Endocrinology and Metabolism

Original Articles

Diagnostic Value of 1microgram Rapid ACTH Stimulation Test According to the Timing of Sampling of Serum Cortisol in Patients with Suspected Central Adrenal Insufficiency.: Sang Wan Kim, Young Min Cho, Do Joon Park, Chan Soo Shin, Kyung Soo Park, Seong Yeon Kim, Bo Youn Cho, Hong Kyu Lee; J Korean Endocr Soc. 2004;19(1):33-41. Published online February 1, 2004

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Abstract PDF: BACKGROUND
Traditional testing of the hypothalamic-pituitary-adrenal axis function has essentially relied upon the insulin tolerance test or the metyrapone test(both tests are not only uncomfortable, but are also dangerous). The standard ACTH stimulation test uses an extremely supra-physiologic amount(250f microgram) of ACTH to evaluate a physiological response, which may result in a false normal response. The 1microgram rapid ACTH stimulation test is more physiological and more sensitive than the standard test, but there exist much controversy about when the serum cortisol should be measured or what the most appropriate cut-off point is for normality or whether the 1microgram ACTH commercial solution is needed. The aims of this study were to investigate 1) whether 1microgram of ACTH is an appropriate amount to stimulate the adrenal gland of patients that have suspected central adrenal insufficiency compared with insulin tolerance test(ITT) and 2) the diagnostic value of the 1microgram rapid ACTH stimulation test according to timing of sampling of serum cortisol. METHODS: In order to evaluate the dose-response relationship between ACTH and cortisol, we performed the ITT in 77 patients with suspected central adrenal insufficiency with serial measurements of serum cortisol and plasma ACTH. We drew the blood samples in 10 min intervals between 10 and 60 min after the administration of 1microgram ACTH in 39 patients with central adrenal insufficiency and in 38 pituitary control patients with pituitary. ITT was used to confirm the diseases for the patients of central adrenal insufficiency, but for pituitary control patients, the ITT indicated normality in the patients. Also, all subjects underwent the 250microgram rapid ACTH stimulation test, and we compared the diagnostic value of the 1microgram ACTH stimulation test with the 250microgram test. RESULTS: 1) The plasma ACTH level after the 1microgram ACTH stimulation test, even if it was be assumed as approximately 300pg/mL, was expected to be sufficient enough to stimulate the adrenal cortex normally(serum cortisol levels >18microgram/dL) compared to the plasma ACTH level in the ITT. 2) The sensitivity and specificity of the 1microgram rapid ACTH stimulation test was highest with 92.3% and 84.2%, respectively, when serum cortisol levels were measured at 20, 30, and 40 min after the ACTH injection. The 1microgram rapid ACTH stimulation test was more sensitive than the 250microgram ACTH test(sensitivity: 92.3%, specificity: 71.8%). CONCLUSION: The 1microgram rapid ACTH stimulation test was more sensitive test in patients with suspected central adrenal insufficiency, and blood samples for cortisol levels should be drawn at 20, 30, and 40 min after ACTH administration.

Usefullness of Urinary Free Cortisol Measurement in Diagnosis of Iatrogenic Cushing Syndrome.: Yong Hyun Kim, Sang Jin Kim, Dong Seop Choi; J Korean Endocr Soc. 2000;15(2):162-169. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Although insulin induced hypoglycemia test is a standard diagnostic method in assessment of hypothalamo-pituitary-adrenal axis, rapid ACTH stimulation test using 250microgram has been used as a first line diagnostic test especially in secondary adrenal insufficiency due to iatrogenic Cushing syndrome because it is easy and safe. However, it was suggested that a maximal cortisol response can be achieved with a much lower ACTH dose and 1microgram ACTH enhances the sensitivity without decreasing specificity of test. Also recently, there was a report that midnight to morning urine cortisol increment is more accurate, noninvasive method can be used for measurement of hypothalmo-pituitary-adrenal axis. In this study, we compared the 1microgram ACTH stimulation test with midnight to morning urinary free cortisol increment in secondary adrenal insufficiency due to iatrogenic Cushing syndrome to study the agreement of two test and accuracy of increment of urinary free cortisol in diagnosis of adrenal insufficiency. METHODS: Double voided urine sample were collected at midnight and 8 A.M. in 12 patients who have Cushing-like feature and history of taking glucocorticoids and in 12 normal controls. Urinary free cortisol was measured and cortisol increment was defined as the morning urine free cortisol minus the midnight urine free cortisol. The 1microgram ACTH stimulation test was performed in 12 iatrogenic Cushing syndrome patients at the same day and compard with the result of cortisol increment. RESULTS: Using the results of 12 controls, normal urine free cortisol increment was defined as greater than 165.5nmol/L(6.0microgram/dL). Subnormal cortisol response in 1microgram ACTH stimulation test was noted in 8 out of 12 patients group and urinary free cortisol increment was not observed in 7 out of 8 subnormal response group. Normal cortisol response in 1microgram ACTH stimulation test was noted in 4 out of 12 patients group and urinary free cortisol increment was observed in 3 out of 4 normal response group. So 83% of concordance rate between 1microgram ACTH stimulation test and urine free cortisol increment was recorded. CONCLUSION: Urinary free cortisol increment has high concordance rate with 1microgram ACTH stimulation test and simple, easy test in diagnosing secondary adrenal insufficiency due to iatrogenic Cushing syndrome. Further study including more patients will be helpful to know the adequacy and reliability of test in evaluation of hypothalamo-pituitary-adrenal axis.

The Effect of Low Dose and High Dose ACTH in the Evaluation of Adrenal Function.: Hyung Joon Yoo, Sung Hee Ihm, Sung Woo Park, Jae Hwan Jee, Hyun Kyu Kim, Doo Man Kim, Jae Myoung Yoo, Moon Ki Choi; J Korean Endocr Soc. 1998;13(4):580-589. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Pharmacological ACTH test provide information only about the ability of the adrenal gland to respond to unusual stimuli and may not reflect the daily cortisol secretion. There were some controversies in the diagnosis of mild adrenal insufficiency by using a pharmacological dose of ACTH. The purpose of the present study was to assess and compare the effect of low dose 1 pg ACTH and high dose 249 pg ACTH in the evaluation of adrenal function. The intravenous injection of a pharmacological dose(250 pg) of ACTH has been used as a standard test in the initial assessment of adrenal function. So we low dose ACTH to evaluate the adrenal function and compare the result of high dose ACTH. METHOD: Basal serum cortisol sampling was done at 2:00 p.m.. And after 1 pg ACTH iv bolus injection, cortisol sampling was done at 20, 30, 45 and 60 min respectively. On the next day same procedure was repeated at same time, but 249 mg ACTH was given instead of the low dose. Normal adrenal function was diagnosed with the criteria of stimulated serum cortisol concentration over 20 mg/dL. Total 65 patients took part in this study. Three hypopituitarism patients and one Addisons disease were included. Sixty-one patients had the history of glucocorticoid ingestion or had physical findings of cushingoid features with symptoms suggest the adrenal insufficiency. RESULTS: Sixteen patients showed normal response to both low dose and high dose ACTH. Thirty-six patients were not stimulated to both low dose and high dose ACTH. The remaining thirteen patients revealed normal response to high dose ACTH, but not to low dose ACTH. CONCLUSION: It appears that low dose ACTH stimulation test is more sensitive and specific than high dose ACTH and is capable of revealing mild adrenal insufficiency.

The Diagnostic Value of a Low Dose (1ug) Rapid ACTH Stimulation Test to Assess the Adrenocortical Function.: In Kyung Jung, Jae Seok Jeon, Young Joo Park, Chan Soo Shin, Kyoung Soo Park, Seong Yeon Kim, Hong Kyu Lee, Hee Jin Kim, Jae Hyeon Kim; J Korean Endocr Soc. 1997;12(3):433-442. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Insulin induced hypoglycemia has been used to assess the adrenocortical function, but may be hazardous. The standard rapid ACTH stimulation test has been advocated as a substitute but is sometimes insensitive. In this study, low dose (1ug) rapid ACTH stimulation test was compared to insulin induced hypoglycemia and standard dose (250ug) rapid ACTH stimulation. METHODS: 27 patients (14 men and 13 women) with pituitary disease and definite adrenocortical dysfunction (14 patients were confirmed by insulin induced hypoglycemia) and 23 controls (pituitary control: 3 men and 7 women, confirmed by insulin induced hypoglycemia, normal control: 8 men and 5 women) were studied. All subjects underwent rapid ACTH stimulation test with 2 different level of stimulation (1 and 250ug). Serum cortisol levels were measured at 0, 30 and 60 min after each dose of ACTH injection. A normal response was defined as a peak cortisol value of 497nrnol/L (18ug/dL) or above, RESULTS: During rapid ACTH stimulation study in controls, the peak serum cortisol level was significantly lower (690+-25lnmol/L (25.0+-9.1ug/dL) vs. 933+-257nmol/L (33.8+-9.3ug/dL); p< 0.01) and the peak appeared earlier (30min. vs. 60min) after the administration of low dose ACTH than after standard dose. However, the serum cortisol level at 30min was not different. In patient group, each serum cortisol level at 30min and 60min had no difference between low and standard dose (p>0.1). None of these 27 patients showed normal response to low dose stimulation, but 2 of 27 did to standard dose. In controls, 19 of 23 showed normal response to low dose, and all of 23 did to standard dose (sensitivity 100% vs 92.5%, specificity 82.5% vs 100%). The results of low and high dose stimulation test agreed with those of insulin induced hypoglycemia (Kendalls g= 0.50 vs 0.92, p<0.01 vs 0.001). CONCLUSIONS: The results of a low dose (1ug) rapid ACTH stimulation test showed good correlation with those of the standard dose (250ug) rapid ACTH stimulation test and insulin induced hypoglycemia. Thus it may be used in screening for the diagnosis of adrenal insufficiency.

The Role of Low-dose ACTH Stimulation Test in the Diagnosis of Adrenal Insufficiency.: Chul Hee Kim, Ghi Su Kim, Hong Kyu Kim, Joong Yeol Park, Young Kee Shong, Ki Up Lee, Il Min Ahn, Sung Kwan Hong; J Korean Endocr Soc. 1997;12(2):222-229. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Rapid adrenocorticotropin (ACTH) stimulation test using 250ug of ACTH (1-24) has been used as a standard test in the initial assessment of adrenal function. However, it has recently been suggested that a rnaximal cortisol response can be achieved with a much lower ACTH dose, and reducing the dose might further enhance the sensitivity of the test in the detection of mild adrenal insufficiency. This study was performed to evaluate the role of low-dose (lug) ACTH stimulation test in the assessment of adrenal function and the diagnosis of subtle adrenal insufficiency. METHODS: Twenty-two subjects with suspected adrenal insufficiency due to long-term corticosteroid use were included in this study. The correlations between clinical features and the serum cortisol responses to low dose (lug) and high dose (250 ug) ACTH stimulation were evaluated. RESULTS: In high dose test, 10 (67%) out of 15 subjects with clinical features of adrenal insufficiency showed decreased serum cortisol response (peak cortisol level <18 ug/dL), but 5 (33%) subjects showed normal response (peak cortisol level > 18ug/dL). On the other hand, 14 (93%) subjects with clinical features of adrenal insufficiency showed decreased serum cortisol response in low dose test, while only one showed normal response. In 7 subjects without clinical features of adrenal insufficiency, 5 subject (71%) showed normal response, and 2 subjects (29%) showed decreased response in both low and high dose tests. CONCLUSION: These results suggest that the 1-ug low dose ACTH stimulation test might be more sensitive than conventional 250-ug test in the detection of mild adrenal insufficiency. Further studies are needed to determine the optimal dose of ACTH and the criteria for normal response to ACTH stimulation.

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