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Diagnosis of Adrenal Insufficiency: Evaluation of the Corticotropin-Releasing Hormone Test and Basal Serum Cortisol in Comparison to the Insulin Tolerance Test in Patients with Hypothalamic-Pituitary-Adrenal Disease

Division of Endocrinology, Medical Center, University of Essen, 45122 Essen, Germany

Address all correspondence and requests for reprints to: Priv.-Doz. Dr. med. Stephan Petersenn, Division of Endocrinology, Medical Center, University of Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: stephan.petersenn{at}uni-essen.de.

	Abstract

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The aim of the study was to evaluate the diagnostic value of the human CRH test and the basal morning serum cortisol for the diagnosis of adrenal insufficiency. Putative peak cortisol cut points for the CRH test and basal cortisol cut points were determined by receiver operating characteristic (ROC) analysis with the insulin tolerance test as reference test. Fifty-four patients with suspected hypothalamic-pituitary-adrenal disease were tested. In 20 healthy controls, CRH led to a mean peak cortisol of 594.8 ± 21.7 nmol/liter. The lower limit of a normal response was calculated as 400 nmol/liter. ROC analysis of peak cortisol levels during CRH testing of patients with suspected hypothalamic-pituitary-adrenal disease suggested an optimal peak cortisol cut point of 377 nmol/liter for the diagnosis of adrenal insufficiency and a 96% specificity but poor sensitivity of 76%. The baseline cortisol in the healthy control group showed a mean of 439.3 ± 24.9 nmol/liter, resulting in a lower limit of 267 nmol/liter. ROC analysis of patients suggested the highest accuracy for basal cortisol levels of 285 nmol/liter or more for the diagnosis of adrenal insufficiency (100% sensitivity and 61% specificity). Within this patient group, a cortisol of more than 98 nmol/liter excluded adrenal insufficiency among those without the disorder, yielding 100% specificity. Using these criteria of upper (285 nmol/liter) and lower (98 nmol/liter) cut-off points with high sensitivity and specificity can reduce the number of individuals who need provocative tests. Basal cortisol is less expensive, and we therefore suggest to use it as a first-line test of adrenal insufficiency. Because of the low sensitivity of the human CRH test, we do not recommend it as a second test.

	Introduction

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ACCURATE ASSESSMENT OF the hypothalamic-pituitary-adrenal (HPA) axis is essential in the management of patients with suspected pituitary or hypothalamic disease. The insulin tolerance test (ITT) is considered to be the gold standard to evaluate adrenal function in such patients (1). Peak cortisol cut points (PCCPs) between 500 and 550 nmol/liter are variably used for the diagnosis of adrenal sufficiency (2). However, the ITT is contraindicated in patients with cardio- or cerebrovascular diseases and convulsive disorders. Furthermore, the test is unpleasant for the patient and costly with respect to the degree of medical supervision required. As a consequence, alternative tests for evaluating HPA axis have been sought, such as glucagon, metyrapone, ACTH, and CRH testing.

The human CRH (hCRH) test may be an alternative test to examine the HPA axis. CRH stimulates the secretion of ACTH at the level of the pituitary. The administration of CRH is free of serious side effects (3). After iv injection of 100 µg CRH, the plasma ACTH value usually peaks at 15 or 30 min, whereas the cortisol value usually peaks between 30 and 60 min (4). In patients treated with synthetic glucocorticoids, testing with hCRH is nearly as useful as the ITT (5).

Besides dynamic testing of the HPA axis, early-morning serum cortisol measurement has gained interest as a screening test. Several cut points have been proposed, leading to further dynamic testing or proving diagnosis (1, 6, 7, 8).

The aim of the present study was to evaluate the diagnostic value of the hCRH test and the early-morning serum cortisol measurement in comparison with the ITT and to define cut points for the diagnosis of adrenal insufficiency using a total of 54 patients with suspected pituitary or hypothalamic diseases. Because there are only limited data for the peak cortisol values (hCRH test) in healthy subjects, we established reference values in a healthy control group. Furthermore, we defined lower limits for baseline cortisol in our control group.

	Subjects and Methods

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Normal volunteers

Twenty volunteers free of any endocrine disorder (Table 1) underwent hCRH administration, and 12 of them also underwent early-morning cortisol sampling (Table 2). The local ethics committee approved the study protocol, and all subjects gave their informed written consent to participate in the study. None of the eight female normal volunteers were taking estrogen at the time of the investigation.

Fifty-four patients were evaluated at our department because of suspected disease of the HPA axis from July 2001 until July 2002 (Table 1). Patients underwent testing by ITT and hCRH administration. Forty-six patients had a history of tumors in the pituitary area (20 nonfunctioning adenomas, eight somatotropic adenomas, six prolactinomas, two cases of neurosarcoidosis, three cases of hypophysitis, six craniopharyngeomas, and one chordoma), three patients had a history of pituitary hormone deficiency of unknown origin (two congenital, one diabetes insipidus), and in five patients disease of the HPA axis was suspected because of clinical symptoms. Forty-one of the above-mentioned patients were also examined by measurement of the morning serum cortisol (Table 2). Thirty-five had a history of tumors in the pituitary area (14 nonfunctioning adenomas, seven somatotropic adenomas, four prolactinomas, one case of neurosarcoidosis, two cases of hypophysitis, six craniopharyngeomas, and one chordoma), one patient had diabetes insipidus, and in five cases disease was suspected because of clinical symptoms. At the time of investigation, none of the female patients were on estrogen.

Methods

Patients underwent an ITT between 0900 and 1030 h by injection of 0.15 IU/kg regular insulin (Actrapid, Novo Nordisk, Mainz, Germany) to achieve blood glucose levels less than 40 mg/dl and until symptoms of hypoglycemia developed. Blood samples were taken at 0, 15, 30, 45, 60, 90, and 120 min. CRH testing in the patient and volunteer groups was performed between 0900 and 1030 h, using 100 µg hCRH (Ferring GmbH, Kiel, Germany) and an indwelling line. Blood samples were taken at 0, 15, 30, and 45 min. Unstimulated serum cortisol values between 0800 and 0900 h were available for comparison with the peak cortisol response to the dynamic testing. If the patients were initially treated with glucocorticoid replacement therapy, it was stopped 24 h before hormonal evaluation. In addition, the other anterior pituitary axes (thyrotropic, gonadotropic, and somatotropic) were evaluated by hormone baseline levels and provocative testing, as required. Function of the posterior pituitary was assessed by determination of 24-h urine volume and urine-osmolality. Further testing was performed, if required.

Serum cortisol levels (nanomoles per liter) were assayed at each time point by competitive immunoassay (ADVIA Centaur System, Bayer, Fernwald, Germany). The lower detection limit was assessed to be 5.5 nmol/liter (0.20 µg/dl). Intraassay variations as coefficient of variation for various cortisol values were 3.69% (107.05 nmol/liter), 3.09% (155.33 nmol/liter), 2.89% (390.95 nmol/liter), 3.82% (759.55 nmol/liter), and 2.98% (1024.97 nmol/liter). Interassay variations for the above-mentioned cortisol concentrations were 5.45, 3.83, 3.07, 1.86, and 3.99%.

Results (mean ± SEM) are expressed as absolute values for cortisol. GraphPad Prism 3.0 software for Macintosh (GraphPad Software, San Diego, CA) was used for statistical analysis. Spearman’s rank correlation analysis was carried out to determine relationships between variables. For further statistical analysis, a Mann-Whitney U test was performed where appropriate. Receiver operating characteristic (ROC) analysis was obtained using MedCalc 6.16 software (MedCalc software, Mariakerke, Belgium).

	Results

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hCRH test

Normal volunteers. Twenty healthy volunteers underwent hCRH testing for determination of reference values. Following hCRH administration, serum cortisol (mean ± SEM, range) rose from baseline to a mean peak of 594.8 ± 21.7 nmol/liter (448.0–843.0 nmol/liter) (Fig. 1A). The lower normal cortisol peak value (mean peak, -2 SD) was calculated as 400 nmol/liter. Neither age nor body mass index (BMI) had significant influence on the peak serum cortisol levels during hCRH testing.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Comparison of peak cortisol levels during hCRH test (A) morning basal cortisol levels (B) to peak cortisol levels during ITT. Individual values of healthy volunteers (N) during hCRH test (A) and for basal cortisol (B) are shown by circles. Individual values during ITT (A+B, squares) and hCRH test (A, triangles) or basal cortisol (B, triangles) are demonstrated. Patients were defined as adrenal insufficient (I, closed symbols) or sufficient (S, open symbols) based on their cortisol peak response to hypoglycemia of less than 500 nmol/liter or more than 500 nmol/liter.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Analysis of percentage increment of serum cortisol (baseline values equal to 100%). Individual values of maximum percentage cortisol increment during hCRH test are shown for a healthy control group by circles. Individual values of maximum percentage cortisol increment during ITT (squares) and hCRH test (triangles) are demonstrated. Classification of patients as adrenal insufficient (I, closed symbols) or sufficient (S, open symbols) was based on their cortisol peak response to hypoglycemia of less than 500 nmol/liter or more than 500 nmol/liter.

Fifty-four patients with suspected disease of the HPA axis were examined by hCRH test and ITT as reference test. Using a PCCP of 500 nmol/liter in the ITT, 29 patients were considered to be adrenal insufficient (AI), whereas 25 were sufficient (AS). The cortisol mean peak of the AI patients (mean ± SEM, range) was 233.8 ± 31.1 nmol/liter (25.00–499.0 nmol/liter), compared with 616.5 ± 25.7 nmol/liter (503.0–1071 nmol/liter) in AS patients (Fig. 1A). With regard to sex and BMI, there was no significant difference between both groups (Table 1). However, age was significantly different between the AI and AS group (P < 0.05). Deficiencies of other pituitary axes were also examined (Fig. 3). Among the AS patients, 15 had no pituitary axis defect at all, nine had one insufficiency, and one patient had a defect in two pituitary axes. In contrast, among the AI patients, three had no insufficiency of other axes, five had insufficiency of one axis, two patients had defect in two pituitary axes, 13 had insufficiency of three axes, and six patients were insufficient in four other pituitary axes. Deficiencies of other pituitary axes correlated with the degree of functional impairment in the ITT.

View larger version (17K): [in this window] [in a new window]   FIG. 3. A, Percentage of additional pituitary axis insufficiencies in relation to adrenal function. Patients were separated as AS (open bars) and AI (closed bars) according to a PCCP of 500 nmol/liter in the ITT. Bars indicate the proportion of patients of each group suffering from zero to four pituitary axis deficiencies. B, Basal cortisol values plotted against the number of pituitary insufficiencies.

View larger version (14K): [in this window] [in a new window]   FIG. 4. Individual cortisol peak levels during ITT in 54 patients (A) and 41 patients (B) plotted against cortisol peaks during hCRH test (A) (r = 0.80, P < 0.0001) and morning basal cortisol (B) (r = 0.72, P < 0.0001).

View larger version (28K): [in this window] [in a new window]   FIG. 5. ROC curve of the hCRH test (A) and the morning basal cortisol (B) with the ITT as reference test. Optimal cut points are given in bold letters. Peak cortisol levels to the ITT more than 500 nmol/liter indicate corticotropic sufficiency.

We analyzed the time points of the cortisol peak during the hCRH test. No significant increment from baseline cortisol was observed in seven subjects (13%). In two subjects (4%), the peak value occurred 15 min after hCRH administration, whereas in eight subjects (15%), it was observed at time point 30 min. In 37 patients (68%), the peak cortisol value was seen 45 min after hCRH administration. We also performed ROC analysis of cortisol values at defined time points during the hCRH test. Regarding a specificity of 96%, the corresponding values for sensitivity are 62% for time point 15 min (AUC = 0.884), 65% for time point 30 min (AUC = 0.894), and 69% for time point 45 min (AUC = 0.888).

Basal cortisol

Normal volunteers. Twelve morning cortisol values of the total of 20 healthy volunteers were available. The mean basal cortisol value was 439.3 ± 24.9 nmol/liter (326.0–600.0 nmol/liter) (Fig. 1B). The lower limit of a normal basal cortisol was calculated as 267 nmol/liter (mean - 2 SD).

Patients. Because there were only 41 baseline cortisol values of the total of 54 patients available (Table 2), a separate analysis of the corresponding results of the ITT was performed. Twenty patients were considered to be AI with a mean cortisol peak (mean ± SEM, range) of 228.0 ± 39.5 nmol/liter (25.00–499.0 nmol/liter), compared with 21 AS patients with a mean cortisol peak of 620.3 ± 30.6 nmol/liter (503.0–1071 nmol/liter) (Fig. 1B). No significant differences concerning sex, age, or BMI could be observed between both groups (Table 2). Basal cortisol values were plotted against the number of pituitary deficiencies (Fig. 3B). On average, patients with intact pituitary axes had higher basal cortisol levels than patients with multiple pituitary hormone deficiencies.

There was a significant correlation for the basal cortisol values and the peak levels during ITT (r = 0.72, P < 0.0001), as shown in Fig. 4B. The results of the baseline cortisol values were grouped according to the classification by ITT peak cortisol values (Fig. 1B). The mean baseline cortisol level for the AI patients was 126.5 ± 21.8 nmol/liter (25.00–285.0 nmol/liter). In contrast, AS patients showed mean morning cortisol levels of 357.1 ± 36.9 nmol/liter (119.0–654.0 nmol/liter). ROC analysis suggested an optimal baseline cortisol cut point of 285 nmol/liter (AUC = 0.88, confidence interval 0.74–0.96), resulting in 100% sensitivity and 62% specificity. A cortisol cut point of 98 nmol/liter determined 100% specificity but low sensitivity of 50% (Fig. 5B).

Combination of basal cortisol and hCRH test

The combination of the basal cortisol measurement and subsequent hCRH testing was analyzed. Using a lower cut-off value of 98 nmol/liter or less for basal cortisol, 10 patients could be classified as AI, whereas an upper cut point of more than 285 nmol/liter permitted the diagnosis of AS in 13 patients. In 18 patients of the total of 41 patients (44%), the diagnosis still remained unclear. On the basis of the subsequent hCRH test, five patients were considered to be AI (349 nmol/liter) and two patients to be AS (>514 nmol/liter). As a consequence, diagnosis obtained by the ITT could not be confirmed in 11 patients (27%).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The diagnosis of secondary adrenal insufficiency is difficult. Considerable controversy exists about which test is best, especially with regard to the low-dose and high-dose ACTH stimulation test (9). In the present study, we compared the hCRH test and morning basal cortisol levels with the ITT with regard to their value for diagnosis of adrenal insufficiency in a cohort of patients with suspected impaired HPA axis. The ITT was used as reference test because it is still be considered the gold standard for diagnosis of adrenal insufficiency (1). The PCCP for separation between normal and subnormal adrenal response to hypoglycemia has been variably defined between 500 and 550 nmol/liter (2). A recent investigation of subjects without endocrine disease (10) suggested a cut point of 500 nmol/liter, which we relied on.

Our investigation of 20 healthy volunteers with hCRH revealed mean cortisol peak levels very similar to the results obtained by Schlaghecke et al. (5). In contrast, higher peak levels in normal subjects have been reported in response to 100 µg ovine CRH administration (11). Ovine CRH was previously found to cause greater peak cortisol and ACTH levels, compared with hCRH (12). It is known to result in prolonged elevation of ACTH and cortisol (13), possibly because of its prolonged circulating half-life (14). To our knowledge, a lower normal limit for serum cortisol during the hCRH test by calculation of mean peak cortisol levels to 2 SD, corresponding to 400 nmol/liter in our study, has not been defined so far.

In the hCRH test of examined patients, peak cortisol levels of 377 nmol/liter or less reflected adrenal insufficiency very accurately (96% specificity), whereas cortisol levels above 377 nmol/liter did not necessarily determine adrenal sufficiency (76% sensitivity). The PCCP is in good agreement with the above-mentioned lower normal peak value of the control group. However, 24% of patients will be misdiagnosed as AS using this cut point. In a previous study of the hCRH test, Dullaart et al. (15) studied a cohort of 80 patients with hypothalamic-pituitary disorders but without normal volunteers by ROC analysis. Peak cortisol values of 420 nmol/liter reflected 100% specificity (349 nmol/liter in our study). A 100% sensitivity was reached by a PCCP of 615 nmol/liter, compared with 514 nmol/liter in our study. Higher cortisol values obtained by Dullaart et al. may be explained by earlier time of testing (0800 to 0900 h).

In our study, the highest cortisol levels were observed 45 min after hCRH administration in 37 of 47 patients (79%). In only two subjects (4%), peak levels occurred at time point 15 min. In agreement, other investigators reported cortisol peak levels between 30 and 60 min after hCRH administration (4, 5). ROC analysis of different time points revealed a sensitivity of 69% for the 45-min value, compared with 76% sensitivity for the peak levels (same specificity of 96%). Therefore, sampling may be limited to the 45-min time point.

Schlaghecke et al. (5) defined an 1.5-fold increase in the plasma cortisol concentration to a value of at least 276 nmol/liter during ITT or hCRH test as a normal response. For differential diagnosis of Cushing’s syndrome, percentage variations between baseline and stimulated cortisol by CRH administration has been established (16). However, based on the percentage cortisol increment during our patient’s hCRH test, ROC analysis revealed an AUC value of 0.54, indicating nearly no discrimination between AS and AI patients. Therefore, the percentage increment of baseline cortisol is inappropriate to analyze the results of the hCRH test with regard to AS. Similarly, Erturk et al. (6) suggested that the use of an incremental rise in plasma cortisol during ITT as a criterion for HPA normalcy should be abolished.

In our study, morning basal cortisol values were assessed in a total of 41 patients in comparison with the ITT. The optimal cut point of 285 nmol/liter (100% sensitivity and 62% specificity) defined by ROC analysis is in good agreement with the normal value obtained in our volunteer group (267 nmol/liter), although the size of the volunteers group is small. Sensitivity and specificity were clearly different for basal cortisol and the hCRH test, suggesting specific diagnostic utility. In contrast, the AUCs of both tests overlapped tremendously, indicating that the tests are the same by ROC. Therefore, a simple comparison of AUC values represents a potential pitfall of ROC determination.

The lower cut point for basal cortisol, proving adrenal insufficiency, was determined as 98 nmol/liter (100% specificity and 50% sensitivity). That value corresponds to other proposed lower cut points for cortisol, ranging between 80 and 110 nmol/liter (1, 6, 7, 8). The upper cortisol cut point to confirm adrenal sufficiency is less well standardized. Cut points of 250 nmol/liter (1) and 300 nmol/liter (7) have been reported, which are in good agreement with the result of our study (285 nmol/liter). However, two other studies demonstrated significantly higher cut points of 470 nmol/liter (6) and 500 nmol/liter (8). The differences may depend on the time point of blood withdrawal, the technique (venipuncture or collection from a catheter), and the conditions of blood sampling (outpatient or inpatient).

The number of pituitary axis deficiencies and basal cortisol levels were inversely correlated. Furthermore, deficiencies of other pituitary axes correlated clearly with the degree of functional impairment in the ITT. Such dependency has been previously demonstrated for the severity of GH deficiency and the degree of hypopituitarism (17).

Our results suggest the use of an algorithm for the diagnosis of AI. Use of a lower cut point of 98 nmol/liter (100% specificity) and a higher cut point of 285 nmol/liter (100% sensitivity) for basal cortisol levels identified 23 of the patients (56%) correctly, as classified by ITT. The remaining 18 patients, who fell between these cut points and could not be identified as sufficient or insufficient, would require further testing. However, the hCRH test did not confirm the diagnosis obtained by ITT in 11 of these patients (27% of the total group).

In conclusion, the measurement of early morning serum cortisol reduces the numbers of individuals who need provocative tests. Adequate upper and lower cut points with high sensitivity and specificity, respectively, need to be applied. Basal cortisol is less expensive, and we therefore suggest to use it as a first-line test of adrenal insufficiency. Because of the low sensitivity of the hCRH test, we do not recommend it as a second test.

	Footnotes

 
Abbreviations: AI, Adrenal insufficient; AS, adrenal sufficient; AUC, area under the curve; BMI, body mass index; hCRH, human CRH; HPA, hypothalamic-pituitary-adrenal; ITT, insulin tolerance test; PCCP, peak cortisol cut point; ROC, receiver operating characteristic.

Received December 3, 2002.

Accepted May 28, 2003.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmidt, I. L. Articles by Petersenn, S. Search for Related Content PubMed PubMed Citation Articles by Schmidt, I. L. Articles by Petersenn, S.