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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1712-1717
Copyright © 2004 by The Endocrine Society

Low- and Standard-Dose Corticotropin and Insulin Hypoglycemia Testing in the Assessment of Hypothalamic-Pituitary-Adrenal Function after Pituitary Surgery

C. Hamish Courtney, Andrew S. McAllister, Patrick M. Bell, David R. McCance, Hilary Leslie, Brian Sheridan and A. Brew Atkinson

Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom

Address all correspondence and requests for reprints to: Professor A. B. Atkinson, Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, United Kingdom, BT12 6BA. E-mail: ab.atkinson{at}royalhospitals.n-i.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The optimal means of assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery remains controversial. We compared low-dose (1 µg iv) and standard-dose (250 µg im) corticotropin tests performed 1 and 4–6 wk after pituitary surgery with an insulin hypoglycemia test performed at 4–6 wk.

Forty-one patients (21 male and 20 female; median age, 52 yr; range, 23–73 yr) who had undergone pituitary surgery were studied (Cushing’s disease excluded). Twenty-two of the 41 patients had normal cortisol responses to all tests both at 1 and 4–6 wk after surgery. Eight patients had subnormal cortisol responses to all tests. Of the 11 patients with discrepant results, seven had subnormal responses only after the low-dose corticotropin test; the remaining four patients had borderline responses to one or more tests. At 4–6 wk after surgery, subjects with a 30-min serum cortisol after standard-dose corticotropin of less than 350 nmol/liter (12.7 µg/dl) consistently had a subnormal response to hypoglycemia, and those with a serum cortisol greater than 650 nmol/liter (23.6 µg/dl) had a normal response to hypoglycemia.

Definitive testing of the HPA axis using the standard-dose corticotropin test can be carried out provided it is performed at least 4 wk after pituitary surgery. A 30-min cortisol level greater than 650 nmol/liter (23.6 µg/dl) indicates adequacy of the HPA axis, and a level of less than 350 nmol/liter (12.7 µg/dl) indicates ACTH deficiency. No further testing is then required. An intermediate level of 350–650 nmol/liter (12.7–23.6 µg/dl) warrants further assessment using the insulin hypoglycemia test.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TESTING OF THE hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery is necessary to allow appropriate decisions regarding corticosteroid replacement therapy to be made. Both the means and timing of this assessment, however, remain controversial. In their recent guidelines, Inder and Hunt (1) highlighted the need for further studies to "define optimal postoperative glucocorticoid management after pituitary surgery." The gold standard for evaluation of the HPA axis is the insulin hypoglycemia test (2), although this is both labor intensive and contraindicated in certain patients (e.g. epilepsy and heart disease). Alternative methods, which are less expensive and easier to perform, include the low- and standard-dose corticotropin tests (3, 4, 5). Because these are indirect assessments of HPA function, concerns regarding their reliability remain (6, 7).

The timing of HPA axis assessment is also important. Testing too early in the postoperative period may diagnose corticotropin deficiency, which turns out to be transient (8). Alternatively, corticotropin sufficiency may be erroneously identified if corticotropin testing is performed too early after sudden ACTH depletion. This is probably because insufficient time has elapsed for adrenal atrophy to occur (5, 8).

Ambiguity has also arisen in previous reports because of the heterogeneity of patient groups studied. Previous studies examining the function of the HPA axis have included not only patients with pituitary adenomas assessed in the months after pituitary surgery but also patients with pituitary adenomas many years after surgery, patients who received radiotherapy, still other patients with diverse pituitary pathology, and finally some patients without pituitary disease but receiving glucocorticoid therapy for other medical disorders (9, 10, 11, 12). We wished therefore to study a relatively homogeneous group of patients immediately after pituitary surgery and to compare the low- and standard-dose corticotropin tests performed 1 wk after surgery with repeat low- and standard-dose corticotropin tests in addition to an insulin hypoglycemia test performed at 4–6 wk postoperatively. We have previously compared the low- and standard-dose corticotropin tests at 1 wk with an insulin hypoglycemia test at 4–6 wk (5), but the present study allowed us to identify temporal changes in HPA axis function over the early postoperative period and, importantly, also to evaluate the optimal means of assessing HPA axis function after surgery.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Forty-one patients (21 male and 20 female; median age, 52 yr; range, 23–73 yr) had assessment of their HPA axis after transsphenoidal surgery for pituitary adenomas. The investigations performed were part of our routine patient care at that time. Thirty patients had nonfunctioning pituitary adenomas, six had GH-secreting adenomas, four had prolactinomas, and one had a TSH-secreting adenoma.

Each patient had a low-dose (1 µg) corticotropin test on d 6 after pituitary surgery and a standard-dose (250 µg) corticotropin test on d 7. Replacement hydrocortisone was omitted for 24 h before each test. These 1-wk data have been reported elsewhere (5).

The low-dose corticotropin test was performed by administering 1 µg corticotropin iv at 0900 h after a basal serum cortisol measurement. Corticotropin (Synacthen 250 µg, Novartis Pharmaceuticals, Surrey, UK) was diluted in sterile 0.9% normal saline solution to a concentration of 1 µg/ml and injected immediately. Samples for serum cortisol were obtained at 30 and 60 min after injection.

Similarly, after basal sampling, the standard-dose corticotropin test was performed by administering corticotropin, 250 µg im, with samples for serum cortisol being taken 30 and 60 min later.

If the 0900 h serum cortisol 1 wk after surgery was greater than 250 nmol/liter (9.1 µg/dl), then replacement hydrocortisone was discontinued and patients were instructed to recommence hydrocortisone at double dose (30 mg at 0900 h and 10 mg at 1700 h) should they become unwell in the interim. None of our patient cohort had to do this.

All patients were readmitted 4–6 wk after surgery for additional testing. This included repeat low- and standard-dose corticotropin tests carried out as outlined above. In addition, an insulin hypoglycemia test was performed. After an overnight fast, an iv cannula was inserted into a forearm vein at 0900 h and soluble insulin (Humulin S, Lilly, Basingstoke, UK), 0.15 U/kg, administered iv at 0930 h. For those patients with acromegaly or suspected insulin resistance, 0.2 U/kg was given, and 0.1 U/kg to those patients in whom hypoadrenalism was thought probable. Peripheral venous blood was sampled at 0, 15, 30, 45, 60, 75, and 90 min for glucose and cortisol. In those subjects still taking replacement corticosteroids, these were omitted for 24 h before each test, the total daily dose being given as a single dose immediately after the performance of low- and standard-dose corticotropin tests.

The basal cortisol level reported at 4–6 wk after surgery was determined as the mean value of the 0900 h serum cortisol measurements taken before the low-dose and standard-dose corticotropin tests.

A lower limit of a normal cortisol response to both low- and standard-dose corticotropin had been determined previously in our center after performance of these tests in 16 normal volunteers. The mean - 2 SD (logarithmic transformation) 30-min serum cortisol value was 496 nmol/liter for the low-dose corticotropin test and 504 nmol/liter for the standard-dose corticotropin test, resulting in our use of a cutoff value of 500 nmol/liter (18.1 µg/dl) for both tests (5). We used a cortisol response to hypoglycemia of 550 nmol/liter (19.9 µg/dl) as indicative of a normal response, provided symptomatic hypoglycemia (glucose <= 2.0 mmol/liter) was achieved (2).

Serum cortisol was measured by RIA, using the Diagnostic Products Corp. (Caernarfon, UK) Coat-a-Count method. It has an established interassay coefficient of variation at all levels of less than 5%.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All patients developed symptomatic hypoglycemia (<=2.0 mmol/liter) in response to insulin administration with none experiencing any adverse effects.

Twenty-two patients had a normal cortisol response to both low- and standard-dose corticotropin tests 1 wk after surgery and a normal cortisol response to both corticotropin tests and the insulin hypoglycemia test 4–6 wk after surgery. Eight patients had subnormal cortisol responses to all tests both at 1 week and 4–6 wk after surgery. The responses of the individual patients who had subnormal and discrepant responses are shown in Table 1Go.


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  		TABLE 1. Patient details

 
There was significant correlation between the 30-min cortisol response to both low- and standard-dose corticotropin at 4–6 wk after surgery and the peak cortisol after insulin-induced hypoglycemia (Figs. 1Go and 2Go).



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  		FIG. 1. Peak serum cortisol response to insulin hypoglycemia vs. 30-min serum cortisol response to low-dose corticotropin (1 µg) at 4–6 wk after surgery.

 


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  		FIG. 2. Peak serum cortisol response to insulin hypoglycemia vs. 30-min serum cortisol response to standard-dose corticotropin (250 µg) at 4–6 wk after surgery.

 
Five patients (patients A–E in Table 1Go) had a subnormal cortisol response to low-dose corticotropin but a normal response to standard-dose corticotropin 1 wk after surgery. Four (A–D) of these subsequently had normal responses to all three tests at 4–6 wk with the remaining patient (E) having subnormal responses to all three tests.

One patient (F) had a subnormal response to low-dose corticotropin at both 1 and 4–6 wk after surgery, with normal responses to both standard-dose corticotropin tests and the insulin hypoglycemia test.

Two patients (G and H) had normal cortisol responses to all tests except for an isolated subnormal response to low-dose corticotropin at 4–6 wk.

One patient (I) had subnormal responses to both low-dose corticotropin tests and to the 4- to 6-wk standard-dose corticotropin test but a normal 1-wk standard-dose corticotropin and a normal insulin hypoglycemia test response.

Two patients (J and K) had normal responses to low- and standard-dose corticotropin tests both at 1 and 4–6 wk yet had subnormal cortisol responses to insulin-induced hypoglycemia.

Mean basal serum cortisol levels 4–6 wk after surgery did not discriminate between those with normal, subnormal, and discrepant cortisol responses to insulin-induced hypoglycemia and corticotropin (Fig. 3Go).



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  		FIG. 3. Comparison of the mean 0900 h serum cortisol levels 4–6 wk after pituitary surgery with the response to dynamic testing.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Based on these findings in this study, we propose that definitive testing of the HPA axis takes place at least 1 month after pituitary surgery. Before this, and as recommended previously by us (5), 0900 h serum cortisol should be checked 1 wk after pituitary surgery (replacement hydrocortisone discontinued for 24 h). A serum cortisol of less than 100 nmol/liter (3.6 µg/dl) indicates ACTH deficiency and the need for lifelong steroid replacement with no additional testing required. Patients with an 0900 h serum cortisol between 100 and 250 nmol/liter (3.6–9.1 µg/dl) should remain on replacement hydrocortisone until definitive testing. A serum cortisol between 250 and 450 nmol/liter (9.1–16.3 µg/dl) permits safe steroid withdrawal until definitive testing, although with instruction to recommence corticosteroids should the patient become unwell in the interim. A serum cortisol greater than 450 nmol/liter (16.3 µg/dl) indicates adequacy of the HPA axis, permitting steroid withdrawal with no additional testing required. At 4–6 wk after surgery, a robust 30-min serum cortisol response of greater than 650 nmol/liter (23.6 µg/dl) to standard-dose corticotropin, 0.25 mg im or iv (13) indicates adequacy of the HPA axis with additional testing unnecessary. Similarly, a low 30-min cortisol response of less than 350 nmol/liter (12.7 µg/dl) to standard-dose corticotropin indicates inadequacy of the HPA axis, with additional testing unnecessary and lifelong corticosteroid replacement indicated. Those patients with a 30-min cortisol response to standard-dose corticotropin between 350 and 650 nmol/liter (12.7–23.6 µg/dl) warrant further, more detailed assessment of their HPA axis. This should ideally be with an insulin hypoglycemia test, although if this is contraindicated, an alternative test such as the overnight metyrapone test could be considered. These recommendations are summarized in Fig. 4Go.



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  		FIG. 4. Algorithm for evaluation of HPA axis after pituitary surgery.

 
Early corticotropin testing at 1 wk after surgery may be unreliable (5, 8), because after sudden ACTH depletion at surgery, insufficient time will have elapsed to allow adrenal atrophy to occur. Therefore, potentially normal responses to exogenous ACTH may be obtained in hypoadrenal patients. We have previously reported this phenomenon (5), and the present study confirms this with subject E demonstrating a normal response to standard-dose corticotropin at 1 wk and subsequent subnormal responses to all tests at 4–6 wk after surgery.

It has been claimed that the use of a lower dose of corticotropin improves the sensitivity of the corticotropin test (4, 10), although any potential advantages remain controversial (7). Taking the insulin hypoglycemia test as the gold standard, in our study, the 4- to 6-wk low-dose corticotropin test had a sensitivity of 81.8% and specificity of 86.7% to detect hypocortisolism. The 30-min cortisol response to low-dose corticotropin at 4–6 wk correlated with the peak cortisol response to insulin-induced hypoglycemia, although this conceals individual discrepancies (Fig. 1Go). However, the clinical consequence, if any, of a subnormal low-dose corticotropin response in a patient with a normal response to hypoglycemia remains unclear. In our series, the low-dose corticotropin test did not give any additional information that influenced clinical decision making, either at 1 wk after surgery as we previously reported (5) or at 4–6 wk after surgery. Therefore, we do not believe its further use in this setting is warranted.

In this study, the standard-dose corticotropin test had a sensitivity of 81.8% and a specificity of 100% to detect hypocortisolism 4–6 wk after pituitary surgery. Despite a correlation between the 30-min cortisol response to standard-dose corticotropin and the peak cortisol response to insulin-induced hypoglycemia (Fig. 2Go), discrepancies exist between the tests in the region around the lower cutoff values. It is of vital importance that, in patients in whom secondary adrenal insufficiency may be present, the correct decision regarding corticosteroid replacement is made. Our results confirm, therefore, that the standard-dose corticotropin test at 6 wk after surgery is accurate in identifying those patients both with moderate to severe secondary adrenal insufficiency and also those with adequate HPA axis function. In those patients with milder ACTH deficiency, concern remains that potentially serious adrenal insufficiency is masked by a normal cortisol response to corticotropin.

In an attempt to improve concordance between the standard-dose corticotropin test and the insulin hypoglycemia test, various lower cutoff levels for the standard-dose corticotropin test have been proposed (9, 10). However, because of uncertainty with regard to the cortisol response in the context of partial ACTH deficiency, it would seem more appropriate to view a borderline 30-min cortisol response to corticotropin 4–6 wk after surgery in the region close to the lower cutoff level as unreliable and to proceed to further assessment. Subjects therefore with a 30-min serum cortisol between 350 and 650 nmol/liter (12.7–23.6 µg/dl) require further assessment. It should be noted that these responses to standard-dose corticotropin are threshold values to assess HPA axis activity after pituitary surgery and thus are not relevant to the establishment of normal cortisol responses in control subjects.

In summary, based on a homogeneous cohort of patients, we have established guidelines for determining the adequacy of the HPA axis after surgery, allowing appropriate decisions to be made regarding glucocorticoid replacement therapy.


   Acknowledgments
 
We acknowledge the assistance of Sisters Reta Humphries and Delene Saunderson and the nursing staff of the Regional Endocrinology and Diabetes Centre in the care of the patients and performance of studies.


   Footnotes
 
During the course of the study, C.H.C. was in receipt of a Royal Victoria Hospital Belfast Research Fellowship.

Abbreviation: HPA, Hypothalamic-pituitary-adrenal.

Received September 9, 2003.

Accepted January 13, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Inder WJ, Hunt PJ 2002 Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab 87:2745–2750[Abstract/Free Full Text]
  2. Plumpton FS, Besser GM 1969 The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 56:216–219[Medline]
  3. Lindholm J, Kehlet H 1987 Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 26:53–59[Medline]
  4. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M 1991 Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 72:773–778[Abstract]
  5. Courtney CH, McAllister AS, McCance DR, Bell PM, Hadden DR, Leslie H, Sheridan B, Atkinson AB 2000 Comparison of one week 0900h serum cortisol, low and standard dose Synacthen tests with a 4 to 6 week insulin hypoglycemia test after pituitary surgery in assessing HPA axis. Clin Endocrinol (Oxf) 53:431–436[CrossRef][Medline]
  6. Ammari F, Issa BG, Millward E, Scanlon MF 1996 A comparison between short ACTH and insulin stress tests for assessing hypothalamo-pituitary-adrenal function. Clin Endocrinol (Oxf) 44:73–476[CrossRef][Medline]
  7. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oeklers W 1998 Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 83:1558–1562[Abstract/Free Full Text]
  8. Dökmetas HS, Çolak R, Kelestimur F, Selçuklu A, Ünlühizarci K, Bayram F 2000 A comparison between the 1-µg adrenocorticotropin (ACTH) test, the short ACTH (250 µg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. J Clin Endocrinol Metab 85:3713–3719[Abstract/Free Full Text]
  9. Hurel SJ, Thompson CJ, Watson MJ, Harris MM, Baylis PH, Kendall-Taylor P 1996 The short Synacthen and insulin stress test in the assessment of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 44:141–146[CrossRef][Medline]
  10. Abdu TAM, Elhadd TA, Neary R, Clayton RN 1999 Comparison of the low dose short Synacthen test (1 µg), the conventional dose short Synacthen test (250 µg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 84:838–843[Abstract/Free Full Text]
  11. Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Torpy DJ, Jackson RV 2001 Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests. Clin Endocrinol (Oxf) 55:625–633[CrossRef][Medline]
  12. Suliman AM, Smith TP, Lahib M, Fiad TM, McKenna TJ 2002 The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol 56:533–539[CrossRef][Medline]
  13. Danowski TS, Hofmann K, Weignad FA, Sunder JH 1968 Steroid responses to ACTH-like polypeptides. J Clin Endocrinol Metab 28:1120–1126[Medline]



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