pg/mL. Both concentrations stimulate cortisol (supra-) maximally.
Together, these data show that in pituitary disorders the results of the LDT and the HDT are almost identical. Plasma tetracosactin levels in the LDT still rise to levels that maximally stimulate the adrenal. Tetracosactin testing with low or high doses cannot generally replace the more expensive and cumbersome insulin or metyrapone tests.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The idea of assessing smaller dosages of tetracosactin or corticotropin
in adrenal testing is sound, because it has been known for 3 decades
that 250 µg tetracosactin is a large overdose (12). Some years ago we
showed that the human adrenal cortex is almost maximally stimulated by
acute increments in plasma corticotropin levels to 70–80 pg/mL, which
is only twice the upper limit of normal in the early morning hours
(13). In the reports by Broide et al. (10) and Tordjman
et al. (11), a cut-off limit of 18 µg/dL (500 nmol/L)
plasma cortisol 30 min after tetracosactin injection was used for the
separation of normal and subnormal responses for both the HDT and HDT.
However, from the data of Tordjman et al. (11), it is clear
that 1 µg tetracosactin stimulated plasma cortisol less than the
250-µg dose in normal subjects, while Broide et al. (10)
state that their low tetracosactin dose (
0.5 µg) led to the same
cortisol rise as the 250-µg dose 30 min postinjection. If the cut-off
point for the LDT and HDT should be different, the use of 18 µg/dL
(500 nmol/L) plasma cortisol for both tests could deceptively indicate
a greater sensitivity of the LDT.
To reevaluate this important issue, we compared the two tetracosactin tests in 35 control subjects and 40 patients (44 studies) with pituitary disease. In these patients, the pituitary-adrenal axis was evaluated, in addition, by the insulin or metyrapone test or, in a few cases, by a CRH test. Plasma tetracosactin levels after injection were also measured in some normal subjects.
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Subjects and Methods |
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Thirty-five subjects without pituitary or adrenal disease served as a control group for establishing the normal range of adrenocortical responses to LDT and HDT. Twenty of them (10 women and 10 men) were healthy volunteers, mostly hospital personnel of varying age, whereas 15 subjects (7 women and 8 men) were in-patients who had recovered from or were undergoing diagnostic procedures for 1 of the following disorders: coronary heart disease or mild heart failure (n = 5), arterial hypertension (n = 3), syncope of undetermined cause (n = 2), pancreatitis type II (n = 1), diabetes mellitus (n = 1), mild anemia (n = 1), deep vein thrombosis (n = 1), or esophagitis (n = 1). Their age ranged from 23–90 yr (mean ± SD, 43 ± 19 yr), height ranged from 158–192 cm (171 ± 9 cm), and body weight ranged from 46–110 kg (70 ± 15 kg). None of the women in the control group took estrogens. Forty patients with confirmed hypothalamic or pituitary disease (21 women and 19 men), in whom a stimulation test of the pituitary-adrenal axis with insulin, metyrapone, or CRH (reference tests) was indicated, were additionally studied with LDT and HDT within up to 4 weeks after performance of the reference stimulation test. In most cases, the reference test and the 2 tetracosactin tests were performed within 3–7 days. Four patients were studied twice with the 3 tests, once before and a second time after pituitary surgery. Therefore, 44 sets of tests could be evaluated. In patients who had undergone pituitary surgery, endocrine tests were performed not earlier than 6 weeks postoperatively. The diagnoses of the 40 patients were as follows: nonsecreting pituitary macroadenoma before or after surgery (n = 20), acromegaly before or after surgery (n = 7), cystic pituitary tumor/dermoid cyst (n = 5), macroprolactinoma (n = 2), diabetes insipidus, idiopathic or due to hypophysitis/histiocytosis X (n = 3), craniopharyngioma, lymphoma (n = 1), or Kallmann’s syndrome (n = 1). The patients’ age ranged from 26–78 yr (mean ± SD, 52 ± 15 yr), height ranged from 151–188 cm (170 ± 9 cm), and body weight ranged from 56–150 kg (79 ± 18 kg). Seventeen of these patients had been treated with 15–25 mg hydrocortisone/day for some months or years before the tests were performed. Three women in the patient group were receiving oral estradiol (1 or 2 mg daily) substitution therapy. In 2 of them, insulin or metyrapone tests and both corticotropin tests were highly pathological, whereas in the third all tests were normal. Thus, estrogens, by their effect on cortisol-binding globulin, could not have biased the results of this study. Written informed consent was obtained for all tests from control subjects and patients after the ethical committee of this hospital had agreed to the study protocol.
Test protocols
The insulin-induced hypoglycemia test and the CRH test (the
latter with 100 µg human CRH) were performed in the morning between
0800–0900 h, as recently outlined (2, 3). The insulin dose was
0.1–0.15 IU/kg BW. The results were accepted if blood glucose levels
had dropped to levels below 40 mg/dL (<2.2 mmol/L), and some
neuroglucopenic symptoms had occurred. In both tests, plasma glucose
was measured at baseline and every 15 up to 90 min in the insulin test
and up to 60 min in the CRH test. A plasma cortisol increase to a
maximum of 20 µg/dL or more (
550 nmol/L) for the insulin test and
14.5 µg/dL or more (400 nmol/l) for the CRH test was regarded as
normal (2, 3, 14). The overnight metyrapone test (30 mg/kg metyrapone
at midnight) was performed as described previously (3, 15), and an
increment in plasma 11-deoxycortisol to 7.0 µg/dL or more (200
nmol/L) was regarded as a normal response. With a subnormal response of
11-deoxycortisol, the test was only accepted if the postmetyrapone
plasma cortisol level at 0800 h was less than 8 µg/dL (<230
nmol/L). The usual contraindications against the insulin test were
carefully observed. This test was often performed in conjunction with
GnRH and TRH testing. In the 44 test sets, the insulin test was the
reference test in 26 cases, the metyrapone test was the reference test
in 10 cases, and the CRH test was the reference test in 3 cases. In 5
patients, a morning plasma cortisol level of less than 3.0 µg/dL
(<82 nmol/L) was regarded as proof of adrenocortical insufficiency (1, 3), and no dynamic test (except the tetracosactin tests) was
performed.
The HDT was performed in all patients between 0800–0930 h. An indwelling venous cannula was placed into one forearm, and 250 µg tetracosactin (Synacten, Ciba-Geigy, Basel, Switzerland) was injected as a bolus after a basal blood sample was taken for plasma cortisol measurement. Additional blood samples were obtained 30 and 60 min after injection. The LDT was also performed in all controls and patients with the individualized tetracosactin dose of 0.5 µg/m2 body surface area in variance from Broide et al. (10). The content of a 250-µg ampule of tetracosactin was injected into a plastic bottle containing 250 mL sterile normal saline and thoroughly mixed. This freshly prepared solution was also injected as a bolus, and blood samples for cortisol measurement were withdrawn at baseline, 20, 30, 40, 50, and 60 min postinjection. The LDT was always performed first, and the HDT was performed on a later day, in most cases on the next day.
In six normal subjects, a second iv cannula was inserted into the opposite forearm to obtain blood samples for the measurement of plasma ACTH at baseline and tetracosactin 1, 3, 5, 7, 10, 20, and 30 min after HDT and LDT. In the HDT, an additional blood sample was taken 60 min after injection.
The lower limit of normal plasma cortisol levels at each time point after HDT and LDT was obtained by subtracting 2 SD from the mean level of 35 tested control subjects.
If a patient was receiving hydrocortisone substitution before any of these tests was performed, the last dose not exceeding 15 mg was given on the morning of the day preceding the test. If a patient had two or three tests performed on subsequent days, he was allowed to take his morning hydrocortisone dose immediately after the first (or second) test.
Laboratory methods
Plasma cortisol was measured using a RIA kit (Diagnostic Products Corp., distributed by H. Biermann, Bad Nauheim, Germany). Intraassay variability in seven trials (n = 20) ranged from 4–5.1%; interassay variability ranged from 4–6.4% (three trials; n = 20). This cortisol kit was recently found to compare favorably with other kits against a gas chromatography-mass spectrometry reference method (16). Plasma tetracosactin was measured using a RIA with an antibody that recognized the N-terminal sequence of ACTH (CIS Diagnostik, Dreieich, Germany). Intraassay variability ranged between 4.2–6.2% (3 trials, n = 20), and intraassay variability ranged between 4.3–8.4% (three trials; n = 20).
Statistical calculations were performed using an SPSS program from SPSS (Chicago, IL). Differences between the two tetracosactin tests in control subjects were analyzed with paired two-tailed Student’s t test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 1
shows the mean basal and
posttetracosactin levels and lower limits of normal responses
(mean - 2 SD) at different time points in the 35
control subjects. Figure 1 is the graphic
plot. Up to 30 min after injection, plasma cortisol rose to almost the
same level in the HDT and LDT (at 30 min, the difference was not
significant; P = 0.07), but at this time, the lower normal
limit was about 3.1 µg/dL (85 nmol) lower in the LDT than the HDT.
Thereafter, cortisol rose further in the HDT, but decreased gradually
in the LDT. Plasma cortisol responses were not significantly different
in the 20 healthy controls and the 15 patients without pituitary
disease. Figure 1 also shows plasma tetracosactin levels in 6 control
subjects. In the HDT, tetracosactin reached an extremely high peak
level 1 min after injection (mean ± SE, 66,000
± 2,600 pg/mL). The levels were 13,070 ± 150 pg/mL after 10 min
and 157 ± 9 pg/mL after 60 min. In the LDT, with a tetracosactin
dose of about 1/250th of the HDT, the level was still 1,920 ± 73
pg/mL after 1 min, 180 ± 5 pg/mL after 10 min, and had returned
to the control level after 60 min.
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shows the results of the LDT (30
min after injection) and the HDT (30 and 60 min) in 44 pairs of tests.
They are grouped according to the results of the reference tests. Group
1 (Fig. 2, 
; n = 21) had a normal reference test result. There
was only 1 patient (the same in both tetracosactin tests) who failed
the lower normal limit in the high dose and LDT by a few percent. Group
2 (Fig. 2, 
) represents 14 patients who had a clearly subnormal
reference test (cortisol in the insulin test <18 mg/dL or <500
nmol/L, in the CRH test <12.5 µg/dL or <345 nmol/L,
11-deoxycortisol in the metyrapone test <6.2 µg/dL or <179 nmol/L).
The steroid responses were at least 10% below the lower normal limits
of the reference tests, as reported in Materials and
Methods. In these patients, the LDT was subnormal in 100%, and 1
patient had a cortisol response slightly higher than the lower normal
limit in the HDT at both 30 and 60 min. The same patient had a cortisol
response to 17.1 µg/dL (472 nmol/L) in the LDT with a lower normal
limit of 19.4 µg/dL. Group 3 (Fig. 2, 
) represents 9 patients with
a slightly abnormal insulin test (peak cortisol levels between 18–20
µg/dL or 500–550 nmol/L) or metyrapone test (11-deoxycortisol
between 6.2–7.0 µg/dL or 179–200 nmol/L). None of these patients
had a CRH test. Only 1 of these patients had a slightly subnormal
response in the LDT (18.6 µg/dL or 512 nmol/L), whereas 2 other
patients had a slightly subnormal response in the HDT 30 and 60 min
after injection. These 2 patients, who just failed the HDT, had
cortisol responses of 20.2 and 22.6 µg/dL (557 and 623 nmol/L) in the
LDT.
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), the differences among
groups 1, 2, and 3 in Fig. 2 were essentially the same as those 30 min
after LDT, i.e. drawing blood at time points later than 30
min does not improve the diagnostic value of the LDT.
Figure 3 shows correlation diagrams of
the tetracosactin test parameters. There was an extremely close
correlation between the 30 and 60 min cortisol responses in the HDT
(r = 0.991), but there was also a linear and very close
correlation between the cortisol responses in the LDT and HDT.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There was also a surprisingly high correlation between the posttetracosactin cortisol levels in the LDT and the HDT. The relation between cortisol levels in both tests was strictly linear, a finding one would not expect if one of the tests was more sensitive than the other in diagnosing adrenocortical insufficiency. The correlation between the LDT and the HDT was apparently similar to recently reported correlations between two repeat HDTs in normal subjects (18).
Figure 2 clearly shows that the two tests do not differ in their
ability to discriminate between patients with pituitary disease with
severe, mild, or no insufficiency of the HPA axis. Both tests
identified patients with moderately to severely impaired responses
(n = 14), but not those with mildly impaired responses (n =
9) in the reference tests. These findings confirm those of other groups
reporting an underdiagnosis of secondary adrenal insufficiency with the
HDT compared with the insulin or the metyrapone test as well as the
development of clinical signs of adrenocortical insufficiency in some
patients with a normal HDT (4, 5, 6, 7, 8, 9). The LDT was developed to overcome
this weakness, but there is no convincing evidence that this purpose
was achieved. When comparing the results we obtained in a much larger
population of patients and controls with those of Tordjman et
al. (11), ours hardly differ from theirs except with regard to
interpretation. Instead of elaborating different lower normal limits
for the cortisol response to 1, 5, or 250 µg tetracosactin, Tordjman
et al. (11) arbitrarily used a lower plasma cortisol limit
of 500 nmol/L (18 µg/dL) for all tetracosactin doses, although it is
evident from their data that their controls had higher cortisol
responses with higher doses of the peptide. By doing so, they
spuriously increased the sensitivity of the LDT. This reservation also
applies to the study of Broide et al. (10), who used only
0.5 µg/1.73 m2 tetracosactin, but applied the same plasma
cortisol cut-off point for the low and HDTs. Rasmuson et al.
(19) recently studied patients with pituitary disease and found a
slightly closer correlation of cortisol responses in the insulin test
with those in the LDT than in the HDT. They suggested using 550 nmol/L
(20 µg/dL) plasma cortisol as the cut-off point for both
tetracosactin tests, but had not studied a population of control
subjects.
Our study not only shows that the LDT is not more sensitive in
detecting mild degrees of secondary adrenal insufficiency than the HDT,
but it also shows why this cannot be the case. In previous
publications, we have shown that the response of the normal human
adrenal to an increment in plasma corticotropin [after sc injection of
corticotropin-(1–39) or iv injection of CRH] to 70–80 pg/mL is
almost maximal. At higher corticotropin levels, the response curve is
very flat (2, 13). Tetracosactin stimulates the human adrenal to about
the same degree as natural human corticotropin-(1–39) (12). In the
HDT, tetracosactin levels rose to more than 60,000 pg/mL and were still
>100 pg/mL 1 h after injection. Therefore, the adrenals were
maximally stimulated for the entire duration of the test, with plasma
cortisol still rising between 30–60 min, indicating accumulation of
cortisol in its distribution space. In the LDT, the initial
tetracosactin level also rises to a supramaximal stimulating level
(1,900 pg/mL) and remains above 100 pg/mL for more than 10 min.
Thus, the cortisol level 20 min after tetracosactin injection is the
result of maximal adrenal stimulation, as in the HDT. Later on, the
tetracosactin level falls rapidly, the adrenals are less vigorously
stimulated, and cortisol distribution and clearance prevail over
secretion, as reflected by an almost linear decline in plasma cortisol.
We had hoped that the cortisol levels 40, 50, or 60 min after
tetracosactin injection in the LDT might enable a better and more
sensitive discrimination between the patient groups than the 30 min
level or the HDT, but the results (not shown numerically) were
identical with those at 30 min.
The question arises as to whether a corticotropin or tetracosactin test with a dose less than 1 or 0.5 µg/m2 that avoids short term maximal adrenal stimulation might be better suited for revealing mild secondary adrenal insufficiency than the 1- and 250-µg tests. The prerequisite for the usefulness of such a very low dose test would be that the dose-response relationship between plasma ACTH and cortisol is different in these patients and in normal subjects, with a flattening of the initially steep part of the dose-response curve as described in normal subjects (13). Such an anomaly of the dose-response curve has never been demonstrated in patients.
The blunted cortisol response in the insulin test or the blunted 11-deoxycortisol response after metyrapone treatment in patients with more severe secondary adrenal insufficiency is due to adrenal hyporesponsiveness (atrophy and functional impairment) and an impaired increment in plasma corticotropin. In patients with milder forms of the disease, in whom adrenal atrophy is minimal or absent, the blunted steroid response in these tests is only due to an insufficient increment in plasma corticotropin. The results of tetracosactin tests with any dose only reflect the degree of adrenal hyporesponsiveness, as the dose of injected ACTH is fixed. For this reason, tests for evaluating corticotropin-adrenal function in hypothalamic-pituitary disease, such as the insulin and metyrapone tests, are preferable to tetracosactin testing to avoid an underdiagnosis of clinically significant adrenal insufficiency.
As insulin and metyrapone testing is more expensive than a tetracosactin test and is not without side-effects, a tetracosactin test can be used to identify patients with moderate to severe pituitary-adrenal insufficiency, but one has to bear in mind that it is not a test for the safe exclusion of mild, although clinically significant, secondary adrenal insufficiency. Our data clearly show that, deplorably, the LDT is not better than the HDT in this regard.
Received November 18, 1997.
Revised January 26, 1998.
Accepted February 3, 1998.
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E. Arvat, L. Di Vito, F. Lanfranco, M. Maccario, C. Baffoni, R. Rossetto, G. Aimaretti, F. Camanni, and E. Ghigo Stimulatory Effect of Adrenocorticotropin on Cortisol, Aldosterone, and Dehydroepiandrosterone Secretion in Normal Humans: Dose-Response Study J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3141 - 3146. [Abstract] [Full Text]
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P. Marik, G. Zaloga, K. Chawla, Y. Kupfer, S. Tessler, D. Annane, and E. Bellissant Prognostic Value of Cortisol Response in Septic Shock JAMA, July 19, 2000; 284(3): 308 - 309. [Full Text] [PDF]
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E. J. Nye, J. E. Grice, G. I. Hockings, C. R. Strakosch, G. V. Crosbie, M. M. Walters, and R. V. Jackson 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., October 1, 1999; 84(10): 3648 - 3655. [Abstract] [Full Text] [PDF]
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M. Zarkovic, J. Ciric, M. Stojanovic, Z. Penezic, B. Trbojevic, M. Drezgic, and M. Nesovic Optimizing the Diagnostic Criteria for Standard (250-{micro}g) and low Dose (1-{micro}g) Adrenocorticotropin Tests in the Assessment of Adrenal Function J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3170 - 3173. [Abstract] [Full Text]
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A. S. Krasner Glucocorticoid-Induced Adrenal Insufficiency JAMA, August 18, 1999; 282(7): 671 - 676. [Full Text] [PDF]
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W. Oelkers Comment on Comparison of the Low Dose Short Synacthen Test (1 {micro}g), the Conventional Dose Short Synacthen Test (250 {micro}g), and the Insulin Tolerance Test for Assessment of the Hypothalamo-Pituitary-Adrenal Axis in Patients with Pituitary Disease J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2973 - 2973. [Full Text]
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D. H. P. Streeten Editorial: Shortcomings in the Low-Dose (1 {micro}g) ACTH Test for the Diagnosis of ACTH Deficiency States J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 835 - 837. [Full Text]
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M. Grino, P. Darmon, F. Dadoun, C. Frachebois, J.-G. Velut, S. Boullu, A. Dutour, and C. Oliver About the Use and Misuse of an ACTH 1-39 Radioimmunoassay to Measure ACTH 1-24 J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 824 - 825. [Full Text]
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) or LDT (0.5
µg/m2; •) in 35 control subjects. At 30 min, the
difference between the tests was not significant (P
= 0.077). At 60 min, it was highly significant (P
< 0.0001). The upper panel is a semilogarithmic plot of
plasma tetracosactin levels after high dose (
