Review 441
Author
J. Lindholm
Affiliation
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Key words ▶ ACTH test ● ▶ adrenocortical insufficiency ● ▶ stress ●
Abstract
▼
ACTH stimulation test has been used for many years. Some important questions remain unsettled. These are reviewed and discussed in detail. Interpretation of a short ACTH test rests on the fact that a close correlation exists between the responses in plasma cortisol concentrations after administration of ACTH and during insulin induced hypoglycaemia which previously was the standard test. It is generally assumed that the plasma cortisol concentration after ACTH (and insulin) mirrors the response in major stress sit-
Early ACTH Tests
▼ received 23.11.2014 first decision 12.03.2015 accepted 16.03.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1548817 Published online: April 21, 2015 Exp Clin Endocrinol Diabetes 2015; 123: 441–445 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence J. Lindholm Department of Endocrinology Aalborg University Hospital, 9000 Aalborg Denmark Harsdorffsvej 12 1874 Frederiksberg C Denmark [email protected]
Hypophysectomy causes atrophy of the adrenal cortex as first shown by Smith [1]. He also demonstrated the benefits of pituitary transplantation in animals. In 1933 Collip et al. of Montreal [2] published the first description of the isolation from the anterior pituitary of a substance acting on the adrenal cortex. 10 years later and in the same issue of the Journal of Biological Chemistry Li and co-workers [3] and Sayers and colleagues [4] reported the structure of pig adreno-corticotrophin (ACTH): a peptide of 39 amino-acids. Using preparations from hogs, the first clinical study in normals and patients with Addison’s disease appeared in 1948 [5]. In early accounts of the ACTH test [6, 7] it is obvious that the issue of testing adrenal function with ACTH was confounding and frustrating. The potency of corticotrophin preparations varied from batch to batch. The methods used to appraise the effect of ACTH were crude and inexact: counting of circulating eosinophils and determination of 17-ketosteroid excretion. In 1952 the first colorimetric assay for plasma corticosteroids was described [8]. The results were surprisingly similar to what today is reported
uations (surgery and critical disease). This notion rests on few observations. Furthermore, extensive changes in protein binding of cortisol occur swiftly during stress. This complicates comparison between cortisol responses to ACTH and to critical disease. Based on published studies it is discussed whether the outcome of an ACTH test is an appropriate indicator of the need for glucocorticosteroid replacement. This issue is of particular importance when deciding if permanent glucocorticosteroid substitution is necessary or not.
with modern assays. The following year a procedure involving determination of 17-hydroxysteroids in urine was published [9]. In 1954 a short test was introduced: plasma corticosteroids were measured after intravenous injection of ACTH [10, 11]. Despite the difficulties, authors at that time did address important points. They demonstrated a significant relation between the pre- and postACTH values [12, 13]. In secondary hypocorticism prolonged ACTH administration caused a slow increase over days in urinary steroid excretion whereas in primary hypoadrenalism there would be no response. In fact, this was proposed as a way of differentiating between the two disorders [9, 11, 14]. It was correctly explained why the ACTH test is valid in hypothalamic-pituitaryadrenal (HPA) insufficiency. The investigators were also well aware of the risk of allergic reactions when injecting crude preparations of protein of animal origin. No case of severe allergic reaction was reported in these papers, but within the following years several examples of fatal anaphylaxis to ACTH were reported [15, 16].
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
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Problems in Interpretation of the Short Acth Test: an Update and Historical Notes
442 Review
▼
In 1961 a Swiss group showed that a peptide made up of the first 24 amino acids of the 39 in corticotrophin had full ACTH effect [17]. In 1968 tetracosactrin was marketed as Synacthen® or Cosyntropin®. It was soon widely used for testing patients for primary adrenal insufficiency [18–21] and later for assessing adrenal function in patients on treatment with glucocorticosteroid [22]. With the availability of easy and quick cortisol assays (fluorometric technique, competitive protein-binding analysis) the task of assessing the HPA function became a simple procedure. The experience from glucocorticoid treated patients revived the idea that the ACTH test might be of value also in patients with hypothalamicpituitary insufficiency [23]. The value of the short Synachten test (SST) was assessed by comparing it to insulin-induced hypoglycaemia or insulin tolerance test (ITT) – at that time the routine procedure. There proved to be a close relationship [24]. Soon, a plasma cortisol concentration of 500 or 550 nmol/l (18 or 19 µg/dl) at 30 min after injection of ACTH came to be defined as the lower normal limit. These values emerged when results from normal subjects were statistically computed. Normal distribution was – wrongly – assumed. There was close agreement between results obtained with synthetic ACTH1-24 and animal ACTH1-39. Initially, the use of a 30 min ACTH1-24 test for assessing the HPA function was met with scepticism. Several papers warned against the test [25–28]. It was assumed that the ITT (or in a few cases the metyrapone test) yielded the true values. Any discrepancy between the results of an ITT and a SST was taken to reflect failure of the SST. Several factors strongly interfere with the outcome of an ITT [29]. A particularly important issue is the inverse relationship between plasma cortisol and glucose concentrations. If a low plasma glucose concentration is further reduced, additional increase in plasma cortisol levels occurs. Thus, Gale et al. [30] reported that the mean plasma cortisol concentration in normal subjects was 568 ± 59 nmol/l (20.6 ± 2.1 µg/dl) at a glucose level of around 2.08 mmol/l (37 mg/dl), but increased to 818 ± 73 (29.7 ± 2.6) when blood glucose concentration was lowered to 0.92 mmol/l (17 mg/dl) These observations agree with those published earlier [31] and later [32]. In clinical settings adrenocortical secretion is very rarely prompted by hypoglycaemia. Performing the SST shortly after acute deprivation of pituitary ACTH (e. g., pituitary surgery, pituitary apoplexy) may cause marked discrepancy between the two tests. By now, it is well established that in the first weeks after cessation of normal ACTH secretion, the SST may yield grossly inaccurate results [33–35]. The ACTH test has often been described as a “screening procedure”. It was argued that an abnormal outcome should be confirmed with an ITT. At present, it seems that there is no justification for this recommendation. It was proposed that a smaller ACTH dose (1 µg) would improve the value of an ACTH test. The usual amount 250 µg causes a high and unphysiological plasma corticotrophin concentration. A meta-analysis has shown that the results of high and low dose tests are comparable [36]. A later meta-analysis [37] maintained that the low dose ACTH test was superior to the usual SST but this conclusion rested upon the view that an ITT or metyrapone test provides a true delineation between normal and subnormal
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
adrenal function. Preparation of small doses requires dilution of 250 µg vials. Adsorption to glass and plastic utensils may occur. The principle of a stimulation test is to measure plasma cortisol concentration under standardized and defined conditions to circumvent spontaneous hormone fluctuations. However, it has been shown again and again that zenith values are closely correlated to nadir (zero time) concentrations [38–40]. This has lead to speculations if a test is necessary and will yield more information than determination of a random plasma cortisol concentration. Actually, several studies have argued that determination of basal cortisol level often may be sufficient – provided the time of day is taken into consideration. It is, however, easier to compare stimulated than spontaneous cortisol concentrations, as peak values after Synacthen are independent of at which time of the day the test is performed [41, 42].
Interpreting the Outcome of the SST
▼
The most frequently used definition of normal outcome of the test is that 30 min after injection (im or iv) of 250 µg Synacthen, a plasma concentration of > 500 or 550 nmol/l should be reached. A recent audit has shown that in the UK a far wider range of values (250–650 nmol/l (9–24 µg/dl)) is used for defining lower normal limit [43]. In insulin hypoglycaemia test a peak cortisol concentration of > 500–550 nmol/l is also the normal limit agreed upon. Based on very few studies it was accepted that this value is similar to the zenith value during major surgery (actually, this point was a main reason why ITT was adopted as a standard for the assessment of HPA function). However, the data published by Plumpton and Besser [44] showed that there was difference between the two sets – the value during surgery being statistically significantly higher. In another study [45] the difference was not statistically significant. As the peak value is a function of blood glucose level, these results are of modest interest. Subsequent studies have dealt with plasma cortisol levels during major surgery. Unfortunately, almost no raw data are available, results being given as means ± SD. It is, however, possible in some studies to deduce that cortisol concentrations may remain below 500 nmol/l at all time points during major surgery in apparently normal subjects [46, 47]. An older, though still relevant study [48] included a group of 9 patients who before surgery had stopped low-dose prednisone therapy. Almost invariably during operation plasma cortisol levels were around 250 nmol/l (9 µg/dl) but nonetheless the patients had a completely uneventful course during and after surgery (one patient developed hypotension at the end of operation). Thus, it appears doubtful if the cortisol response to insulin and ACTH mimics the response to surgery and other acute, stressful situations. A further problem is that some drugs including oestrogens, carbamazepine and anaesthetics influence circulating cortisol concentrations.
Response in Acute Disease
▼
In the very first studies on adrenal function in serious infections, it was observed that in a minority of patients, plasma cortisol concentrations were exorbitantly high ( > 1 500–2 000 nmol/l) [49–51]. In the early studies the cortisol analyses may have been less specific but the results have been corroborated with liquid
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Synthetic ACTH
high pressure chromatography. These values are higher than those normally found during ACTH tests, during major surgery and are rarely seen in patients with Cushing’s syndrome (and then usually in ectopic hypercortisolism). It may be that in some situations other potent adrenocorticotropic factors can be mobilized or clearance of cortisol from circulation is reduced. In any case, this adds another difficulty to defining normal limits for plasma cortisol concentrations in critical diseases. In 1977 Sibbald et al. [52] published an account of plasma cortisol levels in patients with critical infections. They concluded that “five patients who constituted 19.2 % of the 26 patients studied, appeared to have some impairment of adrenocortical function. In spite of severe bacterial infections and no history to support Addison’s disease, the plasma cortisol levels – averaging 13.8 ± 3.3 microgram/dl (381 ± 91 nmol/l) – were not increased above normal and their response (to Synacthen) was much less than would be expected”. Subsequently, a large number of papers have described the adrenocortical response to stressful events, such as severe infections, major surgery, trauma, burns, acute pancreatitis. In brief, these papers found that – as expressed in an eminent review [53] – “during critical illness one will encounter an amazingly wide range of values for serum cortisol levels” – both before and after administration of ACTH – often below what is considered normal in routine testing. As early as 1974, the impact of surgery on steroid binding was pointed out [54]. During major surgery circulating amounts of transcortin (CBG) and albumin – the two proteins which bind and transport the major part of circulating cortisol – decreased within a short period of time. Savu et al. [55] and Pugeat et al. [56] made similar findings in patients with critical infections. Important studies have since expanded on this issue. Beishuizen et al. [57] showed in intensive care patients that while mean plasma cortisol concentration was approximately 3 times higher than in controls, calculated free cortisol was about 10 times higher. Le Roux et al. [58] found in patients during surgery that CBG levels fell within 30 min and 33 % of the patients failed to reach a peak plasma cortisol concentration of 500 nmol/l, without any other evidence of adrenal insufficiency. Hamrahian et al. [59] measured plasma cortisol after ACTH in 66 critically ill patients. In 14 plasma cortisol concentration at 30 min after ACTH was 500 nmol/l. Septic shock seems to be the disease causing particularly large shifts in protein concentrations [60]. Poor reproducibility of the SST in septic shock has been described [61, 62]. It may easily be explained by changes in protein binding. These data suggest that the responses to ACTH (and hypoglycaemia) involve mechanisms different from those operative in surgery and other stressful events. Hence, the cortisol responses are not immediately comparable.
Confounding Issues
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To add to the confusion, at an early stage another definition of normalcy was introduced: the increment (or ∆ value) in cortisol values (peak-basal) [18, 50] – not only in a Synacthen test but also during insulin induced hypoglycaemia [44]. Intuitively, the ∆ value appears strange. Situations can easily be imagined when the adrenals are secreting cortisol at a high rate, which cannot be increased. Patel et al. [39] showed in a large number of nor-
mals, that the increment varied from 10 to 747 nmol/l and laconically concluded: “calculation of the increment is of no value”. In the study by Widmer et al. [63] 40 % of apparently completely normal subjects failed to produce a normal increment. Careful reviews [40, 53] have strongly warned that this parameter should not be employed. Curiously and unfortunately, determination of cortisol increment is still in use. Actually, 89 % of British hormone laboratories retain this definition of adrenal insufficiency despite its obvious shortcomings [64]. Considerable discrepancies have been reported between results in blood samples taken with the patient lying and standing, respectively [65]. For instance, in 14 patients the mean plasma cortisol concentration was 352 nmol/l (patients standing) but 275 nmol/l minutes later (patients lying). Naturally, this may also affect the outcome of an ACTH test but this fact has virtually never been taken into consideration. Finally, methodological problems have been frequently encountered as cortisol analyses evolved from crude colorimetric methods to protein-displacement based procedures to fluorometric analyses to radioimmuno-assays to highly accurate methods involving combined chromatography and spectrometry. Even today, several studies have revealed considerable discrepancy between results obtained with commercially available and widely used methods. The above survey [64] on the performance of 10 modern and state-of-the-art analyses shoved a disturbingly big variability, e. g., values between 398 and 553 nmol/l were found in a sample with an exact cortisol concentration of 500 nmol/l. Plasma concentration of CBG is higher in women than in men. In all probability this is the reason that peak cortisol values after ACTH are higher in women tan in men, though concentrations of non-protein bound hormone are lower in women [66].
Central Problem
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The essential point is that no definition of adrenocortical insufficiency exists if “adrenocortical insufficiency” is taken to indicate the necessity of providing substitution with exogenous glucocorticosteroid. What seems relevant is the plasma (nonprotein bound) cortisol concentration, which allows the patient an uneventful course during major illness and surgery (“severe stress”). It is fair to assume that it is lower than what is accepted today as normal response to ACTH. In acute situations, basing the decision on an ACTH test may be unsatisfactory but often consequences, if any, will be modest. In contrast, if the test is used for deciding on life-long steroid substitution, the problem attains vital importance. Udelsman and Chrousous [46] reported that “physiological glucocorticoid replacement, defined as the daily unstressed cortisol production rate, is both necessary and sufficient for primates to tolerate surgical stress” and “it is possible that hypercortisolemia is not in itself implicitly required for stress adaption”. Widmer et al. [63] reached a similar conclusion: “a maximal utilization of the adrenal capacity is not necessary to achieve good clinical outcome”. This view is supported by the clinical observations reported above and also by recent and important findings that in severe, acute disease cortisol production is almost identical to that in normal subjects, except in patients with infections who had higher secretion rate [67]. The result of a SST may not be a reliable index of adreno-cortical function. It might appear relevant (in particular when taking the Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
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Review 443
findings of Udelsman and Chrousos into account) to consider determination of urinary free cortisol excretion. UFC reflects the 24 h integrated plasma concentration of non-protein bound cortisol. Hence, theoretically UFC could prove to be a valuable indicator when estimating the need for glucocorticoid replacement. This possibility has never been explored.
Declarations: Competing interests: The author has no conflicting interest to declare. Ethical approval: Ethical approval not required for this review. References
1 Smith PE. The disabilities caused by hypophysectomy and their repair. JAMA 1927; 88: 158–161 2 Collip JB, Anderson E, Thomson DL. The adrenotropic hormone of the anterior pituitary lobe. Lancet 1933; 222: 347–348 3 Li CH, Simpson ME, Evans HM. Adrenocorticotropic hormone. J Biol Chem 1943; 149: 413–424 4 Sayers G, White A, Long CNH. Preparation and propertiers of pituitary adrenocorticotropic hormone. J Biol Chem 1943; 149: 425–436 5 Forsham PH, Thorn GW, Prunty FTG et al. Clinical studies with pituitary adrenocorticotropin. J Clin Endocrinol Metab 1948; 8: 15–66 6 Jenkins D, Forsham PH, Laidlaw JC et al. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 8: 3–14 7 Prunty FT. Chemical and clinical problems of the adrenal cortex. BMJ 1956; 2: 615–622 & 673–686 8 Nelson DH, Samuels LT. A method for the determination of 17-hydroxycorticosteroids in blood: 17-hydroxycorticorticosterone in peripheral circulation. J Clin Endocrinol Metab 1952; 12: 519–526 9 Thorn GW, Goetz FC, Streeten DHP et al. Use of the intravenous ACTH test in clinical practice. J Clin Endocrinol Metab 1953; 13: 604–613 10 Eik-Nes K, Sandberg AA, Nelson DH et al. Changes in plasma levels of 17-hydroxysteroids during the intravenous administration of ACTH. I. A test of adrenocortical capacity in the human. J Clin Invest 1954; 33: 1502–1508 11 Christy NP, Wallace EZ, Jailer JW. The effect of intravenously-administered ACTH on plasma 17,21-dihydroxy-20-ketosteroids in normal individuals and in patients with disorders of the adrenal cortex. J Clin Invest 1955; 34: 899–906 12 Birke G, Diczfalusy E, Plantin L-O. Assessment of the functional capacity of the adrenal cortex. I. Establishment of normal values. J Clin Endocrinol Metab 1958; 18: 736–754 13 Gold EM, Starr P. Urinary excretion of 17-ketogenic steroids in normal subjects before and after stimulation with intramuscular zinc-ACTH. J Clin Endocrinol Metab 1959; 19: 907–920 14 Smart GA. Pituitary function. BMJ 1954; 1: 1086–1089 15 Eisalo A, Leskinen O, Oka M. Fatal anaphylactic shock following corticotrophin. Acta Med Scand 1956; 155: 1–4 16 Unger DL, Unger L. Allergic reactions to ACTH. Dis Chest 1961; 40: 359–363 17 Kappeler H, Schwyzer R. Die Synthese eines Tetracosapeptides mit der Aminosäuresequenz eines hochaktiven Abbauproduktes des β-Corticotropins (ACTH) aus Schweine-hypophysen. Helv Chim Acta 1961; 44: 1136–1141 18 Wood JB, Frankland AW, James VHT et al. A rapid test of adrenocortical function. Lancet 1965; 285: 243–245 19 Maynard DE, Folk RL, Riley TR et al. A rapid test for adrenocortical insufficiency. Ann Intern Med 1966; 64: 552–556 20 Musa BU, Dowling JT. Rapid intravenous administration of corticotropin as a test of adrenocortical insufficiency. JAMA 1967; 201: 633–663 21 Danowski TS, Hofmann K, Weigand FA et al. Steroid responses to ACTHlike polypeptides. Clin Endocrinol 1968; 28: 1120–1126 22 Kehlet H, Binder C. Value of an ACTH test in assessing hypothalamicpituitary-adrenocortical function in glucocorticoid-treated patients. BMJ 1973; 2: 147–149 23 Kehlet H, Blichert-Toft M, Lindholm J et al. Short ACTH test in assessing hypothalamic-pituitary-adrenocortical function. BMJ 1976; 1: 249–251 24 Lindholm J, Kehlet H, Blichert-Toft M et al. Reliability of the 30- minute ACTH test in assessing hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 1978; 47: 272–274 25 Borst GC, Michenfelder HJ, O’Brian JT. Discordant cortisol responses to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 1982; 306: 1462–1464
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
26 Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276–2279 27 Ammari F, Issa BG, Millward E et al. A comparison between short ACTH and insulin stress tests for assessing hypothalamo-pituitary-adrenal function. Clin Endocrinol 1996; 44: 473–476 28 Suliman AM, Smith TP, Labib M et al. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol 2002; 56: 533–539 29 Lindholm J. The insulin hypoglycaemia test for the assessment of the hypothalamic-pituitary-adrenal function. Clin Endocrinol 2001; 54: 283–286 30 Gale EA, Bennett T, Macdonald IA et al. The physiological effects of insulin-induced hypoglycaemia in man: responses at differing levels of blood glucose. Clin Sci 1983; 65: 263–271 31 Greenwood FC, Landon J, Stamp TC. The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin. 1. In control subjects. J Clin Invest 1966; 45: 429–436 32 Nye EJ, Grice JE, Hockings GI et al. The insulin hypoglycemia test: hypoglycemic criteria and reproducibility. J Neuroendocrinol 2001; 13: 524–530 33 Hjortrup A, Kehlet H, Lindholm J et al. Value of the 30- minute adrenocorticotropin (ACTH) test in demonstrating hypothalamic-pituitaryadrenocortical insufficiency after acute ACTH deprivation. J Clin Endocrinol Metab 1983; 57: 668–670 34 Kehlet H, Lindholm J, Bjerre P. Value of the 30 min ACTH-test in assessing hypothalamic-pituitary- adrenocortical function after pituitary surgery in Cushing’s disease. Clin Endocrinol 1984; 20: 349–353 35 Alwani RA, de Herder WW, de Jong FH et al. Rapid decrease in adrenal responsiveness to ACTH stimulation after successful pituitary surgery in patients with Cushing’s disease. Clin Endocrinol 2011; 75: 602–607 36 Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003; 139: 194–203 37 Kazlauskaite R, Evans AT, Villabona CV et al. Consortium for Evaluation of Corticotropin Test in Hypothalamic-Pituitary Adrenal Insufficiency. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 2008; 93: 4245–4253 38 May ME, Carey RM. Rapid adrenocorticotropin hormone test in practice. Am J Med 1985; 79: 679–684 39 Patel SR, Selby C, Jeffcoate WJ. The short Synacthen test in acute hospital admissions. Clin Endocrinol 1991; 35: 259–261 40 Clark PM, Neylon I, Raggatt PR et al. Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol 1998; 49: 287–292 41 McGill PE, Greig WR, Browning MCK et al. Plasma cortisol response to synacthen (β-1-24 Ciba) at different times of the day in patients with rheumatic diseases. Ann Rheum Dis 1967; 26: 123–126 42 Dickstein G, Shechner C, Nicholson WE 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: 773–778 43 Reynolds RM, Stewart PM, Seckl JR et al. Assessing the HPA axis in patients with pituitary disease: a UK survey. Clin Endocrinol 2006; 64: 82–85 44 Plumpton FS, Besser GM. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 1969; 56: 216–219 45 Blichert-Toft M, Christiansen C, Engquist A et al. Comparison of pituitary-adrenocortical response to hypoglycaemia and surgery. Acta Anaesthesiol Scand 1979; 23: 103–106 46 Udelsman R, Chrousos GP. Hormonal responses to surgical stress. Adv Exp Med Biol 1988; 245: 265–272 47 Lindh A, Carlström K, Eklund J et al. Serum steroids and prolactin during and after major surgical trauma. Acta Anaesthesiol Scand 1992; 36: 119–124 48 Jasani MK, Freeman PA, Boyle JA et al. Studies of the rise in plasma 11-hydroxycorticosteroids (11-OHCS) in corticosteroid-treated patients with rheumatoid arthritis during surgery: correlations with the functional integrity of the hypothalamo-pituitary-adrenal axis. QJM 1968; 37: 407–421 49 Melby JC, Spink WW. Comparative studies in adrenal cortisol function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958; 37: 1791–1797 50 Greig WR, Browning MCK, Boyle JA et al. Effect of the synthetic polypeptide β1–24 (Synacthen) on adrenocortical function. J Endocrinol 1966; 34: 411–412
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444 Review
51 Schein RM, Sprung CL, Marcial E et al. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990; 18: 259–263 52 Sibbald WJ, Short A, Cohen MP et al. Variations in adrenocortical responsiveness during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg 1977; 186: 29–33 53 Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 2006; 91: 3725–3745 54 Kehlet H, Binder C, Engbæk C. Cortisol binding capacity in plasma during anaesthesia and surgery. Acta Endocrinol 1974; 75: 119–124 55 Savu L, Zouaghi H, Carli A et al. Serum depletion of corticosteroid binding activities. Biochem Biophys Res Commun 1981; 102: 411–419 56 Pugeat M, Bonneton A, Perrot D et al. Decreased immunoreactivity and binding activity of corticosteroid-binding globulin in serum in septic shock. Clin Chem 1989; 5: 1675–1679 57 Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 2001; 27: 1584–1591 58 Le Roux CW, Chapman GA, Kong WM et al. Free cortisol index is better than serum total cortisol in determining hypothalamic-pituitaryadrenal status in patients undergoing surgery. J Clin Endocrinol Metab 2003; 88: 2045–2048 59 Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004; 350: 1629–1638
60 Ho JT, Al-Musalhi H, Chapman MJ et al. Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 2006; 91: 105–114 61 Bouachour G, Roy PM, Guiraud MP. The repetitive corticotropin stimulation test in patients with septic shock. Ann Intern Med 1995; 123: 962–963 62 Loisa P, Uusaro A, Ruokonen E. A single adrenocorticotropic hormone stimulation test does not reveal adrenal insufficiency in septic shock. Anesth Analg 2005; 101: 1792–1798 63 Widmer IE, Puder JJ, Konig C et al. Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab 2005; 90: 4579–4586 64 Chatha KK, Middle JG, Kilpatrick ES. National UK audit of the short Synacthen test. Ann Clin Biochem 2010; 47: 158–164 65 Dhillo WS, Kong WM, Le Roux CW et al. Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamicpituitary-adrenal axis. Eur J Endocrinol 2002; 146: 231–235 66 Burt MG, Mangelsdorf BL, Rogers A et al. Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH₁–₂₄ stimulation in the assessment of pituitary patients. J Clin Endocrinol Metab 2013; 98: 1883–1890 67 Boonen E, van den Berghe G. Endocrine responses to critical illness: novel insights and therapeutic implications. J Clin Endocrinol Metab 2014; 99: 1569–1582
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
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Review 445
Author
J. Lindholm
Affiliation
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Key words ▶ ACTH test ● ▶ adrenocortical insufficiency ● ▶ stress ●
Abstract
▼
ACTH stimulation test has been used for many years. Some important questions remain unsettled. These are reviewed and discussed in detail. Interpretation of a short ACTH test rests on the fact that a close correlation exists between the responses in plasma cortisol concentrations after administration of ACTH and during insulin induced hypoglycaemia which previously was the standard test. It is generally assumed that the plasma cortisol concentration after ACTH (and insulin) mirrors the response in major stress sit-
Early ACTH Tests
▼ received 23.11.2014 first decision 12.03.2015 accepted 16.03.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1548817 Published online: April 21, 2015 Exp Clin Endocrinol Diabetes 2015; 123: 441–445 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence J. Lindholm Department of Endocrinology Aalborg University Hospital, 9000 Aalborg Denmark Harsdorffsvej 12 1874 Frederiksberg C Denmark [email protected]
Hypophysectomy causes atrophy of the adrenal cortex as first shown by Smith [1]. He also demonstrated the benefits of pituitary transplantation in animals. In 1933 Collip et al. of Montreal [2] published the first description of the isolation from the anterior pituitary of a substance acting on the adrenal cortex. 10 years later and in the same issue of the Journal of Biological Chemistry Li and co-workers [3] and Sayers and colleagues [4] reported the structure of pig adreno-corticotrophin (ACTH): a peptide of 39 amino-acids. Using preparations from hogs, the first clinical study in normals and patients with Addison’s disease appeared in 1948 [5]. In early accounts of the ACTH test [6, 7] it is obvious that the issue of testing adrenal function with ACTH was confounding and frustrating. The potency of corticotrophin preparations varied from batch to batch. The methods used to appraise the effect of ACTH were crude and inexact: counting of circulating eosinophils and determination of 17-ketosteroid excretion. In 1952 the first colorimetric assay for plasma corticosteroids was described [8]. The results were surprisingly similar to what today is reported
uations (surgery and critical disease). This notion rests on few observations. Furthermore, extensive changes in protein binding of cortisol occur swiftly during stress. This complicates comparison between cortisol responses to ACTH and to critical disease. Based on published studies it is discussed whether the outcome of an ACTH test is an appropriate indicator of the need for glucocorticosteroid replacement. This issue is of particular importance when deciding if permanent glucocorticosteroid substitution is necessary or not.
with modern assays. The following year a procedure involving determination of 17-hydroxysteroids in urine was published [9]. In 1954 a short test was introduced: plasma corticosteroids were measured after intravenous injection of ACTH [10, 11]. Despite the difficulties, authors at that time did address important points. They demonstrated a significant relation between the pre- and postACTH values [12, 13]. In secondary hypocorticism prolonged ACTH administration caused a slow increase over days in urinary steroid excretion whereas in primary hypoadrenalism there would be no response. In fact, this was proposed as a way of differentiating between the two disorders [9, 11, 14]. It was correctly explained why the ACTH test is valid in hypothalamic-pituitaryadrenal (HPA) insufficiency. The investigators were also well aware of the risk of allergic reactions when injecting crude preparations of protein of animal origin. No case of severe allergic reaction was reported in these papers, but within the following years several examples of fatal anaphylaxis to ACTH were reported [15, 16].
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
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Problems in Interpretation of the Short Acth Test: an Update and Historical Notes
442 Review
▼
In 1961 a Swiss group showed that a peptide made up of the first 24 amino acids of the 39 in corticotrophin had full ACTH effect [17]. In 1968 tetracosactrin was marketed as Synacthen® or Cosyntropin®. It was soon widely used for testing patients for primary adrenal insufficiency [18–21] and later for assessing adrenal function in patients on treatment with glucocorticosteroid [22]. With the availability of easy and quick cortisol assays (fluorometric technique, competitive protein-binding analysis) the task of assessing the HPA function became a simple procedure. The experience from glucocorticoid treated patients revived the idea that the ACTH test might be of value also in patients with hypothalamicpituitary insufficiency [23]. The value of the short Synachten test (SST) was assessed by comparing it to insulin-induced hypoglycaemia or insulin tolerance test (ITT) – at that time the routine procedure. There proved to be a close relationship [24]. Soon, a plasma cortisol concentration of 500 or 550 nmol/l (18 or 19 µg/dl) at 30 min after injection of ACTH came to be defined as the lower normal limit. These values emerged when results from normal subjects were statistically computed. Normal distribution was – wrongly – assumed. There was close agreement between results obtained with synthetic ACTH1-24 and animal ACTH1-39. Initially, the use of a 30 min ACTH1-24 test for assessing the HPA function was met with scepticism. Several papers warned against the test [25–28]. It was assumed that the ITT (or in a few cases the metyrapone test) yielded the true values. Any discrepancy between the results of an ITT and a SST was taken to reflect failure of the SST. Several factors strongly interfere with the outcome of an ITT [29]. A particularly important issue is the inverse relationship between plasma cortisol and glucose concentrations. If a low plasma glucose concentration is further reduced, additional increase in plasma cortisol levels occurs. Thus, Gale et al. [30] reported that the mean plasma cortisol concentration in normal subjects was 568 ± 59 nmol/l (20.6 ± 2.1 µg/dl) at a glucose level of around 2.08 mmol/l (37 mg/dl), but increased to 818 ± 73 (29.7 ± 2.6) when blood glucose concentration was lowered to 0.92 mmol/l (17 mg/dl) These observations agree with those published earlier [31] and later [32]. In clinical settings adrenocortical secretion is very rarely prompted by hypoglycaemia. Performing the SST shortly after acute deprivation of pituitary ACTH (e. g., pituitary surgery, pituitary apoplexy) may cause marked discrepancy between the two tests. By now, it is well established that in the first weeks after cessation of normal ACTH secretion, the SST may yield grossly inaccurate results [33–35]. The ACTH test has often been described as a “screening procedure”. It was argued that an abnormal outcome should be confirmed with an ITT. At present, it seems that there is no justification for this recommendation. It was proposed that a smaller ACTH dose (1 µg) would improve the value of an ACTH test. The usual amount 250 µg causes a high and unphysiological plasma corticotrophin concentration. A meta-analysis has shown that the results of high and low dose tests are comparable [36]. A later meta-analysis [37] maintained that the low dose ACTH test was superior to the usual SST but this conclusion rested upon the view that an ITT or metyrapone test provides a true delineation between normal and subnormal
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adrenal function. Preparation of small doses requires dilution of 250 µg vials. Adsorption to glass and plastic utensils may occur. The principle of a stimulation test is to measure plasma cortisol concentration under standardized and defined conditions to circumvent spontaneous hormone fluctuations. However, it has been shown again and again that zenith values are closely correlated to nadir (zero time) concentrations [38–40]. This has lead to speculations if a test is necessary and will yield more information than determination of a random plasma cortisol concentration. Actually, several studies have argued that determination of basal cortisol level often may be sufficient – provided the time of day is taken into consideration. It is, however, easier to compare stimulated than spontaneous cortisol concentrations, as peak values after Synacthen are independent of at which time of the day the test is performed [41, 42].
Interpreting the Outcome of the SST
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The most frequently used definition of normal outcome of the test is that 30 min after injection (im or iv) of 250 µg Synacthen, a plasma concentration of > 500 or 550 nmol/l should be reached. A recent audit has shown that in the UK a far wider range of values (250–650 nmol/l (9–24 µg/dl)) is used for defining lower normal limit [43]. In insulin hypoglycaemia test a peak cortisol concentration of > 500–550 nmol/l is also the normal limit agreed upon. Based on very few studies it was accepted that this value is similar to the zenith value during major surgery (actually, this point was a main reason why ITT was adopted as a standard for the assessment of HPA function). However, the data published by Plumpton and Besser [44] showed that there was difference between the two sets – the value during surgery being statistically significantly higher. In another study [45] the difference was not statistically significant. As the peak value is a function of blood glucose level, these results are of modest interest. Subsequent studies have dealt with plasma cortisol levels during major surgery. Unfortunately, almost no raw data are available, results being given as means ± SD. It is, however, possible in some studies to deduce that cortisol concentrations may remain below 500 nmol/l at all time points during major surgery in apparently normal subjects [46, 47]. An older, though still relevant study [48] included a group of 9 patients who before surgery had stopped low-dose prednisone therapy. Almost invariably during operation plasma cortisol levels were around 250 nmol/l (9 µg/dl) but nonetheless the patients had a completely uneventful course during and after surgery (one patient developed hypotension at the end of operation). Thus, it appears doubtful if the cortisol response to insulin and ACTH mimics the response to surgery and other acute, stressful situations. A further problem is that some drugs including oestrogens, carbamazepine and anaesthetics influence circulating cortisol concentrations.
Response in Acute Disease
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In the very first studies on adrenal function in serious infections, it was observed that in a minority of patients, plasma cortisol concentrations were exorbitantly high ( > 1 500–2 000 nmol/l) [49–51]. In the early studies the cortisol analyses may have been less specific but the results have been corroborated with liquid
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Synthetic ACTH
high pressure chromatography. These values are higher than those normally found during ACTH tests, during major surgery and are rarely seen in patients with Cushing’s syndrome (and then usually in ectopic hypercortisolism). It may be that in some situations other potent adrenocorticotropic factors can be mobilized or clearance of cortisol from circulation is reduced. In any case, this adds another difficulty to defining normal limits for plasma cortisol concentrations in critical diseases. In 1977 Sibbald et al. [52] published an account of plasma cortisol levels in patients with critical infections. They concluded that “five patients who constituted 19.2 % of the 26 patients studied, appeared to have some impairment of adrenocortical function. In spite of severe bacterial infections and no history to support Addison’s disease, the plasma cortisol levels – averaging 13.8 ± 3.3 microgram/dl (381 ± 91 nmol/l) – were not increased above normal and their response (to Synacthen) was much less than would be expected”. Subsequently, a large number of papers have described the adrenocortical response to stressful events, such as severe infections, major surgery, trauma, burns, acute pancreatitis. In brief, these papers found that – as expressed in an eminent review [53] – “during critical illness one will encounter an amazingly wide range of values for serum cortisol levels” – both before and after administration of ACTH – often below what is considered normal in routine testing. As early as 1974, the impact of surgery on steroid binding was pointed out [54]. During major surgery circulating amounts of transcortin (CBG) and albumin – the two proteins which bind and transport the major part of circulating cortisol – decreased within a short period of time. Savu et al. [55] and Pugeat et al. [56] made similar findings in patients with critical infections. Important studies have since expanded on this issue. Beishuizen et al. [57] showed in intensive care patients that while mean plasma cortisol concentration was approximately 3 times higher than in controls, calculated free cortisol was about 10 times higher. Le Roux et al. [58] found in patients during surgery that CBG levels fell within 30 min and 33 % of the patients failed to reach a peak plasma cortisol concentration of 500 nmol/l, without any other evidence of adrenal insufficiency. Hamrahian et al. [59] measured plasma cortisol after ACTH in 66 critically ill patients. In 14 plasma cortisol concentration at 30 min after ACTH was 500 nmol/l. Septic shock seems to be the disease causing particularly large shifts in protein concentrations [60]. Poor reproducibility of the SST in septic shock has been described [61, 62]. It may easily be explained by changes in protein binding. These data suggest that the responses to ACTH (and hypoglycaemia) involve mechanisms different from those operative in surgery and other stressful events. Hence, the cortisol responses are not immediately comparable.
Confounding Issues
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To add to the confusion, at an early stage another definition of normalcy was introduced: the increment (or ∆ value) in cortisol values (peak-basal) [18, 50] – not only in a Synacthen test but also during insulin induced hypoglycaemia [44]. Intuitively, the ∆ value appears strange. Situations can easily be imagined when the adrenals are secreting cortisol at a high rate, which cannot be increased. Patel et al. [39] showed in a large number of nor-
mals, that the increment varied from 10 to 747 nmol/l and laconically concluded: “calculation of the increment is of no value”. In the study by Widmer et al. [63] 40 % of apparently completely normal subjects failed to produce a normal increment. Careful reviews [40, 53] have strongly warned that this parameter should not be employed. Curiously and unfortunately, determination of cortisol increment is still in use. Actually, 89 % of British hormone laboratories retain this definition of adrenal insufficiency despite its obvious shortcomings [64]. Considerable discrepancies have been reported between results in blood samples taken with the patient lying and standing, respectively [65]. For instance, in 14 patients the mean plasma cortisol concentration was 352 nmol/l (patients standing) but 275 nmol/l minutes later (patients lying). Naturally, this may also affect the outcome of an ACTH test but this fact has virtually never been taken into consideration. Finally, methodological problems have been frequently encountered as cortisol analyses evolved from crude colorimetric methods to protein-displacement based procedures to fluorometric analyses to radioimmuno-assays to highly accurate methods involving combined chromatography and spectrometry. Even today, several studies have revealed considerable discrepancy between results obtained with commercially available and widely used methods. The above survey [64] on the performance of 10 modern and state-of-the-art analyses shoved a disturbingly big variability, e. g., values between 398 and 553 nmol/l were found in a sample with an exact cortisol concentration of 500 nmol/l. Plasma concentration of CBG is higher in women than in men. In all probability this is the reason that peak cortisol values after ACTH are higher in women tan in men, though concentrations of non-protein bound hormone are lower in women [66].
Central Problem
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The essential point is that no definition of adrenocortical insufficiency exists if “adrenocortical insufficiency” is taken to indicate the necessity of providing substitution with exogenous glucocorticosteroid. What seems relevant is the plasma (nonprotein bound) cortisol concentration, which allows the patient an uneventful course during major illness and surgery (“severe stress”). It is fair to assume that it is lower than what is accepted today as normal response to ACTH. In acute situations, basing the decision on an ACTH test may be unsatisfactory but often consequences, if any, will be modest. In contrast, if the test is used for deciding on life-long steroid substitution, the problem attains vital importance. Udelsman and Chrousous [46] reported that “physiological glucocorticoid replacement, defined as the daily unstressed cortisol production rate, is both necessary and sufficient for primates to tolerate surgical stress” and “it is possible that hypercortisolemia is not in itself implicitly required for stress adaption”. Widmer et al. [63] reached a similar conclusion: “a maximal utilization of the adrenal capacity is not necessary to achieve good clinical outcome”. This view is supported by the clinical observations reported above and also by recent and important findings that in severe, acute disease cortisol production is almost identical to that in normal subjects, except in patients with infections who had higher secretion rate [67]. The result of a SST may not be a reliable index of adreno-cortical function. It might appear relevant (in particular when taking the Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
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findings of Udelsman and Chrousos into account) to consider determination of urinary free cortisol excretion. UFC reflects the 24 h integrated plasma concentration of non-protein bound cortisol. Hence, theoretically UFC could prove to be a valuable indicator when estimating the need for glucocorticoid replacement. This possibility has never been explored.
Declarations: Competing interests: The author has no conflicting interest to declare. Ethical approval: Ethical approval not required for this review. References
1 Smith PE. The disabilities caused by hypophysectomy and their repair. JAMA 1927; 88: 158–161 2 Collip JB, Anderson E, Thomson DL. The adrenotropic hormone of the anterior pituitary lobe. Lancet 1933; 222: 347–348 3 Li CH, Simpson ME, Evans HM. Adrenocorticotropic hormone. J Biol Chem 1943; 149: 413–424 4 Sayers G, White A, Long CNH. Preparation and propertiers of pituitary adrenocorticotropic hormone. J Biol Chem 1943; 149: 425–436 5 Forsham PH, Thorn GW, Prunty FTG et al. Clinical studies with pituitary adrenocorticotropin. J Clin Endocrinol Metab 1948; 8: 15–66 6 Jenkins D, Forsham PH, Laidlaw JC et al. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 8: 3–14 7 Prunty FT. Chemical and clinical problems of the adrenal cortex. BMJ 1956; 2: 615–622 & 673–686 8 Nelson DH, Samuels LT. A method for the determination of 17-hydroxycorticosteroids in blood: 17-hydroxycorticorticosterone in peripheral circulation. J Clin Endocrinol Metab 1952; 12: 519–526 9 Thorn GW, Goetz FC, Streeten DHP et al. Use of the intravenous ACTH test in clinical practice. J Clin Endocrinol Metab 1953; 13: 604–613 10 Eik-Nes K, Sandberg AA, Nelson DH et al. Changes in plasma levels of 17-hydroxysteroids during the intravenous administration of ACTH. I. A test of adrenocortical capacity in the human. J Clin Invest 1954; 33: 1502–1508 11 Christy NP, Wallace EZ, Jailer JW. The effect of intravenously-administered ACTH on plasma 17,21-dihydroxy-20-ketosteroids in normal individuals and in patients with disorders of the adrenal cortex. J Clin Invest 1955; 34: 899–906 12 Birke G, Diczfalusy E, Plantin L-O. Assessment of the functional capacity of the adrenal cortex. I. Establishment of normal values. J Clin Endocrinol Metab 1958; 18: 736–754 13 Gold EM, Starr P. Urinary excretion of 17-ketogenic steroids in normal subjects before and after stimulation with intramuscular zinc-ACTH. J Clin Endocrinol Metab 1959; 19: 907–920 14 Smart GA. Pituitary function. BMJ 1954; 1: 1086–1089 15 Eisalo A, Leskinen O, Oka M. Fatal anaphylactic shock following corticotrophin. Acta Med Scand 1956; 155: 1–4 16 Unger DL, Unger L. Allergic reactions to ACTH. Dis Chest 1961; 40: 359–363 17 Kappeler H, Schwyzer R. Die Synthese eines Tetracosapeptides mit der Aminosäuresequenz eines hochaktiven Abbauproduktes des β-Corticotropins (ACTH) aus Schweine-hypophysen. Helv Chim Acta 1961; 44: 1136–1141 18 Wood JB, Frankland AW, James VHT et al. A rapid test of adrenocortical function. Lancet 1965; 285: 243–245 19 Maynard DE, Folk RL, Riley TR et al. A rapid test for adrenocortical insufficiency. Ann Intern Med 1966; 64: 552–556 20 Musa BU, Dowling JT. Rapid intravenous administration of corticotropin as a test of adrenocortical insufficiency. JAMA 1967; 201: 633–663 21 Danowski TS, Hofmann K, Weigand FA et al. Steroid responses to ACTHlike polypeptides. Clin Endocrinol 1968; 28: 1120–1126 22 Kehlet H, Binder C. Value of an ACTH test in assessing hypothalamicpituitary-adrenocortical function in glucocorticoid-treated patients. BMJ 1973; 2: 147–149 23 Kehlet H, Blichert-Toft M, Lindholm J et al. Short ACTH test in assessing hypothalamic-pituitary-adrenocortical function. BMJ 1976; 1: 249–251 24 Lindholm J, Kehlet H, Blichert-Toft M et al. Reliability of the 30- minute ACTH test in assessing hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 1978; 47: 272–274 25 Borst GC, Michenfelder HJ, O’Brian JT. Discordant cortisol responses to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 1982; 306: 1462–1464
Lindholm J. ACTH Test … Exp Clin Endocrinol Diabetes 2015; 123: 441–445
26 Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276–2279 27 Ammari F, Issa BG, Millward E et al. A comparison between short ACTH and insulin stress tests for assessing hypothalamo-pituitary-adrenal function. Clin Endocrinol 1996; 44: 473–476 28 Suliman AM, Smith TP, Labib M et al. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol 2002; 56: 533–539 29 Lindholm J. The insulin hypoglycaemia test for the assessment of the hypothalamic-pituitary-adrenal function. Clin Endocrinol 2001; 54: 283–286 30 Gale EA, Bennett T, Macdonald IA et al. The physiological effects of insulin-induced hypoglycaemia in man: responses at differing levels of blood glucose. Clin Sci 1983; 65: 263–271 31 Greenwood FC, Landon J, Stamp TC. The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin. 1. In control subjects. J Clin Invest 1966; 45: 429–436 32 Nye EJ, Grice JE, Hockings GI et al. The insulin hypoglycemia test: hypoglycemic criteria and reproducibility. J Neuroendocrinol 2001; 13: 524–530 33 Hjortrup A, Kehlet H, Lindholm J et al. Value of the 30- minute adrenocorticotropin (ACTH) test in demonstrating hypothalamic-pituitaryadrenocortical insufficiency after acute ACTH deprivation. J Clin Endocrinol Metab 1983; 57: 668–670 34 Kehlet H, Lindholm J, Bjerre P. Value of the 30 min ACTH-test in assessing hypothalamic-pituitary- adrenocortical function after pituitary surgery in Cushing’s disease. Clin Endocrinol 1984; 20: 349–353 35 Alwani RA, de Herder WW, de Jong FH et al. Rapid decrease in adrenal responsiveness to ACTH stimulation after successful pituitary surgery in patients with Cushing’s disease. Clin Endocrinol 2011; 75: 602–607 36 Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003; 139: 194–203 37 Kazlauskaite R, Evans AT, Villabona CV et al. Consortium for Evaluation of Corticotropin Test in Hypothalamic-Pituitary Adrenal Insufficiency. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 2008; 93: 4245–4253 38 May ME, Carey RM. Rapid adrenocorticotropin hormone test in practice. Am J Med 1985; 79: 679–684 39 Patel SR, Selby C, Jeffcoate WJ. The short Synacthen test in acute hospital admissions. Clin Endocrinol 1991; 35: 259–261 40 Clark PM, Neylon I, Raggatt PR et al. Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol 1998; 49: 287–292 41 McGill PE, Greig WR, Browning MCK et al. Plasma cortisol response to synacthen (β-1-24 Ciba) at different times of the day in patients with rheumatic diseases. Ann Rheum Dis 1967; 26: 123–126 42 Dickstein G, Shechner C, Nicholson WE 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: 773–778 43 Reynolds RM, Stewart PM, Seckl JR et al. Assessing the HPA axis in patients with pituitary disease: a UK survey. Clin Endocrinol 2006; 64: 82–85 44 Plumpton FS, Besser GM. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 1969; 56: 216–219 45 Blichert-Toft M, Christiansen C, Engquist A et al. Comparison of pituitary-adrenocortical response to hypoglycaemia and surgery. Acta Anaesthesiol Scand 1979; 23: 103–106 46 Udelsman R, Chrousos GP. Hormonal responses to surgical stress. Adv Exp Med Biol 1988; 245: 265–272 47 Lindh A, Carlström K, Eklund J et al. Serum steroids and prolactin during and after major surgical trauma. Acta Anaesthesiol Scand 1992; 36: 119–124 48 Jasani MK, Freeman PA, Boyle JA et al. Studies of the rise in plasma 11-hydroxycorticosteroids (11-OHCS) in corticosteroid-treated patients with rheumatoid arthritis during surgery: correlations with the functional integrity of the hypothalamo-pituitary-adrenal axis. QJM 1968; 37: 407–421 49 Melby JC, Spink WW. Comparative studies in adrenal cortisol function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958; 37: 1791–1797 50 Greig WR, Browning MCK, Boyle JA et al. Effect of the synthetic polypeptide β1–24 (Synacthen) on adrenocortical function. J Endocrinol 1966; 34: 411–412
Downloaded by: Collections and Technical Services Department. Copyrighted material.
444 Review
51 Schein RM, Sprung CL, Marcial E et al. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990; 18: 259–263 52 Sibbald WJ, Short A, Cohen MP et al. Variations in adrenocortical responsiveness during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg 1977; 186: 29–33 53 Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 2006; 91: 3725–3745 54 Kehlet H, Binder C, Engbæk C. Cortisol binding capacity in plasma during anaesthesia and surgery. Acta Endocrinol 1974; 75: 119–124 55 Savu L, Zouaghi H, Carli A et al. Serum depletion of corticosteroid binding activities. Biochem Biophys Res Commun 1981; 102: 411–419 56 Pugeat M, Bonneton A, Perrot D et al. Decreased immunoreactivity and binding activity of corticosteroid-binding globulin in serum in septic shock. Clin Chem 1989; 5: 1675–1679 57 Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 2001; 27: 1584–1591 58 Le Roux CW, Chapman GA, Kong WM et al. Free cortisol index is better than serum total cortisol in determining hypothalamic-pituitaryadrenal status in patients undergoing surgery. J Clin Endocrinol Metab 2003; 88: 2045–2048 59 Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004; 350: 1629–1638
60 Ho JT, Al-Musalhi H, Chapman MJ et al. Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 2006; 91: 105–114 61 Bouachour G, Roy PM, Guiraud MP. The repetitive corticotropin stimulation test in patients with septic shock. Ann Intern Med 1995; 123: 962–963 62 Loisa P, Uusaro A, Ruokonen E. A single adrenocorticotropic hormone stimulation test does not reveal adrenal insufficiency in septic shock. Anesth Analg 2005; 101: 1792–1798 63 Widmer IE, Puder JJ, Konig C et al. Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab 2005; 90: 4579–4586 64 Chatha KK, Middle JG, Kilpatrick ES. National UK audit of the short Synacthen test. Ann Clin Biochem 2010; 47: 158–164 65 Dhillo WS, Kong WM, Le Roux CW et al. Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamicpituitary-adrenal axis. Eur J Endocrinol 2002; 146: 231–235 66 Burt MG, Mangelsdorf BL, Rogers A et al. Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH₁–₂₄ stimulation in the assessment of pituitary patients. J Clin Endocrinol Metab 2013; 98: 1883–1890 67 Boonen E, van den Berghe G. Endocrine responses to critical illness: novel insights and therapeutic implications. J Clin Endocrinol Metab 2014; 99: 1569–1582
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