Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.     

Low- and standard-dose corticotropin and insulin hypoglycemia testing in the assessment of hypothalamic-pituitary-adrenal function after pituitary surgery

The optimal means of assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery remains controversial. We compared low-dose (1 micro g iv) and standard-dose (250 micro g 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 micro g/dl) consistently had a subnormal response to hypoglycemia, and those with a serum cortisol greater than 650 nmol/liter (23.6 micro g/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 micro g/dl) indicates adequacy of the HPA axis, and a level of less than 350 nmol/liter (12.7 micro g/dl) indicates ACTH deficiency. No further testing is then required. An intermediate level of 350-650 nmol/liter (12.7-23.6 micro g/dl) warrants further assessment using the insulin hypoglycemia test.     

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods

CONTEXT: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. OBJECTIVES: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. DESIGN: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. SETTING: The study was conducted at an academic medical center. PATIENTS/PARTICIPANTS: Participants were critically ill subjects. Intervention: There was no intervention. MAIN OUTCOME MEASURE: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. RESULTS: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 microg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 microg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 microg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. CONCLUSIONS: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.     

A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery

The short ACTH stimulation test is an easy, reliable, and extensively used test in the assessment of the hypothalamo-pituitary-adrenal (HPA) axis. However, its use immediately after pituitary surgery is a matter of debate. The insulin tolerance test (ITT) is the gold standard in the evaluation of the HPA axis, but it is not always without side effects and may be unpleasant early after pituitary surgery. Our aim was to investigate the value of the 1-microg ACTH test in the assessment of the HPA axis early after pituitary surgery. We also aimed to determine the value of the 1-microg and 250-microg ACTH tests and the ITT in the estimation of HPA axis status after 3 months postoperatively. Nineteen patients subjected to pituitary tumor surgery were included in the study, and the ITT and the 1-microg and 250-microg ACTH tests were performed between the 4th and 11th days of surgery. The tests were repeated at the first month in 3 patients with subnormal peak cortisol responses (454, 125, and 301 nmol/L) and in 18 patients at the third month postoperatively. ACTH stimulation tests were performed by using 1 microg and 250 microg ACTH iv as a bolus injection, and blood samples were drawn at 0, 30, and 60 min for measurement of serum cortisol levels. The ITT was performed by using iv regular insulin, and serum glucose and cortisol levels were measured. The 1-microg and 250-microg ACTH stimulation tests and the ITT were performed consecutively. At least 48 h were allowed between each test. A peak serum cortisol level of 550 nmol/L or greater was considered as a normal response for both the ITT and the ACTH tests. The serum cortisol level was measured by RIA using commercial kits. Serum glucose was determined by glucose oxidase method. There were correlations between the peak cortisol response to the ITT and the 1-microg ACTH test (r = 0.39, P < 0.05) in the early postoperative period. No correlation was found between the ITT and the 250-microg ACTH test responses. In the early postoperative period, two patients showed normal cortisol responses (> or =550 nmol/L) to the 1-microg ACTH test and five patients showed normal cortisol responses to the 250-microg ACTH test among the six patients with subnormal cortisol responses to the ITT. Three patients with subnormal cortisol responses to ITT and baseline cortisol values less than 240 nmol/L showed normal HPA axis at the end of the first month. In the late postoperative period, at the third month, all the patients showed normal HPA axis. In the early postoperative period of pituitary surgery, the 1-microg ACTH test results are more concordant than the 250-microg ACTH test in comparison with the ITT. Our results also indicate that HPA axis dysfunction shown by ACTH stimulation tests and the ITT in early postoperative period may be normalized 1-3 months after surgery. For this reason, we think that dynamic tests including the ITT may not be useful early after pituitary surgery.     

Comparison of one week 0900 h serum cortisol, low and standard dose synacthen tests with a 4 to 6 week insulin hypoglycaemia test after pituitary surgery in assessing HPA axis

OBJECTIVE: To compare the use of 0900 h serum cortisol and both low and standard dose Synacthen tests, one week after pituitary surgery with an insulin hypoglycaemia test performed 4-6 weeks after surgery in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: 0900 h basal serum cortisol was measured on days 6 and 7 after pituitary surgery (24 h off replacement hydrocortisone) followed by a low dose Synacthen test (1 microg intravenously) on day 6 and a standard dose Synacthen test (250 microg intramuscularly) on day 7. Three to 5 weeks later an insulin hypoglycaemia test was performed on all patients. Both low and standard dose Synacthen tests were performed on control subjects using an identical protocol. SUBJECTS: Forty-two patients (21 male, 21 female), median age 49 years (range 23-73) who had pituitary surgery (Cushing's disease excluded). One patient had undergone repeat surgery for residual tumour and was studied following each operation. Sixteen healthy normal volunteers, median age 37 years (range 21-55). MEASUREMENTS: Serum cortisol measured by radioimmunoassay. RESULTS: Two standard deviations below the mean serum cortisol (logarithmic transformation) in the normal volunteers 30 minutes after low dose Synacthen (1 microg) was 496 nmol/l and after standard dose Synacthen (250 microg) was 504 nmol/l. A normal response was therefore taken as serum cortisol > 500 nmol/l at 30 minutes in both tests (using 496 and 504 nmol/l did not alter results). 0900 h serum cortisols 1 week after surgery were > 250 nmol/l in 31 patients and 29 of these had a normal response to hypoglycaemia (peak serum cortisol > 550 nmol/l). Of the remaining two patients, one had 0900 h serum cortisol on day 6 and 7 after surgery of 405 and 441 nmol/l with a peak serum cortisol response to hypoglycaemia of 451 nmol/l; the other patient had 0900 h serum cortisols of 416 and 251 nmol/l and a peak cortisol response to hypoglycaemia of 498 nmol/l. All eight patients who had a 0900 h serum cortisol < 100 nmol/l failed a subsequent insulin hypoglycaemia test. Seven discrepancies were noted between the low dose Synacthen test and the insulin hypoglycaemia test in the 41 patients who had both tests. In six of these, a subnormal response to low dose Synacthen was followed by a normal response to hypoglycaemia. Three discrepancies were noted between the standard dose Synacthen test and the insulin hypoglycaemia test in the 40 patients who had both tests. In all three cases a normal response to Synacthen was followed by a subnormal response to hypoglycaemia. CONCLUSIONS: A 0900 h serum cortisol < 100 nmol/l (24 h off replacement hydrocortisone) indicated ACTH deficiency and need for lifelong steroid replacement. A 0900 h serum cortisol > 450 nmol/l one week after pituitary surgery is highly suggestive of a normal cortisol response to hypoglycaemia. A 0900 h serum cortisol between 250 and 450 nmol/l one week after pituitary surgery permits safe withdrawal of steroid therapy pending an insulin hypoglycaemia test 1 month after surgery. Patients with 0900 h serum cortisol between 100 and 250 nmol/l should continue replacement steroids until definitive testing. Low dose and standard dose Synacthen tests 1 week after pituitary surgery are unreliable and should not be used.     

Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease

OBJECTIVE: The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently. DESIGN AND PATIENTS: We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition. RESULTS: With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P<0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose-response relationship between ACTH and cortisol in the patients resembled a dose-response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1-39). CONCLUSIONS: The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substitution is a discretionary decision.     

Long-term basal and dynamic evaluation of hypothalamic-pituitary-adrenal (HPA) axis in acromegalic patients

Objective Long‐term effects of trans‐naso‐sphenoidal surgery (TNS) or long‐acting somatostatin analogs (SSA) on the function of hypothalamic–pituitary–adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow‐up in patients with GH‐secreting pituitary adenomas and preserved HPA function post‐TNS or prior SSA. Design and patients This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 ± 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long‐term follow‐up (median: 72 months, range: 12–240). No patient previously underwent radiotherapy. Measurements HPA function was studied by morning circulating cortisol and ACTH levels, 24‐h urinary free cortisol (UFC) and cortisol response to low‐dose short Synacthen test (LDSST, 1 µg) with a peak > 500 nmol/l as cut‐off for normal function. Results Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow‐up duration, serum GH/IGF‐I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed. Conclusions The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.     

Relationship of non-alcoholic hepatic steatosis to cortisol secretion in diet-controlled Type 2 diabetic patients.

AIMS: To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. METHODS: The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). RESULTS: Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 +/- 4 vs. 102 +/- 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 +/- 2 vs. 14.4 +/- 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist-hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations (P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. CONCLUSIONS: These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals.     

Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke

OBJECTIVE: Elevated cortisol levels are associated with confusion and poor outcome after stroke. Dehydroepiandrosterone sulphate (DS), the most abundant adrenal androgen may act as an anti-glucocorticoid. An altered regulation of these steroids may affect numerous brain functions, including neuronal survival. The purpose of this study was to investigate serum cortisol and DS levels and the cortisol/DS ratio early after stroke and relate our findings to the presence of disorientation and mortality. DESIGN: Patients with acute ischaemic stroke (n = 88, 56 men and 32 women) admitted to a stroke unit were investigated with repeated clinical assessments and scores for degree of confusion, extent of paresis and level of functioning. Serum cortisol (C) and DS were measured on day 1 and/or day 4. Data for 28-day and 1-year mortality are presented. A control group of 65 age-matched healthy individuals was used. Multivariate analyses of mortality rates in the different tertiles or sixtiles of serum cortisol were performed with logistic regression, adjusting for age, sex, diabetes and level of consciousness. RESULTS: There was no difference in serum cortisol levels on day 1 for stroke patients when compared with control group values. Initial cortisol levels were significantly higher in the patients with acute disorientation versus orientated patients (P < 0.05). Cortisol levels on day 1 were an independent predictor of 28-day mortality, and patients with low cortisol levels (<270 nmol L(-1)) and increased levels (>550 nmol L(-1)) both had an increased 1-year mortality. DS levels on day 1 were significantly elevated in stroke patients. CONCLUSION: Hypercortisolism is associated with cognitive dysfunction early after ischaemic stroke. High and low circulating cortisol levels are associated with increased mortality after stroke. DS levels were not associated with clinical outcome.     

Screening for hypothalamo-pituitary-adrenal axis suppression in asthmatics taking high dose inhaled corticosteroids

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 micrograms; range 1200-2650 micrograms) beclomethasone dipropionate (n = 69) or budesonide (n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol less than 190 nmol l-1; urine free cortisol less than 80 nmol 24 h-1; rise in cortisol in response to tetracosactrin or hypoglycaemia less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1. HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol (rs = 0.84; P = 0.001) and post-tetracosactrin cortisol (r = 0.75; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function

Dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) are corticotropin-dependent adrenal androgen precursors that are uniformly low in treated patients with corticotropin deficiency. There are no data investigating the diagnostic value of DHEA-S measurements in the prospective assessment of adrenal function. This study examined serum DHEA-S levels as possible markers for hypothalamic- pituitary-adrenal (HPA) function in patients with large pituitary adenomas. Patients were characterized to have normal HPA (n = 47) or abnormal HPA (ABN-HPA, n = 35) function based on their respective responses to insulin-induced hypoglycemia. Patients also underwent low-dose Cortrosyn (1 micro g, LDC) and standard-dose Cortrosyn stimulation testing. All patients with ABN-HPA had very low age- and gender-matched serum DHEA-S levels. When the normal response to LDC was set at a cortisol level of at least 18.1 micro g/dl, 10 of 31 patients with ABN-HPA exhibited normal responses. Receiver operating characteristic curves for baseline DHEA-S and for maximal cortisol responses to LDC had areas of 0.984 (confidence interval, 0.962-1.000) and 0.893 (confidence interval, 0.817-0.969), respectively. LDC- or SDC-stimulated serum cortisol levels have significant limitations in defining HPA function. A normal age- and gender-specific serum DHEA-S level makes the diagnosis of corticotropin deficiency extremely unlikely. However, when serum DHEA-S levels are low, further testing is necessary to define HPA function.     

Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease

OBJECTIVES: To assess associations between the activity of hypothalamo-pituitary-adrenal (HPA) axis and liver histology in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND PATIENTS: In a cross-sectional study, we enrolled 50 consecutive, overweight, NAFLD patients and 40 control subjects who were comparable for age, sex and body mass index (BMI). MEASUREMENTS: NAFLD (by liver biopsy), HPA axis activity (by 24-hour urinary free cortisol [UFC] excretion and serum cortisol levels after 1 mg dexamethasone), insulin resistance (by homeostasis model assessment: HOMA-IR), and metabolic syndrome (MetS) features. RESULTS: NAFLD patients had markedly higher (P < 0.001) 24-h UFC (149 +/- 24 vs. 90 +/- 16 nmol/day) and postdex suppression cortisol concentrations (32 +/- 10 vs. 16 +/- 7 nmol/l) than controls. The MetS and its individual components were more frequent among NAFLD patients. The marked differences in urinary/serum cortisol concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, waist circumference, systolic blood pressure, triglycerides, homeostasis model assessment for insulin resistance score and presence of diabetes. Importantly, 24-h UFC and postdex cortisol concentrations strongly correlated to hepatic necroinflammatory grade (P < 0.01) and fibrosis stage (P < 0.001) among NAFLD patients. By logistic regression analysis, 24-h UFC (odds ratio (OR) 1.80, 95%CI 1.3-2.8) or postdex cortisol concentrations (OR 1.95, 95%CI 1.4-3.1) independently predicted the severity of hepatic fibrosis, but not necroinflammation, after adjustment for potential confounders. CONCLUSIONS: These results suggest that NAFLD patients have a subtle, chronic overactivity in the HPA axis (that is closely associated with the severity of liver histopathology) leading to subclinical hypercortisolism that might be implicated in the development of NAFLD.     

Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests

OBJECTIVES: Patients with organic growth hormone deficiency (GHD) or with structural hypothalamic-pituitary abnormalities may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis (HPA) is essential in these patients because, although clinically asymptomatic, their HPA cannot appropriately react to stressful stimuli with potentially life-threatening consequences. DESIGN AND METHODS: In this study we evaluated the integrity of the HPA in 24 patients (age 4.2-31 years at the time of the study) with an established diagnosis of GHD and compared the reliability of the insulin tolerance test (ITT), short synacthen test (SST), low-dose SST (LDSST), and corticotropin releasing hormone (CRH) test in the diagnosis of adrenal insufficiency. RESULTS: At a cortisol cut-off for a normal response of 550 nmol/l (20 microg/dl), the response to ITT was subnormal in 11 subjects, 6 with congenital and 5 with acquired GHD. Four patients had overt adrenal insufficiency, with morning cortisol concentrations ranging between 66.2-135.2 nmol/l (2.4-4.9 microg/dl) and typical clinical symptoms and laboratory findings. In all these patients, a subnormal cortisol response to ITT was confirmed by LDSST and by CRH tests. SST failed to identify one of the patients as adrenal insufficient. In the seven asymptomatic patients with a subnormal cortisol response to ITT, the diagnosis of adrenal insufficiency was confirmed in one by LDSST, in none by SST, and in five by CRH tests. The five patients with a normal cortisol response to ITT exhibited a normal response also after LDSST and SST. Only two of them had a normal response after a CRH test. In the seven patients with asymptomatic adrenal insufficiency mean morning cortisol concentration was significantly higher than in the patients with overt adrenal insufficiency. ITT was contraindicated in eight patients, and none of them had clinical symptoms of overt adrenal insufficiency. One of these patients had a subnormal cortisol response to LDSST, SST, and CRH, and three exhibited a subnormal response to CRH but normal responses to LDSST and to SST. CONCLUSION: We conclude that none of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency. Consequently, clinical judgment remains one of the most important issues for deciding which patients need assessment or re-assessment of adrenal function.     

Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor

The impact of cranial irradiation (CIR) and chemotherapy on the hypothalamo-pituitary (HP)-adrenal (HPA) axis was assessed in a population-based follow-up study of patients treated for childhood brain tumor not directly involving the HP axis. HPA function was evaluated and compared with that in healthy controls (n = 17), measuring basal cortisol and the peak cortisol response to an insulin tolerance test (ITT) and an ACTH test(.) The cortisol cut-off level was 500 nmol/liter. The biological effective dose (BED) of radiotherapy was determined for the HP region and spine and was expressed in Gray units, as BED gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-three children (46 males and 27 females), less than 15 yr of age when diagnosed during 1970-1997 in the Eastern part of Denmark, were included. The median age at time of radiotherapy was 8.4 yr (range, 0.8-14.9). The median length of follow-up was 15 yr (range, 2-29). Fourteen patients (19%) had basal cortisol levels below 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT, and thus, they had insufficiency of the HPA axis. Even though a peak cortisol above 500 nmol/liter was reached in the rest of the cohort (n = 59) after either an ACTH test (30 or 60 min) or an ITT, they had significantly lower peak cortisol levels compared with controls (P = 0.0099). Thirteen patients failed the ACTH test (30 min), but passed the ACTH test (60 min), implying a risk of misinterpreting the cortisol capacity of the patient if only the ACTH test (30 min) is obtained. The basal cortisol levels and the cortisol levels in the ACTH test (30 min) and the ACTH test (60 min) were significantly lower in the patient group compared with controls. There was a significant correlation between the peak cortisol after the ITT compared with the peak cortisol after the ACTH test (30 or 60 min; r(s) = 0.56; P = 0.0006), but 48% failed the ITT, and there was discordance in 10 of 33 (30%) patients who passed the ACTH but failed the ITT, indicating the recommendation of continuous use of the ITT as the gold standard for evaluation of the HPA axis. Stepwise backward multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included BED (P = 0.04) and length of follow-up (P = 0.06). In contrast, age at RT, chemotherapy, BED to the spine, and gender were not included in the model. In conclusion, these data suggest that CIR for a childhood brain tumor may affect the HPA axis, resulting in secondary adrenal insufficiency, whereas adjuvant chemotherapy does not seem to add to the deleterious effect of CIR. We recommend life-long surveillance of the HPA axis and performing regular ITTs.     

Levels of GH binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients

OBJECTIVE: To investigate levels of serum GH binding activity, insulin-like growth factor binding protein-1 (IGFBP-1), blood glucose, serum insulin, and cortisol in patients on the Intensive Therapy Unit. DESIGN: Case-control study of severely ill patients admitted to the Intensive Therapy Unit. PATIENTS: Six critically ill patients (51-78 years) who required ventilatory and nutritional support and six healthy age, sex, height and weight matched controls. MEASUREMENTS: Patients and controls were studied for two 24-hour periods; the patients before and after commencing parenteral nutrition, the controls whilst fasted and on a second occasion when fed a diet equal in protein and calories to that of the patients' parenteral nutrition. Samples were taken hourly for measurement of IGFBP-1, blood glucose, serum insulin and cortisol. Growth hormone binding activity was measured at 0 hours. RESULTS: Blood glucose levels were higher in the patients than controls in both the fasted (mean +/- SEM 5.1 +/- 0.5 vs 3.8 +/- 0.2 mmol/l, P = 0.04) and fed states (10.1 +/- 1.6 vs 5.0 +/- 0.1 mmol/l, P = 0.02) and patients' insulin levels were also higher when fed (81.5 +/- 31.6 vs 24.2 +/- 4.8 mU/l, P = 0.046) although there were no significant differences between patients and controls when fasted. IGFBP-1 levels were inversely related to insulin levels in both the patients and controls; mean IGFBP-1 concentrations were higher in fasted patients than in controls (123 +/- 38 vs 52 +/- 9, P = 0.046) but when fed, both groups had similar mean levels. Serum GH binding activity was low in the patients and did not change with feeding. Mean 24-hour cortisol levels were higher in the patients than in controls, whether fasted or fed, and showed no nyctohemeral rhythm. CONCLUSIONS: We have previously reported that critically ill patients have low levels of IGF-I with augmented basal levels of GH. The present results demonstrate that these changes in the GH-IGF-I axis are associated with insulin resistance with respect to blood glucose and high levels of IGFBP-1 when patients are fasted. However, when fed, the inverse relationship of IGFBP-1 to insulin is preserved. Patients have low levels of GH binding activity and increased mean cortisol levels. Interventional studies in this patient group with GH and IGF-I must take account of these changes in binding protein and cortisol levels.     

A retrospective audit of the combined pituitary function test, using the insulin stress test, TRH and GnRH in a district laboratory

OBJECTIVE: To assess the value of the combined insulin stress test (IST), thyrotrophin-releasing hormone (TRH) and gonadotrophin hormone-releasing hormone (GnRH) tests. DESIGN: A retrospective audit of 232 such tests performed between 1980 and 1989 inclusive. PATIENTS: One hundred and ninety-seven patients with known or suspected pituitary disease. MEASUREMENTS: IST, TRH and GnRH responses were retrieved from laboratory records. Case notes were surveyed for clinical data and additional results. RESULTS: A basal serum cortisol level of less than 100 nmol/l (or less than 200 nmol/l in patients who had recently received glucocorticoid replacement therapy) accurately predicted a subnormal response to hypoglycaemia. All patients with a basal cortisol level of greater than 400 nmol/l, except those who had recently received steroids, showed a normal cortisol response. In retrospect, by consideration of such basal values, 55% of ISTs could have been avoided if the only aim was to assess cortisol reserve. A deficient growth hormone (GH) response to hypoglycaemia was, however, common in patients with a normal cortisol response. Two-thirds of patients with GH deficiency would have been missed if an IST had been avoided on the basis either of basal cortisol levels alone, or of cortisol responses to an alternative test which did not test GH reserve. There was poor agreement between the pituitary response to TRH and GnRH and basal levels of thyroxine and gonadotrophins respectively, suggesting that these releasing hormone tests are misleading. CONCLUSIONS: The IST provides information regarding pituitary function not provided by other tests of the hypothalamic-pituitary-adrenal axis, so that the choice between the IST and alternative tests must depend on a critical assessment of what information is required. Routine TRH and GnRH testing appears to yield little information of practical clinical value.     

High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate

INTRODUCTION: Megestrol acetate (MA) is a progestational agent used for palliation of breast and endometrial cancer. The drug promotes weight gain via appetite stimulation. This property has led to widespread use in patients with wasting illnesses. Increasing numbers of reports suggest glucocorticoid activity. OBJECTIVE: Unrecognized adrenal suppression may result from MA use. This is the first study to examine the prevalence of adrenal suppression in hospitalized patients treated with MA. SUBJECTS AND DESIGN: This is a cross-sectional study of hospitalized patients receiving MA compared to control subjects. Morning cortisol levels, endocrine signs and symptoms, and duration of MA therapy were evaluated in 28 hospitalized medical patients treated with MA, and 21 control patients admitted to the same hospital service during the study period. RESULTS: Median cortisol levels were significantly lower in patients using MA vs controls (160 vs 386 nmol/l, p=0.003). Forty-three percent of subjects on MA demonstrated morning cortisol levels below the normal range (138-690 nmol/l), compared with 10% of controls (p=0.013). Ninety-three percent of subjects taking MA had morning cortisol levels below the level that excludes adrenal insufficiency in hospitalized patients (497 nmol/l) vs 71% of controls (p=0.06). CONCLUSIONS: MA use is associated with significant adrenal suppression in acutely ill individuals. This should alert physicians to the possibility of adrenal insufficiency and the need to assess for signs or symptoms of adrenal insufficiency, and mandates a low threshold for testing adrenal function in hospitalized patients taking MA.     

A comparison between low-dose (1 µg), standard-dose (250 µg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo–pituitary–adrenal axis in primary fibromyalgia syndrome

OBJECTIVE: Primary fibromyalgia syndrome (PFS) is a nonarticular rheumatological syndrome characterized by disturbances in the hypothalamo-pituitary-adrenal (HPA) axis. The site of the defect in the HPA axis is a matter of debate. Our aim was to evaluate the HPA axis by the insulin-tolerance test (ITT), standard dose (250 microg) ACTH test (SDT) and low dose (1 microg) ACTH test (LDT) in patients with PFS. DESIGN AND PATIENTS: Sixteen patients (13 female, three male) with PFS were included in the study. Sixteen healthy subjects (12 female, four male) served as matched controls. ACTH stimulation tests were carried out by using 1 microg and 250 microg intravenous (i.v.) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. The ITT was performed by using i.v. soluble insulin, and serum glucose and cortisol levels were measured before and after 30, 60, 90 and 120 min. The 1 microg and 250 microg ACTH stimulation tests and the ITT were performed consecutively. RESULTS: Peak cortisol responses to both the low dose test (LDT) and standard dose test (SDT) (589 +/- 100 nmol/l; 777 +/- 119 nmol/l, respectively) were lower in the PFS group than in the control group (1001 +/- 370 nmol/l; 1205 +/- 386 nmol/l, respectively) (P < 0.0001). Peak cortisol responses to ITT (730 +/- 81 nmol/l) in the PFS group were lower than in the control group (1219 +/- 412 nmol/l) (P < 0.0001). Six of the 16 patients with PFS had peak cortisol responses to LDT lower than the lowest peak cortisol response of 555 nmol/l obtained in healthy subjects after LDT. There was a significant difference between the peak cortisol responses to LDT (589 +/- 100 nmol/l) and peak cortisol responses to ITT (730 +/- 81 nmol/l) in the PFS group (P < 0.0001). Peak cortisol responses to SDT (777 +/- 119 nmol/l) were similar to peak cortisol responses to ITT (730 +/- 81 nmol/l) in the PFS group. CONCLUSION: We conclude that the perturbation of the HPA axis in PFS is characterized by underactivation of the HPA axis. Some patients with PFS may have subnormal adrenocortical function. LDT is more sensitive than SDT or ITT in the investigation of the HPA axis to determine the subnormal adrenocortical function in patients with PFS.     

Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic--pituitary--adrenal axis

OBJECTIVE: Assessment of the hypothalamic--pituitary--adrenal (HPA) axis relies on the interpretation of serum (total) cortisol in response to dynamic tests of the HPA axis. Most cortisol is bound to cortisol-binding globulin (CBG) and serum total cortisol levels are significantly affected by variation in CBG. We hypothesised that CBG variation significantly affects interpretation of dynamic tests of the HPA axis. DESIGN: We investigated the effect of CBG variation on the outcome of the 250 microg short Synacthen test (SST) in 30 healthy adults. METHODS: Blood was sampled at time -30, 0 (at which point Synacthen was given) and +30 min. CBG and total cortisol were measured at each time-point. Integrity of the HPA axis was confirmed by measurement of urine cortisol. RESULTS: We found that CBG varied significantly within individuals, falling from 51+/-3.4 to 43 +/-3.2 microg/ml (P<0.0001) on changing from standing to lying. Total cortisol levels strongly correlated with CBG (r=0.88, P<0.0001). Thirteen subjects had a +30 min total cortisol <550 nmol/l. In these subjects, the CBG levels at each time-point were significantly lower compared with subjects who had a +30 min total cortisol of >550 nmol/l (P<0.05). To correct for variation in CBG we calculated the total cortisol:CBG ratio and found no significant difference in the +30 min ratio between these two groups. CONCLUSION: CBG varies significantly within and between individuals. This is accompanied by changes in serum total cortisol large enough to affect the outcome of an SST and, by implication, other tests of the HPA axis.     

Cortisol levels and mortality in severe sepsis

OBJECTIVE: Serum cortisol levels rise in response to the stress of critical illness but the optimal range of serum cortisol in such settings is not clearly defined. The objectives of this study were to determine the range of serum cortisol levels in a group of medical intensive care unit patients with severe sepsis/septic shock using uniform criteria, and to correlate serum cortisol levels to mortality. DESIGN AND PATIENTS: In a prospective observational fashion, 100 medical intensive care unit patients at Northwestern Memorial Hospital in Chicago were enrolled within 48 h of developing severe sepsis/septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine. MEASUREMENTS: A serum cortisol level was measured during the morning hours in the first 48 h of developing severe sepsis/septic shock. The severity of critical illness was measured by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS: The average patient age was 63 +/- 17 years, 54 patients were men. The average APACHE II score for all patients was 23 +/- 7. In-hospital and 90-day mortality were 51% and 60%, respectively. Four patient groups were defined a priori based on morning serum cortisol levels and their in-hospital mortalities were as follows: group 1 (cortisol < or = 345 nmol/l), n = 11, mortality 54%; group 2 (cortisol 345-552 nmol/l), n = 19, mortality 53%; group 3 (cortisol 552-1242 nmol/l), n = 54, mortality 41%; and group 4 (cortisol > or = 1242 nmol/l), n = 16, mortality 81% (P < 0.01). CONCLUSIONS: Cortisol levels were elevated in most patients with septic shock. Cortisol levels less than 552 nmol/l occurred in 30% of patients with septic shock but the mortality in these patients was not significantly increased. Serum cortisol levels > or = 1242 nmol/l were associated with significantly higher mortality.