X/99/$03.00/0 Vol. 84, No. 3 The Journal of Clinical Endocrinology & Metabolism Copyright 1999 by The Endocrine Society

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1 X/99/$03.00/0 Vol. 84, No. 3 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 1999 by The Endocrine Society Comparison of the Low Dose Short Synacthen Test (1 g), the Conventional Dose Short Synacthen Test (250 g), and the Insulin Tolerance Test for Assessment of the Hypothalamo-Pituitary-Adrenal Axis in Patients with Pituitary Disease T. A. M. ABDU, T. A. ELHADD, R. NEARY, AND R. N. CLAYTON Departments of Endocrinology and Clinical Chemistry (R.N.), North Staffordshire Hospitals; and the Department of Medicine, School of Postgraduate Medicine, Keele University, Staffordshire, Stoke on Trent, United Kingdom ST4 6QG ABSTRACT There is still uncertainty about what is the most appropriate test for assessment of the integrity of the hypothalamo-pituitary-adrenal (HPA) axis. Many advocate the insulin tolerance test (ITT), but this is unpleasant and resource intensive, and may occasionally give misleading results. The conventional [250 g tetracosactrin, ACTH-(1 24)] short synacthen test (SST) has been used as a simple alternative to the ITT, but it has produced some falsely reassuring results with potentially serious consequences. A low dose [1 g tetracosactrin, ACTH-(1 24)] short synacthen test (LDSST) has recently been advocated as a more reliable and safer alternative to ITT. Some studies, however, have failed to demonstrate any difference between SST and LDSST. The purpose of this study was to assess the clinical usefulness of LDSST compared to SST and ITT in patients with pituitary disease. We studied 64 patients with suspected or proven pituitary disease. All patients underwent SST and LDSST. Forty-two patients underwent ITT. There was a high correlation between the ITT and LDSST peak cortisol responses (r 0.89; P ), the ITT and SST 30 min cortisol levels (r 0.83; P ), and the LDSST peak cortisol Received August 26, Revision received November 4, Accepted December 2, Address all correspondence and requests for reprints to: Dr. T. A. M. Abdu, Department of Endocrinology and Diabetes, North Staffordshire Hospitals, National Health Service Trust, City General Hospital, Stoke on Trent, United Kingdom ST4 6QG. response and the SST 30 min cortisol level (r 0.85; P ). In the LDSST, all but six patients achieved maximal cortisol response by 30 min. A plasma cortisol cut-off of 600 nmol/l is more helpful than 500 nmol/l for clinical decision-making using either the SST 30 min cortisol level or the LDSST peak cortisol response. The sensitivity of the LDSST was 100% (cortisol response of 600 nmol/l indicates intact HPA axis), with no falsely reassuring results. SST (pass cortisol level, 600 nmol/l) was less sensitive than LDSST, it produced 2 of 64 (3%) falsely reassuring results. Even the ITT (pass cortisol level, 500 nmol/l) failed to identify one patient with clinically evident cortisol deficiency. The results of this study indicate that both SST and LDSST, at a cortisol cut-off of 600 nmol/l, are safe for the purpose of clinical decision-making with regard to steroid replacement therapy in patients with pituitary disease. As the LDSST produced no falsely reassuring decisions, we suggest that this could replace the SST and ITT for initial evaluation of the HPA axis in patients with pituitary disease. We suggest administering 1 g tetracosactrin, iv, with sampling at 0, 20, and 30 min. (J Clin Endocrinol Metab 84: , 1999) THE INTEGRITY of the hypothalamo-pituitary-adrenal (HPA) axis is essential for appropriate cortisol response to stress. The established reference test for the assessment of the HPA axis is to measure the cortisol response to insulin-induced hypoglycemia (1 3). This test is unpleasant to the patient, potentially dangerous, resource intensive (4), contraindicated in patients with ischemic heart disease and epilepsy, and not advisable in children and the elderly. Various studies have evaluated the basal cortisol value, 30 and 60 min cortisol responses to the 250- g short synacthen [ACTH-(1 24), tetracosactrin] test (SST), as well as the incremental rise on SST. The 30 min cortisol response to SST has become increasingly accepted as an alternative test (5, 6). The rationale for using the SST is the assumption that endogenous ACTH is required for maintenance of the integrity and acute responsiveness of the zona fasciculata. When the secretion of ACTH falls the zona fasciculata atrophies and fails to mount an adequate cortisol response when stimulated by exogenous tetracosactrin. A highly significant correlation between the short synacthen test and the insulin tolerance test (ITT) has been a consistent finding in the literature (4 9). The short synacthen test gradually gained popularity as a reliable simple alternative first line test, as evidenced by two surveys of UK endocrinologists 5 yr apart, showing an increase in the number of those who use the short synacthen test from 25% in 1988 (6) to 50% in 1994 (10). The short synacthen test, however, has been falsely reassuring in some reports, with potentially serious consequences (11 15). It is well recognized that the 250- g dose used in the conventional short synacthen test is a supraphysiological dose originally designed as a test for primary adrenal failure. Several groups have reduced this dose considerably and demonstrated that the cortisol response to 1 g is equivalent to that obtained with 250 g in normal subjects (16 18). It seems logical to assume that the supraphysiological dose of 250 g used in the conventional dose test might overstim- 838

2 COMPARISON OF TESTS FOR ASSESSMENT OF HPA AXIS IN PITUITARY DISEASE 839 ulate partially atrophied adrenals and produce a deceivingly adequate cortisol response. This could account for the various reported failings of the short synacthen test. Over the last few years a number of small studies have looked at the clinical usefulness of the low dose (1 g) synacthen test (LDSST) compared to the conventional dose (250 g) test in patient receiving long term steroid therapy (18) and in patients with pituitary disease (19, 20). These studies showed that the low dose produced fewer falsely reassuring decisions than the conventional dose test. However, two recent reports suggested no difference between the low and conventional dose tests in adults with pituitary disease (21) and in children with idiopathic multiple pituitary hormone deficiency (22). The present study was designed to consider the following questions in a large group of patients with pituitary disease. 1) Can the low dose, 1- g test (LDSST) provide a better indication of the state of the HPA axis than the conventional dose, 250- g test (SST)? 2) Can the low dose test replace the ITT for assessment of the HPA axis? Subjects and Methods Patients and tests Patients with suspected or proven pituitary disease (n 64) were recruited from the endocrine service at Stoke on Trent. Forty-two of these patients (mean sd age, yr; range, 28 70) underwent an ITT, a conventional dose SST, and a LDSST in random order. The remaining 22 (mean sd, yr; range, 26 86), underwent SST and LDSST only. The minimum and maximum intervals between tests were 48 h and 6 weeks, respectively. In each test a cannula was inserted in the anticubital fossa 15 min before initiation of sampling. In the ITT we injected soluble insulin (0.1 U/kg BW, iv), with sampling at 15, 0, 30, 45, 60, 90, and 120 min. In three patients it was necessary to give a second injection of insulin at a dose of 0.15 U/kg BW to achieve adequate hypoglycemia (plasma glucose, 2.2 mmol/l). For the SST we injected 250 g tetracosactrin, with sampling at 0, 30, and 60 min. In the LDSST 1 g tetracosactrin was injected after obtaining a basal blood sample with subsequent sampling at 20, 30, 40, and 60 min. Eighteen patients were tested before any treatment, 14 patients were tested 6 weeks to 27 yr after surgery (12 transsphenoidal pituitary adenomectomies and 2 craniotomies, 1 for a craniopharyngioma and the other for a parasellar meningioma), and 16 patients were tested 2 25 yr postradiotherapy. An additional group of 16 patients was tested after undergoing both surgery (13 transsphenoidal pituitary adenomectomies and 3 craniotomies for a parasellar chordoma, a sphenoid ridge meningioma, and an optic nerve glioma) and radiotherapy; the minimum and maximum intervals between intervention and testing in these cases were 28 weeks and 28 yr, respectively. The categories of pituitary disease were 25 nonfunctioning macroadenomas, 10 somatotropinomas, 7 prolactinomas, 3 suspected hypopituitarism (presenting with spontaneous hypoglycemia), 6 craniopharyngiomas, 2 chordomas, 2 meningiomas, and 1 patient each with idiopathic partial hypopituitarism, isolated ACTH deficiency, psychogenic polydypsia, pituitary incidentaloma, Rathke s cleft cyst, pineal germ cell tumor, optic nerve glioma, pituitary apoplexy, and lymphocytic hypophysitis. The 1- g synacthen dose was prepared by diluting 0.2 ml of a 250- g/ml ampule to 10 ml with normal saline (5 g/ml); this was stored at 4 C for up to 7 days (18). Immediately before use, 0.2 ml of this stock solution was diluted to 1 ml in normal saline, giving a final concentration of 1 g/ml. Cortisol assay. Plasma cortisol was measured using a nonisotopic immunoassay based on fluorescence polarization (TDX, Abbott Diagnostics, North Chicago, IL), with intra- and interassay coefficients of variation of 4 7%. Sensitivity and specificity. When considering the reliability of any test against a reference test, the sensitivity and specificity are evaluated as follows: sensitivity number of patients with true deficiency on the test/number of all patients with deficiency on the reference test 100. Specificity is the number of patient without deficiency on the test/ number of all patients without deficiency on the reference test 100. We used the SPSS package (Standard Version, 1996) for calculation of correlation. The study was approved by the North Staffordshire District ethical committee, and informed consent was obtained from all patients. Definitions of response criteria A peak plasma cortisol of 500 nmol/l or more (5, 6) was considered an adequate response to hypoglycemia of less than 2.2 mmol/l on ITT. Plumpton and Besser (23) suggested a cortisol level greater than 580 nmol/l as indicative of an adequate response to ITT using a fluorimetric assay for cortisol measurement. Fluorimetric assays for cortisol have a 20 30% positive bias compared to the current, more specific RIAs (24) or a mean positive bias of 96 nmol/l (25), i.e. 580 nmol/l in the former assay is equivalent to 484 nmol/l in the latter. Therefore, we consider that with the present cortisol assays a value of 500 nmol/l represents an acceptable pass on ITT. We compared the performance of the SST (30 min cortisol response) and LDSST (peak cortisol response) with that of the ITT at two cut-off cortisol levels (500 and 600 nmol/l). We looked at these two cut-off value because although the commonly used figure for SST is 500 nmol/l (26), Patel et al. (27) have shown that all 50 endocrinologically normal patients admitted as acute medical emergencies achieved a minimum plasma cortisol of 600 nmol/l, 30 min after 250 g synacthen in a test performed within 24 h of admission. Hurel et al. (4) also found 600 nmol/l to be a more reliable cut-off level. Results Unwanted effects No side-effects were reported with either SST or LDSST. Two patients lost consciousness during ITT; both recovered quickly after iv glucose infusion. LDSST In the LDSST, peak cortisol was reached in 27 patients at 20 min, in 24 patients at 30 min, and in 6 patients at 40 min. In these latter patients, the difference between the 40 and 30 min cortisol values ranged between 8 26 nmol/l, with a mean of 15.4 nmol/l. In 7 patients, the response was flat, with a cortisol response of less than 50 nmol/l at all time points. Correlation Pearson s correlation coefficient between ITT and SST (30 min cortisol value) was r 0.83; P , that between ITT and LDSST (peak cortisol value) was r 0.89; P , and that between SST and LDSST was r 0.85; P (Fig. 1). SST vs. ITT At a cortisol cut-off level of 500 nmol/l, the SST achieved a sensitivity of 100% and a specificity of 90% (Table 1a). At a cortisol cut-off level of 600 nmol/l, the SST achieved a sensitivity of 100%, with a specificity of 77%. LDSST vs. ITT At a cortisol cut-off level of 500 nmol/l, the LDSST achieved a sensitivity of 100% and a specificity of 93.3% (Table 1b). At a cortisol cut-off level of 600 nmol/l, the

3 840 ABDU ET AL. JCE&M 1999 Vol 84 No 3 TABLE 1. Comparison of SST (a) and LDSST (b) with ITT at two different cortisol cut-off levels (500 and 600 nmol/l; n 42) 1a ITT vs. SST Pass 500 Pass 600 P P P F 3 7 F P 0 0 F F Sensitivity (%) Specificity (%) b ITT vs. LDSST Pass 500 Pass 600 P P P F 2 6 F P 0 0 F F Sensitivity (%) Specificity (%) P, Pass; F, fail. TABLE 2. Comparison of LDSST with SST at two different cortisol cut-off levels (500 and 600 nmol/l); SST vs. LDSST (n 64) SST vs. LDSST Pass 500 Pass 600 P P P F 4 a 3(2 a ) F P 2 1 F F P, Pass; F, fail. a Clinical cortisol deficiency; in parentheses, two of three. LDSST achieved a sensitivity of 100% and a specificity of 80%. All patients who failed the ITT also failed the LDSST. LDSST vs. SST Of the 64 patient who underwent SST and LDSST, when the cortisol cut-off level was taken as 500 nmol/l, 14 failed both tests, and 44 passed both tests with 6 discordant results, 4 of these passed the SST and failed the LDSST (Table 2). All 4 had unequivocal clinical evidence of cortisol deficiency (Table 3), giving a false reassurance rate of 4 of 64 (6%) for the conventional dose test. At a cortisol cut-off level of 600 nmol/l, 21 patients failed both tests, and 39 passed both tests with 4 discordant results. Three of these passed the SST while failing the LDSST, 2 had unequivocal clinical evidence of cortisol deficiency (Table 3), giving a false reassurance rate of 2 of 64 (3%) for the SST. Thus, the overall sensitivity of LDSST is slightly greater than that of SST. At a cortisol cut-off of 600 nmol/l, the LDSST is 100% sensitive without any falsely reassuring results. However, 7 of 64 patient (11%) failed the LDSST with neither clinical nor biochemical evidence (maximum cortisol response to ITT, 500 nmol/l) of HPA axis impairment (Table 4). FIG. 1. Pearson s correlation coefficient shows strong linear correlation among the three tests. The strongest correlation was between LDSST vs. ITT (r 0.89; P ; a). The correlation between SST vs. ITT was r 0.83; P (b). The correlation between LDSST vs. SST was r 0.85; P (c). Discussion Biochemical tests for HPA axis integrity are used to support clinical decision-making. Tests that assess the integrity of the entire axis, such as the cortisol response to hypoglycemia and metyrapone tests, are thought to reflect the real state of the axis. It is not surprising, therefore, that the ITT

4 COMPARISON OF TESTS FOR ASSESSMENT OF HPA AXIS IN PITUITARY DISEASE 841 TABLE 3. Clinical characteristics of patients put at risk with the falsely reassuring result of SST at cortisol cut-off levels of 500 nmol/l (all four) and 600 nmol/l (no. 1 and 2) Patient no. Age (yr), sex Diagnosis and Rx Axis deficient SST LDSST Comments 1 48, F Macroadenoma pre-op T, G Hypotention, hyponatraimia H/C-dependent post-op 2 86, F Macroadenoma post-op G Tired and lethargic H/C recommended 3 a 34, M Surgery and Dxt for ONG T, GH Tired, no energy promptly improved on H/C (ITT 530) 4 71, F Acromegaly Dxt T, G Tired, promptly improved on H/C ONG, Optic nerve glioma; H/C, hydrocortisone; DXT, radiotherapy. a Patient achieved maximum cortisol of 530 nmol/l on ITT. TABLE 4. Clinical data of patients who failed the LDSST (peak cortisol, 600 nmol/l) without clinical or biochemical evidence of cortisol deficiency Patient no. Age (yr), sex Diagnosis Axis deficient LDSST SST ITT Clinical decision 1 49, F Null macroadenoma G, T, GH H/C for stress 2 51, M Null macroadenoma G, T, GH, DI On H/C long term 3 42, F?Hypopituitarism None H/C not required 4 27, F?Hypopituitarism None Repeat LDSST or perform ITT 5 46, F Acromegaly T H/C for stress 6 61, F Incidentaloma None Not done H/C not required 7 76, M Apoplexy G, T,?GH Not done H/C for stress T, Thyroid axis; G, gonadal axis; GH, GH axis; DI, diabetes insipidus; H/C, hydrocortisone. has become widely accepted as the gold standard test. However, the reliability of any test is based on two characteristics, its reproducibility and a critical evaluation of its diagnostic sensitivity and specificity. The cortisol response to hypoglycemia has been shown to be reproducible in normal subjects (28), although the reproducibility in patients with pituitary disease is unknown. The ITT, however, is not 100% sensitive. Tsatsoulis et al. (29) reported failure of the ITT to detect HPA axis impairment in four patients with clinically evident cortisol deficiency who improved promptly with hydrocortisone replacement. Indeed, one of our patients had clinically evident cortisol deficiency, having falsely passed the ITT (patient 3, Table 3). On the other hand, Lindholm and Kehlet (7) have shown that in some patients with normal HPA axis function, who underwent major surgery with no problem, a maximum plasma cortisol response may not be elicited during insulin-induced hypoglycemia despite blood glucose levels usually assumed to be sufficiently low for this purpose. Thus, even the gold standard ITT can give misleading results, and when discrepancy between clinical data and test results is encountered, the decision-making process is best informed by clinical judgment. Our results suggest that the SST is safe for the purpose of clinical decision-making at a cortisol cut-off of 600 nmol/l with a false reassurance rate of 2 of 64 (3%). This is in keeping with other retrospective data from our center (30) and with findings from other studies (4, 7, 8, 22). A false reassurance rate of less than 3.5% is probably small enough to justify the use of the conventional SST as a simple alternative to ITT provided that certain precautions are observed (31). The sensitivity for the LDSST compared to the ITT in 42 patients as well as to decisions made on biochemical and/or clinical grounds in all 64 patients is 100%. The LDSST did not give any falsely reassuring results. This finding supports the evidence that the synacthen test can be more sensitive if physiological or near-physiological doses of synacthen are used (32, 33). The study by Crowley et al. (16) confirmed the reproducibility of the cortisol response to low dose ACTH stimulation. The high sensitivity combined with good reproducibility make the LDSST an attractive simple reliable alternative to the ITT. The specificity of the LDSST at a cut-off of 600 is 80% in the 42 patients who also underwent ITT. Looking at the whole study population, 7 of 64 (11%) patients failed the LDSST without any clinical or biochemical evidence of cortisol deficiency (peak response to ITT, 500 nmol/l). To avoid unnecessary cortisol replacement based on the LDSST result, careful clinical evaluation of these patients is needed. If any doubt remains about the HPA axis status, an ITT can be employed. Thus, by using the LDSST as the initial test, 57 of 64 ITTs (89%) could be avoided. The clinical characteristics of the 7 patients are shown in Table 4. Patients 3 and 6 achieved maximum cortisol of 580 and 587 nmol/l, respectively. In the absence of clinical evidence of cortisol deficiency or other axis impairment, it would be safe to pass both. In patients 1, 2, 5, and 7 (achieving maximum cortisol levels of 587, 502, 578, and 554 nmol/l), because of other axis impairment, a safe practice would be to recommend hydrocortisone cover for stressful situations, supply a steroid card, and maintain close follow-up. For patient 4, an ITT or, alternatively, a repeat LDSST may be required. Perhaps only this 1 patient of all 64 may require an ITT for evaluation of HPA axis. Thus, 98.4% (63 of 64) of ITTs could be avoided without exposing any patient to the risks of either unrecognized cortisol deficiency or unnecessary long term steroid treatment. In other words, careful consideration of the clinical data greatly improved the specificity of the LDSST. Thus, the low dose test is a simple reproducible, sensitive, and, in conjunction with clinical evaluation, specific test. A small, but definite, superiority of the LDSST over the SST has been demonstrated in most studies examining the usefulness of LDSST compared to SST (19, 20, 32), with two exceptions (21, 22). The study by Weintrob et al. (22) in children with idiopathic multiple pituitary hormone defi-

5 842 ABDU ET AL. JCE&M 1999 Vol 84 No 3 ciency, although suggesting no difference between the low and conventional dose SSTs, in fact shows that both are equivalent to the insulin stress test in detecting ACTH insufficiency. The latter finding is in agreement with our finding in the adult population. The study by Mayenknecht et al. (21) concluded that there is no difference between the low dose and conventional dose synacthen tests, but their data clearly show that of 14 patients who failed the reference test, 1 passed the conventional dose test at both 30 and 60 min, i.e. this means a 1 in 14 false reassurance rate for the conventional dose test. All those who failed the reference test, however, also failed the low dose test. The low dose test seemed to be more sensitive than the high dose test (100% vs. 93%, respectively). However, because of the small number of patients failing the reference test in their study, firm conclusions are not warranted. Interestingly, Mayenknecht et al. (21) clearly confirmed previous evidence that the adrenals are maximally stimulated by 1 g synacthen, iv (32). Thus, it may be worth exploring the use of a lower dose of ACTH in future studies, as it may be even more sensitive than the 1- g test. However, the concern might be that lower synacthen doses would result in more false failures (lower specificity) and may therefore potentially trigger more ITTs. Our results suggest that in the LDSST, sampling at 0, 20, and 30 min should be sufficient. Crowley et al. (32) have shown that the maximum cortisol level during low dose testing is attained at 15 min in the majority of their observations in normal subjects; all had attained maximum response by 35 min. All but six of our patients attained the maximum cortisol by 30 min. These six patients achieved a maximum cortisol response by 40 min. The deference between the 30 and 40 min responses in these six patients was small, and the classification into pass or fail was not affected when the 30 min cortisol value was used instead of the 40 min cortisol value. Clinical data are crucial in the process of evaluation of the HPA axis in patients with pituitary disease. Our study confirms that both SST and LDSST, when used in conjunction with clinical information, are safe for clinical decision-making with regard to hydrocortisone replacement therapy. LDSST is potentially safer, particularly in patients with partial adrenal atrophy. Our study indicates a false positive (failure) rate of 11% (7 of 64) for LDSST. Careful clinical evaluation of these patients would obviate the risk of unnecessary cortisol replacement. Only the occasional patient may still require the ITT. Our results suggest that the LDSST can replace the SST and ITT for initial assessment of the HPA axis in patients with pituitary disease. This will confine the use of an insulin stress test to only a minority of patients. Pharmaceutical companies should be encouraged to provide synthetic ACTH-(1 24) in 1- g vials to facilitate testing, and until that time, care is required when diluting a 250- g vial (34). Acknowledgments We are grateful to the North Staffordshire National Health Service Trust for providing the resources for this study. We are also grateful to Sister Maureen Brown, Mrs. J. Hodgins, Mrs. J. James, and Mrs. S. Salt for performing the tests, and the patients for their cooperation. References 1. Greenwood FC, Landon J, Stamp TCB The plasma sugar, free fatty acid, cortisol and growth hormone response to insulin in control subjects. J Clin Invest. 45: Jacobs HS, Nabarro JDN Test of hypothalamopituitary adrenal function in man. Q J Med. 152: Edwards CRW, Besser GM Diseases of the hypothalamas and pituitary gland. 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6 COMPARISON OF TESTS FOR ASSESSMENT OF HPA AXIS IN PITUITARY DISEASE Vestergarad P, Hoeck HC, Jakobsen PE, Laurberg P Reproducibility of growth hormone and cortisol responses to the insulin tolerance test and the short ACTH test in normal adults. Horm Metab Res. 29: Tsatsoulis A, Shalet SM, Harrison J, Ratcliffe WA, Beardwell CG, Robinson L Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf). 28: Banger V, Clayton RN How reliable is the short synacthen test for the investigation of the HPA axis in patients with pituitary disease. Eur J Endocrinol. 139: Clayton RN Short synacthen test vs. insulin stress test for the assessment of the hypothalamo-pituitary-adrenal axis: controversy revisited. Clin Endocrinol (Oxf). 44: Crowley S, Hindmarsh PC, Holownia P, Honour JW, Brook CGD The use of low doses of ACTH in the investigation of adrenal function in man. J Endocrinol. 130: Rasmuson S, Olsson T, Hagg E A low dose ACTH test to assess the function of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf). 44: Thaler LM, Blevins Jr LS The low dose (1- g) adrenocorticotrophin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab. 83: th Postgraduate Clinical Endocrinology Course of the European Federation of Endocrine Societies May 20 22, 1999 Szeged, Hungary For information, contact: Professor Janos Julesz, Chairman, by fax: ; or congress@ tiszanet.hu.