Original Article
The Effect of Long-Term Glucocorticoid Therapy on Pituitary–Adrenal Responses to Exogenous Corticotropin-Releasing Hormone
N Engl J Med 1992; 326:226-230January 23, 1992
- Abstract
- Abstract
Background.
Suppression of pituitary--adrenal function is a well-known consequence of glucocorticoid therapy, manifested principally by decreased corticotropin secretion. To determine the degree of suppression of pituitary—adrenal function in patients treated with different doses of synthetic glucocorticoid medication for different periods, we measured the pituitary—adrenal response to the administration of exogenous human corticotropin-releasing hormone (CRH).
Methods.
We studied 279 patients who were receiving daily therapy with 5 to 30 mg of prednisone or its equivalent to treat various chronic diseases, principally collagen vascular disorders, and 50 normal subjects. Therapy ranged in duration from 1 week to 15 years. Stimulation tests using 100 μg of CRH as a bolus injection were performed in the morning, 24 hours after the most recent dose of glucocorticoids. In 61 patients an insulin hypoglycemia test, thought by many to be the reference standard, was also performed to assess the reliability of the CRH results.
Results.
After the administration of CRH, 43 patients had no increase in plasma concentrations of corticotropin and cortisol. The response was blunted in 133 patients and normal in 103. There was poor correlation between the plasma cortisol response after the administration of CRH and the dose or duration of therapy or the basal plasma cortisol concentration. Although plasma cortisol concentrations after stimulation with CRH were generally lower than those after insulin administration, there was a significant correlation between the plasma cortisol responses to the two stimuli (r = 0.82).
Conclusions.
Pituitary—adrenal function in patients treated with synthetic glucocorticoids cannot be reliably estimated from the dose of glucocorticoid, the duration of therapy, or the basal plasma cortisol concentration. In such patients, testing with CRH is nearly as useful as insulin hypoglycemia testing in the assessment of pituitary—adrenal function. (N Engl J Med 1992,326: 226–30.)
Media in This Article
Figure 1
Mean Plasma Concentrations of Corticotropin and Cortisol before and after the Administration of CRH in 50 Normal Subjects and 279 Patients Receiving Glucocorticoid Therapy.Figure 2
Mean Plasma Cortisol Concentrations in 61 Patients Receiving Glucocorticoid Therapy before and after the Administration of Insulin or CRH.Article Activity
- Article
SYNTHETIC glucocorticoids are commonly used drugs.1 One of their major limitations in long-term use is suppression of pituitary—adrenal function.2 , 3 The degree of such suppression is believed to depend on many factors, such as the duration and dosage of treatment, and it is not predictable in individual patients.2 , 4 , 5 The presence of suppression is neither ruled out by a normal random plasma Cortisol value nor proved by a subnormal value.6 Therefore, stimulation tests are usually required to identify those patients with suppressed production of endogenous corticotropin (ACTH) and cortisol. Of these tests, the insulin hypoglycemia test is considered by many to be the reference standard,4 , 7 although corticotropin-releasing hormone (CRH) is the most important physiologic stimulator of the synthesis and secretion of corticotropin.8 , 9
We undertook this study to examine pituitary—adrenal function basally and in response to the administration of human CRH in a large group of patients receiving daily synthetic glucocorticoid therapy. To test the reliability of the CRH stimulation test, we compared the plasma corticotropin and cortisol responses to both insulin hypoglycemia and CRH in some of these patients.
Methods
Subjects
CRH tests were performed in 50 normal subjects (21 women and 29 men; mean [±SD] age, 32±4 years) and 279 patients (143 women and 136 men; mean age, 48±15 years) who were receiving daily glucocorticoid therapy for various reasons (collagen vascular disorders, inflammatory bowel disease, chronic obstructive lung disease, or sarcoidosis) (Table 1Table 1
Selected Characteristics of the Study Subjects. ). Sixty-one of these patients (33 women and 28 men; mean age, 56±10 years) also underwent insulin hypoglycemia tests.The study patients were receiving prednisolone, methylprednisolone, or fluocortolone. The doses given are presented as prednisone equivalent doses (the doses equivalent to a 20-mg dose of hydrocortisone were 5 mg of prednisone, prednisolone, and fluocortolone and 4 mg of methylprednisolone10 11 12). The duration of glucocorticoid therapy in these patients ranged from 1 week to 15 years, and the daily doses were constant for at least 1 week before the study. Treatment was continued after the study in most of the patients.
The study was approved by the institutional review committee, and all subjects gave informed consent.
CRH Test
CRH tests were performed with a bolus intravenous injection of 100 μg of human CRH (Corticobiss, Bissendorf Peptide, Hannover, Germany). The tests were carried out between 8:00 and 9:00 a.m. after an overnight fast, 24 hours after the most recent dose of glucocorticoids. Blood was drawn for measurements of plasma corticotropin and cortisol 15 minutes before the administration of CRH, at the time of administration, and 15, 30, 60, 90, and 120 minutes afterward.
Insulin Hypoglycemia Test
Insulin hypoglycemia tests were performed with 0.15 IU of regular insulin (Actrapid HM, Novo Industries, Mainz, Germany) per kilogram of body weight, given intravenously. The stimulus was regarded as adequate if the blood glucose concentration decreased to less than 2.2 mmol per liter (40 mg per deciliter). These tests were performed two days after the CRH tests, between 8:00 and 9:00 a.m. after an overnight fast, 24 hours after the most recent dose of glucocorticoids. Blood was drawn for measurements of plasma corticotropin and cortisol 15 minutes before the administration of insulin, at the time of administration, and 15, 30, 60, 90, and 120 minutes afterward.
Hormone Assays
Plasma corticotropin was measured by immunoradiometric assay (Nichols Institute, Los Angeles). Plasma cortisol was measured by radioimmunoassay (Bio Mérieux, Nürtingen, Germany). The intraassay and interassay coefficients of variation were 5.2 percent and 10.8 percent for corticotropin and 4.4 percent and 6.8 percent for cortisol, respectively. The sensitivity of the assay for corticotro-pin was 0.3 pmol per liter, and that of the assay for cortisol was 3 nmol per liter. The basal plasma corticotropin and cortisol concentrations were calculated as the means of the values obtained 15 minutes before the administration of CRH or insulin and at the time of administration. To convert values for plasma cortisol concentrations from nanomoles per liter to micrograms per deciliter, multiply by 0.036.
Analysis of Data The plasma corticotropin and cortisol responses to CRH or insulin hypoglycemia were analyzed according to the guidelines proposed earlier for the interpretation of the responses to insulin hypoglycemia.4 , 13 A normal response was defined as a peak plasma cortisol concentration above 552 nmol per liter or a 1.5-fold increase in the plasma cortisol concentration, to a value of at least 276 nmol per liter. For basal plasma cortisol concentrations of 179 nmol per liter or less, a blunted response was defined as one in which the peak cortisol value was between 83 and 276 nmol per liter. For basal plasma cortisol concentrations above 179 nmol per liter, a response was defined as blunted if there was less than a 1.5-fold increase, unless the peak cortisol values exceeded 552 nmol per liter. No response was defined as basal and stimulated plasma cortisol concentrations below 83 nmol per liter.
When basal plasma cortisol concentrations were considered by themselves, values above 138 nmol per liter were defined as normal,14 values below 83 nmol per liter as decreased, and values between these thresholds as blunted.
We used SPSS/PC+ software (Chicago) and BMDP (1990) Statistical Software (Los Angeles) for the statistical analyses. The results are given as means ±SD unless otherwise noted. Pearson's correlation coefficient (r) was calculated with linear regression analysis. Statistical comparisons were made with Student's two-tailed group t-test (for comparisons between groups) or the two-tailed paired t-test (for comparisons in the same patient). Unifactorial analysis of variance was carried out with SPSS/PC+, including the a posteriori test of Scheffé to compare the individual CRH-test groups. We used polychotomous logistic regression (BMDP) and the chi-square method to establish the goodness of fit in the analysis of regression.
Results
CRH-Test Results in Normal Subjects
The mean plasma corticotropin concentrations increased from 5.4±3.8 pmol per liter to a maximum of 10.8±5.9 pmol per liter after the administration of CRH in the normal subjects. Their mean plasma cortisol concentrations increased from 333±101 nmol per liter to a maximum of 568±188 nmol per liter 60 minutes after CRH administration. The increase in levels of both hormones was statistically significant (P<0.001).
CRH-Test Results in Patients Receiving Glucocorticoid Therapy
The patients were divided into three groups according to their plasma cortisol responses to CRH. Forty-three patients had no increase in plasma cortisol after the administration of CRH (group 1), 133 patients had blunted responses (group 2), and 103 patients had normal responses (group 3).
In group 1, the basal plasma corticotropin concentration was 3.3±3.1 pmol per liter, and the peak value after the administration of CRH was 4.8±4.1 pmol per liter. The mean basal cortisol level was 30±10 nmol per liter, and the maximal level was 53±24 nmol per liter. In group 2, the mean plasma corticotropin concentration increased from 3.5±3.3 pmol per liter to 6.3±5.7 pmol per liter, whereas the mean plasma cortisol level increased from 218±125 nmol per liter to 296±111 nmol per liter. In group 3, the mean plasma corticotropin concentration increased from 4.9±4.0 pmol per liter to 9.4±6.3 pmol per liter, and the mean plasma cortisol level increased from 360±125 nmol per liter to 600±178 nmol per liter. The differences between the basal and peak plasma hormone concentrations in groups 2 and 3 were statistically significant (P<0.001) (Fig. 1Figure 1
Mean Plasma Concentrations of Corticotropin and Cortisol before and after the Administration of CRH in 50 Normal Subjects and 279 Patients Receiving Glucocorticoid Therapy.).As expected, the plasma corticotropin response to CRH preceded the plasma Cortisol response. The peak plasma corticotropin and cortisol values occurred 30 and 60 minutes, respectively, after the administration of CRH in groups 2 and 3. The plasma cortisol responses to CRH stimulation were similar in the 103 patients in group 3 and the 50 normal subjects.
With respect to basal plasma cortisol concentrations, 68 patients had decreased values, 24 patients had blunted values, and 187 patients had normal values. These results agreed with the results of the CRH test in 164 patients (59 percent). Of the 68 patients who had basal plasma cortisol values below 83 nmol per liter, 25 patients (37 percent) had blunted responses to CRH stimulation, but none had normal responses. Of the 24 patients with blunted basal responses, 3 had normal responses to CRH. Of the 187 patients who had normal basal plasma cortisol values, 87 (46 percent) had blunted responses to CRH. In summary, no patient with a basal plasma cortisol concentration below 83 nmol per liter had a normal response to CRH, but some had no responses and others blunted responses. Among the patients with basal plasma cortisol concentrations above 138 nmol per liter, nearly half had impaired pituitary—adrenal function.
Table 2Table 2
Relation between the Dosage of Glucocorticoid and the Plasma Cortisol Response to CRH. shows the number of patients who had normal, blunted, or no plasma cortisol responses to CRH according to the dosage of glucocorticoid, and Table 3Table 3
Relation between the Duration of Glucocorticoid Therapy and the Plasma Cortisol Response to CRH. shows the distribution according to the duration of therapy. Table 4Table 4
Relation between the Cumulative Dose of Glucocorticoid and the Plasma Cortisol Response to CRH. shows the relation between the cumulative doses of glucocorticoid medication and the responses to CRH. The distribution of responses in relation to the duration and dosage of therapy was skewed. After logarithmic transformation, we performed an analysis of variance comparing the dosage and duration of therapy in the three groups. Only the duration of therapy differed among groups at the 1 percent level of significance. An a posteriori test of Scheffé showed that group 2 (patients with blunted responses) and group 3 (those with normal responses) differed with respect to the duration of therapy.There was an inverse correlation between the dosage and duration of therapy and the plasma cortisol response to CRH. However, the chi-square measure for goodness of fit showed that the logistic regression did not fit the data well, suggesting an effect of unidentified factors. Analysis of the residuals confirmed the hypothesis that other unknown factors influence the response to the CRH test. There were numerous large residuals in all groups, and the distribution of the residuals was highly skewed in group 1 (patients with no response).
Results of CRH and Insulin Hypoglycemia Tests in Patients Receiving Glucocorticoid Therapy
Thirty-six patients receiving glucocorticoid therapy had normal plasma cortisol responses to insulin hypoglycemia. Their mean plasma corticotropin concentrations increased from 3.6±1.9 pmol per liter to 13.0±8.0 pmol per liter, and their mean plasma cortisol concentrations increased from 290±140 nmol per liter to 585±213 nmol per liter (P<0.001 for both). Thirty of these 36 patients had normal responses to CRH; their mean plasma corticotropin levels increased from 2.9±2.1 pmol per liter to 8.3±5.2 pmol per liter, and their mean plasma cortisol levels increased from 282±115 nmol per liter to 517±147 nmol per liter (Fig. 2Figure 2
Mean Plasma Cortisol Concentrations in 61 Patients Receiving Glucocorticoid Therapy before and after the Administration of Insulin or CRH.). In the other six patients, the mean plasma cortisol levels increased from 262±142 nmol per liter to only 364±137 nmol per liter.Twelve patients had blunted plasma cortisol responses to hypoglycemia. Their plasma corticotropin concentrations increased from 2.5±1.9 pmol per liter to 7.1±5.8 pmol per liter, and their plasma cortisol concentrations increased from 225±197 nmol per liter to 438±280 nmol per liter. Nine of these patients had blunted responses to CRH as well, with an increase in plasma cortisol levels of from 162±137 nmol per liter to 282±122 nmol per liter. Three patients had no response to CRH.
Thirteen patients had no cortisol response to either hypoglycemia or CRH.
The responses to the two stimuli were similar in 85 percent of the patients, and the correlation (r = 0.82) between plasma cortisol responses in the two tests was highly significant (P<0.001). The plasma corticotropin and cortisol responses to insulin hypoglycemia were more pronounced than those to CRH (P<0.001).
Discussion
Therapy with synthetic glucocorticoids results in an inhibition of pituitary—adrenal function. Pituitary—adrenal function in patients receiving this therapy can be assessed by considering the dose and duration of therapy and measurements of basal plasma cortisol concentrations.2 , 4 , 5 , 15 A single measurement of plasma cortisol does not permit a reliable appraisal of pituitary—adrenal function, however, since it may be normal only because of episodic secretion.6 Stimulation tests are therefore usually required to identify patients with suppressed endogenous cortisol production.4 , 7 Such suppression is due primarily to inhibition of the synthesis and secretion of corticotropin16 17 18 19 as a result of inhibited transcription of the corticotropin gene.17 , 20
Test methods that have a central effect, such as the insulin hypoglycemia test and the CRH test, are the only approaches sufficient to investigate this pituitary suppression.4 , 7 , 21 , 22 Stimulation tests with ovine or human CRH have been used to examine pituitary—adrenal function in various clinical disorders9 and in a limited number of patients receiving alternate-day or daily glucocorticoid therapy.23 24 25 In humans ovine CRH has prolonged action, probably as a result of its long plasma half-life. In contrast, human CRH causes shorter episodes of corticotropin and cortisol secretion in plasma, similar to the physiologic episodes of secretion of these hormones.26
In this study of the effects of human CRH in a large group of patients receiving glucocorticoid therapy and of the effects of insulin hypoglycemia in some of them, the peak plasma corticotropin and cortisol concentrations were higher after insulin hypoglycemia. Nevertheless, 85 percent of the test results were in agreement, and the correlation between the peak plasma cortisol responses to the two stimuli was significant. Only six patients who had normal responses to hypoglycemia had blunted responses to CRH, and three patients with blunted responses to hypoglycemia had no response to CRH. The good agreement between the two tests is all the more remarkable in that evaluation criteria based on the insulin hypoglycemia test were used for both tests, and it is known that the peak plasma corticotropin and cortisol responses after maximal CRH stimulation are not as high as those after hypoglycemia.27 , 28 The responses to hypoglycemia are greater because this condition activates not only endogenous CRH but also other stimuli of corticotropin secretion (e.g., vasopressin).29
The 279 patients were classified in groups according to whether their plasma cortisol responses to CRH were absent, blunted, or normal. These responses could be predicted by measuring the basal plasma cortisol concentration alone in only 59 percent of the patients. On the one hand, 37 percent of the 68 patients with decreased basal plasma cortisol concentrations had blunted responses to CRH. On the other hand, 46 percent of the 187 patients with normal basal plasma cortisol concentrations had blunted responses to CRH. According to the results of this study, the recent suggestion that basal plasma cortisol values can be used as an indicator of pituitary—adrenal function in patients receiving glucocorticoid therapy is not tenable.15 The daily dose of glucocorticoids, the duration of glucocorticoid administration, and the cumulative dose would be expected to be correlated with the degree of pituitary—adrenal function in treated patients. We found little correlation between these factors and the results of the CRH tests, however. The dose and duration of glucocorticoid therapy affect the results of the CRH test, but these measures are only some of the operative factors, and they do not allow a prediction of the response to CRH administration. We do not know what the other factors might be.
We conclude that pituitary—adrenal function in patients receiving synthetic glucocorticoids cannot be appraised adequately on the basis of the dose or duration of therapy alone. If the termination of therapy is planned, a stimulation test may be warranted so that impaired pituitary—adrenal function is not overlooked. Such impairment would have been missed in nearly half the patients in this study if the basal plasma cortisol values had been considered alone. However, pituitary—adrenal function may also be examined with the intention of identifying patients who have no impairment of pituitary—adrenal function despite long-term glucocorticoid therapy, since in such patients therapy could be discontinued rapidly. We think the CRH test is suitable for both purposes, and it is safer than the insulin hypoglycemia test.30
Source Information
From the Department of Endocrinology and Rheumatology, Heinrich Heine University Düsseldorf. Moorenstr. 5,4000 Düsseldorf. Germany, where reprint requests should be addressed to Dr. Sehlaghecke.
- References
References
1
Christy NP. Iatrogenic Cushing's syndrome. In: Christy NP, ed. The human adrenal cortex. New York: Harper & Row, 1971:395.
2
Melby
Web of Science | Medline3
Streck
CrossRef | Web of Science | Medline4
Harrison
CrossRef | Web of Science | Medline5
Livanou
CrossRef | Web of Science | Medline6
Wand
CrossRef | Medline7
Stewart
CrossRef | Web of Science | Medline8
Vale
CrossRef | Web of Science | Medline9
Taylor
Full Text | Web of Science | Medline10
Bolt 11
Axelrod
CrossRef | Web of Science | Medline12
Voigt 13
Streeten
CrossRef14
Becker KL. Endocrine drugs and values. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. Philadelphia: J.B. Lippincott, 1990:1740.
15
Hägg
CrossRef | Web of Science | Medline16
Carnes
CrossRef | Web of Science | Medline17
Jingami
CrossRef | Web of Science | Medline18
Keller-Wood
CrossRef | Web of Science | Medline19
McEven
Web of Science | Medline20
Eberwine
Web of Science | Medline21
Cunningham
CrossRef | Web of Science | Medline22
Borst
Full Text | Web of Science | Medline23
Watson
CrossRef | Web of Science | Medline24
Schürmeyer
CrossRef | Web of Science | Medline25
Hashimoto
CrossRef | Web of Science | Medline26
Schürmeyer
CrossRef | Web of Science | Medline27
Müller
CrossRef | Web of Science | Medline28
Orth
CrossRef | Web of Science | Medline29
Vale
CrossRef | Web of Science | Medline30
Nink
CrossRef | Medline
- Citing Articles (84)
Citing Articles
1
Simona E. Bianconi, Sandra K. Conley, Meg F. Keil, Ninet Sinaii, Kristina I. Rother, Forbes D. Porter, Constantine A. Stratakis. (2011) Adrenal function in Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics Part A 155:11, 2732-2738
CrossRef2
(2011) Präoperative Evaluation erwachsener Patienten vor elektiven, nichtkardiochirurgischen Eingriffen. Der Urologe 50:9, 1169-1184
CrossRef3
Hye-Suk Han, Young Kwang Shim, Jeong Eun Kim, Hyun-Jung Jeon, Sung-nam Lim, Tae-Keun Oh, Ki Hyeong Lee, Seung Taik Kim. (2011) A pilot study of adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients. Supportive Care in Cancer
CrossRef4
Kevin M. Schuster, Jana B.A. Macleod, Jesus B. Fernandez, Mahendra Kumar, Erik S. Barquist. (2011) Adrenocorticotropic hormone and cortisol response to corticotropin releasing hormone in the critically ill—a novel assessment of the hypothalamic-pituitary-adrenal axis. The American Journal of Surgery
CrossRef5
Mary F. Dallman, Seema Bhatnagar. 2011. Chronic Stress and Energy Balance: Role of the Hypothalamo-Pituitary-Adrenal Axis. .
CrossRef6
Lynne G. Maxwell, Salvatore R. Goodwin, Thomas J. Mancuso, Victor C. Baum, Aaron L. Zuckerberg, Philip G. Morgan, Etsuro K. Motoyama, Peter J. Davis, Kevin J. Sullivan. 2011. Systemic Disorders. , 1098-1182.
CrossRef7
Michelle J. Ormseth, John S. Sergent. (2010) Adrenal Disorders in Rheumatology. Rheumatic Disease Clinics of North America 36:4, 701-712
CrossRef8
(2010) Präoperative Evaluation erwachsener Patienten vor elektiven, nichtkardiochirurgischen Eingriffen. Der Anaesthesist 59:11, 1041-1050
CrossRef9
Mark E. Molitch, Alan Peaceman. 2010. Pituitary and Adrenal Disease in Pregnancy. , 335-351.
CrossRef10
Zachariah Thomas, Farooq Bandali, Karen McCowen, Atul Malhotra. (2010) Drug-induced endocrine disorders in the intensive care unit. Critical Care Medicine 38, S219-S230
CrossRef11
S. J. MURPHY, L. WANG, L. A. ANDERSON, A. STEINLAUF, D. H. PRESENT, J. I. MECHANICK. (2009) Withdrawal of corticosteroids in inflammatory bowel disease patients after dependency periods ranging from 2 to 45 years: a proposed method. Alimentary Pharmacology & Therapeutics 30:10, 1078-1086
CrossRef12
Sin Leong Yong, Paul Marik, Marco Esposito, Paul Coulthard, Sin Leong Yong. 2009. Supplemental perioperative steroids for surgical patients with adrenal insufficiency. .
CrossRef13
P. Kolar, F. Buttgereit. (2009) Evidenzbasierte EULAR-Empfehlungen zum Management einer systemischen Glukokortikoid-Therapie bei rheumatischen Erkrankungen. Zeitschrift für Rheumatologie 68:4, 349-352
CrossRef14
Toshihide Yamamoto. (2009) Isolated ACTH Deficiency. The Endocrinologist 19:3, 108-113
CrossRef15
A C Ng, S K Kumar, S J Russell, S V Rajkumar, M T Drake. (2009) Dexamethasone and the risk for adrenal suppression in multiple myeloma. Leukemia 23:5, 1009-1011
CrossRef16
Stefanie Hahner, Bruno Allolio. (2009) Therapeutic management of adrenal insufficiency. Best Practice & Research Clinical Endocrinology & Metabolism 23:2, 167-179
CrossRef17
Ashley Leak, Ellen D. Davis, Laura B. Houchin, Melanie Mabrey. (2009) Diabetes Management and Self-Care Education for Hospitalized Patients With Cancer. Clinical Journal of Oncology Nursing 13:2, 205-210
CrossRef18
Dylan W. de Lange, Marleen Kars. (2008) Perioperative glucocorticosteroid supplementation is not supported by evidence. European Journal of Internal Medicine 19:6, 461-467
CrossRef19
Nada Usta-Makkaoui, Timothy L. Lacy, Neil Roy Connelly. (2008) Hydrocortisone improves somnolence without hypotension in the postpartum period. Journal of Anesthesia 22:1, 49-51
CrossRef20
Karin M. Fuchs, Danny Wu, Zeynep Ebcioglu. (2007) Pregnancy in Renal Transplant Recipients. Seminars in Perinatology 31:6, 339-347
CrossRef21
Kwame Asare. (2007) Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient. Pharmacotherapy 27:11, 1512-1528
CrossRef22
Esther M. te Poele, Eveline S.J.M. de Bont, H. Marike Boezen, Tom Revesz, Jos P.M. Bökkerink, Auke Beishuizen, Ilse J.M. Nijhuis, Claudi S.M. Oude Nijhuis, Anjo J.P. Veerman, Willem A. Kamps. (2007) Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: Is the risk of lethal infections too high?. European Journal of Cancer 43:17, 2532-2536
CrossRef23
Michael J. Owens, Charles B. Nemeroff. 2007. The Role of Corticotropin-Releasing Factor in the Pathophysiology of Affective and Anxiety Disorders: Laboratory and Clinical Studies. , 296-316.
CrossRef24
Klaus von Werder, O. Albrecht Müller. 2007. The Role of Corticotropin-Releasing Factor in the Investigation of Endocrine Diseases. , 317-341.
CrossRef25
Bernard Schwartz, Paul A. Rabin, Alice Wysocki, Jeff Martin. (2007) Decreased Plasma Cortisol in Response to Intramuscular ACTH in Ocular Hypertensives and Primary Open-angle Glaucomas. Journal of Glaucoma 16:3, 282-286
CrossRef26
Arnaldo Neves Da Silva, David Schiff. (2007) Adrenal insufficiency secondary to glucocorticoid withdrawal in patients with brain tumor. Surgical Neurology 67:5, 508-510
CrossRef27
Herwig Pieringer, Ulrike Stuby, Georg Biesenbach. (2007) Patients with Rheumatoid Arthritis Undergoing Surgery: How Should We Deal with Antirheumatic Treatment?. Seminars in Arthritis and Rheumatism 36:5, 278-286
CrossRef28
Ioanna Dimopoulou, Panagiota Alevizopoulou, Urania Dafni, Stylianos Orfanos, Olga Livaditi, Marinella Tzanela, Anastasia Kotanidou, Emmanouil Souvatzoglou, Petros Kopterides, Irini Mavrou, Nikolaos Thalassinos, Charis Roussos, Apostolos Armaganidis, Stylianos Tsagarakis. (2007) Pituitary-adrenal responses to human corticotropin-releasing hormone in critically ill patients. Intensive Care Medicine 33:3, 454-459
CrossRef29
Kathryn E. Ackerman, Jennifer S. Myers. 2007. Endocrine Issues During Acute Illness, Sepsis, and the Perioperative Period. , 308-345.
CrossRef30
C. Frantz, D. Annane. (2006) Hydrocortisone in septic shock, ARDS and severe pneumonia. Intensivmedizin und Notfallmedizin 43:4, 286-295
CrossRef31
John R. Kirwan, Sarah H. Hickey, Roger Hällgren, Herman Mielants, Ewa Björck, Tore Persson, Frank A. Wollheim. (2006) The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis. Arthritis & Rheumatism 54:5, 1415-1421
CrossRef32
Patricia J. Ashwood, Caroline A. Crowther, Kristyn J. Willson, Ross R. Haslam, David J. Kennaway, Janet E. Hiller, Jeffrey S. Robinson. (2006) Neonatal adrenal function after repeat dose prenatal corticosteroids: A randomized controlled trial. American Journal of Obstetrics and Gynecology 194:3, 861-867
CrossRef33
Ravi Munver, Ilya A. Volfson. (2006) Adrenal insuficiency: Diagnosis and management. Current Urology Reports 7:1, 80-85
CrossRef34
Lynne Maxwell, Salvatore R. Goodwin, Thomas J. Mancuso, Victor C. Baum, Aaron L. Zuckerberg, Philip G. Morgan, Etsuro K. Motoyama, Peter J. Davis. 2006. Systemic Disorders in Infants and Children. , 1032-1109.
CrossRef35
2005. Hypertension (High Blood Pressure). .
CrossRef36
2005. Iodine (In Biological Systems). .
CrossRef37
Tanya Gulliver, Nemr Eid. (2005) Effects of Glucocorticoids on the Hypothalamic-Pituitary-Adrenal Axis in Children and Adults. Immunology and Allergy Clinics of North America 25:3, 541-555
CrossRef38
Kevin J. Mortimer, Anne E. Tattersfield. (2005) Benefit Versus Risk for Oral, Inhaled, and Nasal Glucocorticosteroids. Immunology and Allergy Clinics of North America 25:3, 523-539
CrossRef39
Sin Leong Yong, Paul Coulthard, Marco Esposito, Paul Marik, Sin Leong Yong. 2005. Supplemental perioperative steroids for surgical patients with adrenal insufficiency. .
CrossRef40
J. Briegel. (2005) Wie viel Hydrokortison braucht der Patient wirklich?. Der Anaesthesist 54:7, 637-638
CrossRef41
A. S. Milde, B. W. Böttiger, M. Morcos. (2005) Nebennierenrinde und Steroide. Der Anaesthesist 54:7, 639-654
CrossRef42
Eliza B Geer, Rita E Landman, Sharon L Wardlaw, Irene M Conwell, Pamela U. Freda. (2005) Stimulation of the Hypothalamic-Pituitary-Adrenal Axis with the Opioid Antagonist Nalmefene. Pituitary 8:2, 115-122
CrossRef43
H. M. van Santen, N. M. Thonissen, J. de Kraker, T. Vulsma. (2005) Changes in thyroid hormone state in children receiving chemotherapy. Clinical Endocrinology 62:2, 250-257
CrossRef44
Adarsh M. Kumar, Maria P. Solano, Jesus B. Fernandez, Mahendra Kumar. (2005) Adrenocortical Response to Ovine Corticotropin-Releasing Hormone in Young Men: Cortisol Measurement in Matched Samples of Saliva and Plasma. Hormone Research 64:2, 55-60
CrossRef45
Rainer H. Straub, Firdaus S. Dhabhar, Johannes W. J. Bijlsma, Maurizio Cutolo. (2005) How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis. Arthritis & Rheumatism 52:1, 16-26
CrossRef46
N Gibson, J W Ferguson. (2004) Steroid cover for dental patients on long-term steroid medication: proposed clinical guidelines based upon a critical review of the literature. British Dental Journal 197:11, 681-685
CrossRef47
M. Miozzari. (2004) Steroid withdrawal after long-term medication for immunosuppressive therapy in renal transplant patients: adrenal response and clinical implications. Nephrology Dialysis Transplantation 19:10, 2615-2621
CrossRef48
Mark B. Bromberg, Orly Carter. (2004) Corticosteroid use in the treatment of neuromuscular disorders: Empirical and evidence-based data. Muscle & Nerve 30:1, 20-37
CrossRef49
Jeffry A Katz. (2004) Treatment of inflammatory bowel disease with corticosteroids. Gastroenterology Clinics of North America 33:2, 171-189
CrossRef50
Ioanna Dimopoulou, Stylianos Tsagarakis, Andreas T. Kouyialis, Paraskevi Roussou, Georgios Assithianakis, Marietta Christoforaki, Ioannis Ilias, Damianos E. Sakas, Nikolaos Thalassinos, Charis Roussos. (2004) Hypothalamic-pituitary-adrenal axis dysfunction in critically ill patients with traumatic brain injury: Incidence, pathophysiology, and relationship to vasopressor dependence and peripheral interleukin-6 levels*. Critical Care Medicine 32:2, 404-408
CrossRef51
Suzanne Crowley. (2003) Inhaled glucocorticoids and adrenal function: an update. Paediatric Respiratory Reviews 4:2, 153-161
CrossRef52
Robert L Schiff, Gail A Welsh. (2003) Perioperative evaluation and management of the patient with endocrine dysfunction. Medical Clinics of North America 87:1, 175-192
CrossRef53
Scott C Howard, Ching-Hon Pui. (2002) Endocrine complications in pediatric patients with acute lymphoblastic leukemia. Blood Reviews 16:4, 225-243
CrossRef54
T. Revermann, M. Soergel, A. Hellinger, G. Klaus. (2002) Stimulated cortisol secretion is not correlated with prednisone dose or with steroid side-effects in children after renal transplantation. Pediatric Transplantation 6:4, 288-294
CrossRef55
A. Uhl, D. Czock, B.-O. Boehm, D. Zellner, A. Mertz, F. Keller. (2002) Pharmacokinetics and pharmacodynamics of methylprednisolone after one bolus dose compared with two dose fractions. Journal of Clinical Pharmacy and Therapeutics 27:4, 281-287
CrossRef56
J. Desrame, J.M. Sabate, R. Agher, C. Bremont, M. Gaudric, D. Couturier, S. Chaussade. (2002) Assessment of hypothalamic-pituitary-adrenal axis function after corticosteroid therapy in inflammatory bowel disease. The American Journal of Gastroenterology 97:7, 1785-1791
CrossRef57
L. Kumrah, M. Ramam, P. Shah, R.M. Pandey, J.S. Pasricha. (2001) Pituitary-adrenal function following dexamethasone-cyclophosphamide pulse therapy for pemphigus. British Journal of Dermatology 145:6, 944-948
CrossRef58
P. J. Rutgeerts. (2001) The limitations of corticosteroid therapy in Crohn's disease. Alimentary Pharmacology and Therapeutics 15:10, 1515-1525
CrossRef59
Stefan Schroeder, Maria Wichers, Dietrich Klingmüller, Martina Höfer, Lutz Eric Lehmann, Tilman von Spiegel, Rudolf Hering, Christian Putensen, Andreas Hoeft, Frank Stüber. (2001) The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: Altered response to corticotropin-releasing hormone. Critical Care Medicine 29:2, 310-316
CrossRef60
Charlene E. McEvoy, Dennis E. Niewoehner. (2000) Corticosteroids in Chronic Obstructive Pulmonary Disease. Clinics in Chest Medicine 21:4, 739-752
CrossRef61
Kentaro Matsuda, Toshio Katsunuma, Yoji Iikura, Hirohisa Kato, Hirohisa Saito, Akira Akasawa. (2000) Adrenocortical function in patients with severe atopic dermatitis. Annals of Allergy, Asthma & Immunology 85:1, 35-39
CrossRef62
Christoph Henzen. (2000) Adrenal response to glucocorticoid treatment. The Lancet 355:9213, 1459
CrossRef63
Christoph Henzen, Alex Suter, Erika Lerch, Ruth Urbinelli, Xaver H Schorno, Verena A Briner. (2000) Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. The Lancet 355:9203, 542-545
CrossRef64
Marianne Shaw, Brian F. Mandell. (1999) PERIOPERATIVE MANAGEMENT OF SELECTED PROBLEMS IN PATIENTS WITH RHEUMATIC DISEASES. Rheumatic Disease Clinics of North America 25:3, 623-638
CrossRef65
Maria Wichers, Wolfram Springer, Frank Bidlingmaier, Dietrich Klingmuller. (1999) The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clinical Endocrinology 50:6, 759-765
CrossRef66
Fernando J. Martinez, Robert W. Lash. (1999) ENDOCRINOLOGIC AND METABOLIC COMPLICATIONS IN THE INTENSIVE CARE UNIT. Clinics in Chest Medicine 20:2, 401-421
CrossRef67
Robin P. F. Dullaart, Susanne H. Pasterkamp, John A. M. Beentjes, Wim J. Sluiter. (1999) Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance test. Clinical Endocrinology 50:4, 465-471
CrossRef68
Andrew M. Wilson, Erika J. Sims, Brian J. Lipworth. (1999) Dose response with fluticasone propionate on adrenocortical activity and recovery of basal and stimulated responses after stopping treatment. Clinical Endocrinology 50:3, 329-335
CrossRef69
Stewart G Albert, Raymond G Slavin. (1998) Adrenal Insufficiency in an Adult on Inhaled Corticosteroids; Recovery of Adrenal Function with Inhaled Nedocromil Sodium. Annals of Allergy, Asthma & Immunology 81:6, 582-584
CrossRef70
G. Nicholson, J. M. Burrin, G. M. Hall. (1998) Peri-operative steroid supplementation. Anaesthesia 53:11, 1091-1104
CrossRef71
Gregory F. Keenan. (1997) MANAGEMENT OF COMPLICATIONS OF GLUCOCORTICOID THERAPY. Clinics in Chest Medicine 18:3, 507-520
CrossRef72
Jerry V Glowniak, D.Lynn Loriaux. (1997) A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery 121:2, 123-129
CrossRef73
Oelkers, Wolfgang, . (1996) Adrenal Insufficiency. New England Journal of Medicine 335:16, 1206-1212
Full Text74
B Meij. (1996) Assessment of a combined anterior pituitary function test in beagle dogs: Rapid sequential intravenous administration of four hypothalamic releasing hormones. Domestic Animal Endocrinology 13:2, 161-170
CrossRef75
I. Fujiwara, Y. Igarashi, E. Ogawa. (1995) A comparison of pituitary-adrenal responses to corticotropin-releasing hormone, hypoglycaemia and metyrapone in children with brain tumours and growth hormone deficiency. European Journal of Pediatrics 154:9, 717-722
CrossRef76
Greenberg, Gordon R.Feagan, Brian G.Martin, FrancoisSutherland, Lloyd R.Thomson, AlanWilliams, C. NoelNilsson, Lars-GoranPersson, Torethe Canadian Inflammatory Bowel Disease Study Group. (1994) Oral Budesonide for Active Crohn's Disease. New England Journal of Medicine 331:13, 836-841
Full Text77
J.W. Honour. (1994) Hypothalamic-pituitary-adrenal axis. Respiratory Medicine 88, 9-15
CrossRef78
Vance, Mary Lee. (1994) Hypopituitarism. New England Journal of Medicine 330:23, 1651-1662
Full Text79
Tarek M. Fiad, John M. Kirby, Sean K. Cunningham, T. Joseph McKenna. (1994) The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clinical Endocrinology 40:5, 603-609
CrossRef80
Brian J. Lipworth. (1993) Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacology & Therapeutics 58:2, 173-209
CrossRef81
A.M. de Vos. (1993) Crystal structure of the complex between human growth hormone and the extracellular domain of its reception. Biomedicine & Pharmacotherapy 47:1, 46-47
CrossRef82
Mary F. Dallman, Susan F. Akana, Karen A. Scribner, Margaret J. Bradbury, C.-Dominique Walker, Alison M. Strack, Caren S. Cascio. (1992) Stress, Feedback and Facilitation in the Hypothalamo-Pituitary-Adrenal Axis. Journal of Neuroendocrinology 4:5, 517-526
CrossRef83
(1992) Glucocorticoid Therapy and Pituitary–Adrenal Responses to Corticotropin-Releasing Hormone. New England Journal of Medicine 327:4, 282-284
Full Text84
Christy, Nicholas P., . (1992) Pituitary–Adrenal Function during Corticosteroid Therapy. New England Journal of Medicine 326:4, 266-267
Full Text
- Letters
