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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2350-2354
Copyright © 1998 by The Endocrine Society

Original Studies

Evaluation of the Integrity of the Hypothalamic-Pituitary-Adrenal Axis by Insulin Hypoglycemia Test1

Erdinc Erturk2, Craig A. Jaffe and Ariel L. Barkan

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., Division of Endocrinology and Metabolism, 3920 Taubman, Box 0354, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 µg/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 µg/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 µg/dL or below 4 µg/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 µg/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia is still the best indicator of the integrity of the response of the HPA axis to stress.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
COMPLETE or partial ACTH deficiency due to hypothalamic-pituitary-adrenal (HPA) dysfunction is often asymptomatic in nonstressed individuals. However, during stressful stimuli (trauma, infection, surgery, etc.) failure of the HPA axis to mount a biologically sufficient cortisol response may lead to deleterious consequences and endanger survival. Therefore, testing the ability of the HPA axis to respond appropriately to stress is an important therapeutic consideration in patients who have diseases involving the hypothalamic- pituitary unit or who have received long term pharmacological glucocorticoid therapy. The insulin-induced hypoglycemia test (IHT) is widely regarded as a "gold standard" dynamic test for this purpose (1, 2, 3, 4, 5). Whereas most studies agree that an absolute increase in plasma cortisol above 18 µg/dL constitutes the only valid criterion in establishing the normalcy of the HPA axis, some sources still regard a rise in cortisol to 7 µg/dL over the baseline value or a doubling of the baseline cortisol concentration as acceptable criteria for integrity of the HPA axis (1). The performance of an IHT, however, is relatively complex and is potentially unpleasant to the patient. As an alternative to the provocative testing of the HPA axis, several studies suggest that an early morning baseline cortisol level above 10 µg/dL reliably predicts normalcy of the axis (6, 7, 8, 9, 10). We have analyzed data from 193 IHTs in patients with suspected ACTH deficiency in an attempt to quantify the relationships between ACTH and cortisol dynamics and validate the criteria for a normal IHT response.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Data from 231 patients who had been subjected to an adequately performed IHT at the Endocrine Testing Facility Unit between 1990–1997 were reviewed. Subjects with glucose nadir above 45 mg/dL (n = 12), patients with Cushing’s disease (n = 17), and those who mistakenly took their usual dose of glucocorticoids on the morning of the study (n = 9) were excluded from the analysis. The study group consisted of 120 women and 73 men who were 43.4 ± 14.1 (mean ± SD) yr old (range, 15–82 yr). Known or suspected organic hypothalamic-pituitary diseases (tumors, cysts, granulomas, radiation, etc.) were present in 189 patients, and 4 patients were recovering from long term pharmacological glucocorticoid therapy for autoimmune diseases or asthma. Thirty-seven patients took oral hydrocortisone (20–35 mg/24 h), and the last dose was taken 16–24 h before the test.

The IHT was performed in the morning between 0800–0900 h after an overnight fast. The patients remained recumbent during the test. Hypoglycemia was induced by a bolus injection of 0.15 U/kg BW human regular insulin through an indwelling cannula that had been inserted into a forearm vein 30 min previously. If sufficient hypoglycemia (<45 mg/dL) was not achieved 30 min after injection, an additional dose of insulin was given, and the timing of blood sampling was rescheduled appropriately. Twenty-eight subjects needed a second and 10 subjects needed a third dose to become hypoglycemic. All patients exhibited clinical symptoms and signs of hypoglycemia: perspiration, tachycardia, mental confusion, and/or sense of hunger. These symptoms were allowed to persist for 5–10 min, after which oral or iv glucose was given to abort hypoglycemia. Blood samples were taken before (time zero) and 30, 60, and 90 min after insulin injection. Blood samples for plasma ACTH assay were collected in ice-chilled siliconized glass tubes with ethylenediamine tetraacetate and immediately centrifuged at 4 C, and the plasma was frozen and stored at -20 C until it was assayed.

All assays were performed by the University of Michigan Center Pathology Laboratories. Blood glucose levels were measured by the glucose oxidase method at 0, 30, and 60 min. Cortisol was determined by a chemiluminescence assay using commercial kits (Chiron Diagnostics Corp., East Walpole, MA) at 0, 60, and 90 min. ACTH was determined by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA) at 0, 30, 60, and 90 min.

All results are expressed as the mean ± SE. Data were analyzed using Student’s t test for paired or nonpaired data as appropriate. Correlation coefficients were calculated using actual or logarithmically transformed data as described in Results. Bonferroni’s correction was used as appropriate when multiple comparisons were made. Statistical significance was assumed at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All subjects tolerated the testing procedure well. Using a maximum stimulated plasma cortisol level above 18 µg/dL during the IHT as the criterion for a sufficiently functioning HPA axis, 133 of the 193 subjects were classified as having normal responses. Mean (±SE) values for plasma glucose, cortisol, and ACTH are shown in Fig. 1Go. In subjects with normal HPA responses (n = 133), plasma ACTH increased from 29.2 ± 1.4 pg/mL to a maximum of 134.2 ± 12 pg/mL at 30 min (P < 0.0001, baseline vs. maximum). In HPA-deficient subjects (n = 60), plasma ACTH levels rose from 23.6 ± 1.9 to 48.2 ± 6.7 pg/mL at 30 min (P < 0.0001). The peak ACTH values were significantly (P < 0.0001) different in the two groups.



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  		Figure 1. Plasma glucose, cortisol, and ACTH responses to IHT in subjects with ({circ}; n = 133) and without (•; n = 60) a maximal cortisol response above 18 µg/dL. *, P < 0.0001. At some points the SE bars are smaller than the symbols.

 
Plasma cortisol levels of normal responders rose from 13.7 ± 0.4 µg/dL to a maximum of 23.4 ± 0.4 µg/dL at 60 min (P < 0.0001). In HPA-deficient subjects, cortisol levels rose from 8.0 ± 0.7 µg/dL to a maximum of 10.9 ± 0.7 µg/dL at 60 min (P < 0.0001). Both baseline (P < 0.0001) and maximal (P < 0.0001) cortisol levels were significantly higher in the normal responders. Blood glucose nadir concentrations were similar between the two groups. There were no correlations between the degree of hypoglycemia and the magnitude of either the plasma cortisol or the ACTH rises. This was the case for both normal and abnormal cortisol responses (data not shown).

A comparison between the peak ACTH and the peak cortisol responses in the entire set of subjects is shown in the upper panel of Fig. 2Go. Because cortisol peak levels reached a plateau as related to ACTH peak levels, ACTH data were logarithmically transformed before calculation of a correlation coefficient (r = 0.61; P < 0.0001). There was a similar relationship between the logarithm of the incremental rise (peak minus basal value) in ACTH and cortisol levels (r = 0.65; P < 0.0001). To better define the ACTH peak concentrations above which plasma cortisol reached a plateau, the data were grouped accordingly to the peak ACTH values (0–10, 11–25, 26–50, 51–100, 101–200, 201–300, 301–400, and >400 pg/mL). The results are shown in the lower panel of Fig. 2Go. A plateau of plasma cortisol (~22 µg/dL) was achieved at peak ACTH concentrations above 75 pg/mL.



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  		Figure 2. Relationship between maximal ACTH and maximal cortisol concentrations during IHT.

 
There was a strong linear correlation between the basal plasma cortisol level and the maximum cortisol level after hypoglycemia (Fig. 3Go; r = 0.63; P < 0.0001). A scatter diagram of basal cortisol concentrations in normal and HPA-deficient subjects is shown in Fig. 4Go. Basal cortisol levels ranged between 4.1–35.0 µg/dL in normal subjects and between 1.0–16.5 µg/dL in HPA-deficient subjects. Sensitivity and specificity rates of different levels of basal morning plasma cortisol are shown in Fig. 5Go. A true positive test was defined as baseline serum cortisol below the cut-off in subjects who had inadequate response during IHT. Using a baseline cortisol value of 10 µg/dL as a predictor of subsequent normalcy of cortisol responsiveness to hypoglycemia, 38% of HPA-deficient subjects would be classified as normal, and 23% of normal subjects would be classified as HPA deficient. Using a criterion of a cortisol rise equal to or more than 7 µg/dL above the baseline, 24% of HPA-deficient subjects would be classified as normal, and 27% of normal subjects would be classified as HPA deficient. Using a criterion of doubling the baseline cortisol, 23% of HPA-deficient subjects would be classified as normal, and 59% of normal subjects would be classified as HPA deficient. Using both criteria (7 µg/dL above the baseline and doubling the basal cortisol concentration), 31% of HPA-deficient subjects would be classified as normal, and 27% of normal subjects would be classified as HPA deficient.



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  		Figure 3. Correlation between basal and maximal cortisol levels in 193 subjects (r = 0.63; P < 0.0001).

 


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  		Figure 4. The distribution of basal cortisol levels according to the maximal cortisol response (above or below 18 µg/dL) during IHT.

 


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  		Figure 5. Predictive power of different basal cortisol concentrations in assessing the dynamic integrity of the HPA axis.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The IHT is a direct assessment of pituitary and adrenal hormone reserve. Despite the anecdotal reports of dangerous reactions, very few serious untoward effects were encountered in large series of patients (1). Although all of our patients became briefly symptomatic during hypoglycemia, none experienced angina, seizure, or cardiac arrhythmia.

The absolute value of glucose nadir, and not the decrement or rate of decline, determines the counterregulatory hormone response (1, 2, 11). Streeten et al. (2) have shown that plasma cortisol concentrations do not increase until the plasma glucose concentration has fallen below 70 mg/dL and are maximally stimulated at a plasma glucose level of 45 mg/dL or less. Based on these data, we used a glucose nadir below 45 mg/dL as the criterion for sufficient hypoglycemia. Consistent with data demonstrating maximum cortical stimulation with glucose of 45 mg/dL, we did not find a significant correlation between the glucose nadir in the range below 45 mg/dL and maximal cortisol or ACTH responses in subjects with a normal HPA axis. Previous studies have demonstrated cortisol values of 18 µg/dL and above in healthy subjects undergoing a severe stressful procedure (12). Thus, we used a maximal posthypoglycemia cortisol concentration of 18 µg/dL as a cut-off for defining normalcy of the entire HPA axis. Although unquestionably arbitrary, this value is the lowest limit of the normal response to stress, and plasma cortisol concentrations may be as high as 260 µg/dL shortly before death (13).

The secretory response of ACTH (range, 5.0–755 pg/mL) showed a wide variation, in contrast to that of cortisol (range, 1.0–53.1 µg/dL), which was more uniform. Maximum cortisol levels and increments in cortisol above the basal value were strongly correlated with the logarithms of maximum and increment in ACTH, respectively. Plasma cortisol increased steeply as mean ACTH levels rose from undetectable to approximately 75–100 pg/mL and then reached a plateau at higher ACTH concentrations. Oelkers et al. (14) found a very similar dose-response relation using exogenous ACTH. The finding that plasma cortisol values do not increase further as endogenous ACTH values exceed 75 pg/mL is consistent with our data (15, 16, 17, 18, 19). Other studies have not been able to demonstrate a correlation between endogenous cortisol and ACTH levels in normal subjects (11, 20, 21, 22). This discrepancy may be explained by the small number of subjects studied and by assuming a linear relationship between cortisol and ACTH.

In subjects with an intact HPA axis, IHT increased plasma ACTH to a peak of 134 ± 12 pg/mL. This rise is similar to that of plasma ACTH during stress in normal subjects, which infrequently reaches levels above 150 pg/mL (12, 22). This together with the fact that plasma cortisol reaches its plateau at a plasma ACTH level above 75 pg/mL validated IHT as an appropriate and physiologically relevant test to predict the adequacy of cortisol responses during severe stress of another nature, such as surgery, trauma, or shock. In contrast, in the conventional 250-µg ACTH stimulation test, plasma ACTH levels rise above 4500 pg/mL (23). Supraphysiological ACTH doses may cause falsely normal cortisol responses in mild forms of secondary adrenal insufficiency when the adrenal cortex is not yet atrophic (23, 25, 26, 27). The low dose (1 µg, iv) of ACTH may be adequate to provide physiological adrenocortical stimulation (10, 17, 24, 28, 29).

In an attempt to obviate the need for a dynamic testing of HPA axis, various levels of early morning cortisol have been proposed to predict the integrity of the HPA axis. Hagg et al. (6) found that basal morning plasma cortisol levels above 10.9 µg/dL correctly identified patients with normal responses to hypoglycemia with a calculated sensitivity of 67% and a specificity of 94%. Similarly, Lange et al. (7) found that a basal cortisol level below 9.4 µg/dL has 96% sensitivity and 64% specificity as a predictor of abnormal cortisol responses to IHT. Other researchers also suggested that the basal cortisol level was a good predictor of HPA axis function (9, 10).

Similar to previous studies, the sensitivity and specificity values of 62% and 77% for baseline plasma cortisol level of 10 µg/dL were found in this group. Despite seemingly acceptable numerical values, the consequences of using the cut-off of 10 µg/dL as an absolute predictive parameter might be clinically unacceptable. Thirty-eight percent of ACTH-deficient patients would not have received chronic glucocorticoid coverage and would have remained unprotected during intercurrent illnesses. Similarly, 23% of healthy individuals would have been unnecessarily administered chronic steroid replacement. Thus, the basal plasma cortisol level is not a reliable test to assess HPA axis function. Based on our sample, only plasma cortisol values above 17 µg/dL or below 4 µg/dL can serve as reliable predictors of normalcy or dysfunction of the HPA axis, respectively. In these patients, further dynamic tests may be safely omitted. Also, because of the wide variability of maximal ACTH concentrations and the overlaps between the two groups, plasma ACTH concentrations cannot be used as a criterion and need not be measured in clinical practice. Derangement of HPA function does not necessarily affect the baseline activity and stress responses to the same extent, as evidenced by a wide variability of baseline/maximal ACTH and cortisol concentrations in this study. When HPA dysfunction is suspected on clinical grounds, performing IHT allows clear discrimination between normal and ACTH-deficient subjects. Our data also demonstrate that using criteria other than absolute cortisol maximum (such as absolute increment or function of baseline) is associated with high false positive and false negative rates.

In conclusion, our data show that IHT produces plasma ACTH values comparable to severe endogenous stress and is a physiologically relevant test to assess the integrity of the HPA axis. The relationship between ACTH and cortisol is log-linear, and a maximal adrenal response is achieved by ACTH concentrations of approximately 75 pg/mL. The early morning cortisol level has only limited value in predicting the integrity of the HPA axis. Finally, the use of an incremental rise in plasma cortisol as a criterion for HPA normalcy should be abolished.


   Footnotes
 
1 This work was supported by NIH Grant RO1–38449 (to A.L.B.). Back

2 On leave from the Department of Internal Medicine, Division of Endocrinology, Uludag University School of Medicine, Bursa 16059, Turkey. Back

Received February 6, 1998.

Revised April 2, 1998.

Accepted April 10, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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