Metyrapone Test Research Articles

ACTH deficiency in childhood cancer survivors

Adrenocorticotropin deficiency (ACTHD) can be clinically subtle, but life-threatening if not recognized. We assessed the prevalence of ACTHD in survivors of childhood cancer according to tumor diagnosis/therapy. Chart review of endocrine/oncology history was performed in 310 childhood cancer survivors. Patients were referred to endocrine clinic because of slow growth, fatigue, or abnormal pubertal timing. Evaluation of growth hormone (GH), thyrotropin (TSH), ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was performed. Low response to metyrapone and/or low dose ACTH test defined ACTHD. ACTHD was identified in 56 (18%), [44 of 182 (24%) central nervous system (CNS) tumors, 3 of 18 (17%) non-CNS cranial tumors, 9 of 97 (9%) hematologic malignancies]. Of the 56 with ACTHD, 53 (95%) had received cranial irradiation (mean 45.5 Gy, range 14-70 Gy); three had not: one each with craniopharyngioma, hypothalamic astrocytoma, and brain stem glioma. All but one also had GH deficiency and/or central hypothyroidism. Childhood cancer survivors with greatest risk for ACTHD had craniopharyngioma, other suprasellar tumor, or medulloblastoma or > or =24 Gy cranial irradiation. We recommend annual testing for ACTHD for 10-15 years and continued lifelong surveillance after CNS tumor or cranial irradiation, in patients with other hypothalamic-pituitary deficiencies or symptoms of ACTHD.

Metyrapone tests in patients with panic disorder

Studies of hypothalamic secretion of corticotropin-releasing hormone (CRH) in patients with panic disorder in the nonpanic state (using CRH tests) are contradictory. No data about the hypothalamic-pituitary response to metyrapone are available. Study participants included 14 patients with panic disorder (DSM-IV criteria) and 14 healthy control subjects who underwent a standard overnight metyrapone test and a combined metyrapone/low-dose dexamethasone test. Significant treatment effects of metyrapone and combined metyrapone/dexamethasone were found on plasma corticotropin, cortisol, and 11-deoxycortisol, but no differences between patients and control subjects emerged. Considering visual analogue scale ratings of anxiety, tension, restlessness, and Beck Depression Inventory scores as covariates, no group effects were detected. Standard overnight metyrapone tests do not support a hypersecretion of hypothalamic CRH in panic disorder. Furthermore, no evidence for increased glucocorticoid negative feedback in panic was found. Hypothalamic CRH secretion in the nonpanic state needs further research.

High-Dose and Low-Dose Cosyntropin Stimulation Tests for Diagnosis of Adrenal Insufficiency

Letters17 February 2004High-Dose and Low-Dose Cosyntropin Stimulation Tests for Diagnosis of Adrenal InsufficiencyRichard I. Dorin, MD, Clifford R. Qualls, PhD, and Lawrence M. Crapo, MD, PhDRichard I. Dorin, MDFrom New Mexico Veterans Affairs Healthcare System and University of New Mexico School of Medicine, Albuquerque, NM 87108; and Santa Clara Valley Medical Center, San Jose, CA 95128.Search for more papers by this author, Clifford R. Qualls, PhDFrom New Mexico Veterans Affairs Healthcare System and University of New Mexico School of Medicine, Albuquerque, NM 87108; and Santa Clara Valley Medical Center, San Jose, CA 95128.Search for more papers by this author, and Lawrence M. Crapo, MD, PhDFrom New Mexico Veterans Affairs Healthcare System and University of New Mexico School of Medicine, Albuquerque, NM 87108; and Santa Clara Valley Medical Center, San Jose, CA 95128.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-140-4-200402170-00027 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:The paper by Gandhi and associates (1) was excluded from our analysis because of inadequate stratification of patients by gold standard testing (only 7 of 31 patients had an insulin tolerance or metyrapone test). The paper by Choi and coworkers (2) appeared on MEDLINE in April 2003, after our final draft was submitted, and includes 72 patients who underwent the 1-µg test and the insulin tolerance test. The paper by Rose and colleagues (3) was not detected by our MEDLINE search and includes 2 separate samples of pediatric patients: 38 who had 250-µg testing and metyrapone testing and ...

Significance of Low-Dose and Standard-Dose ACTH Tests Compared to Overnight Metyrapone Test in the Diagnosis of Adrenal Insufficiency in Childhood

Objective: To discover the value of low-dose (LDAT) and standard-dose ACTH tests (SDAT) as compared with the metyrapone test in the diagnosis of secondary adrenal insufficiency. Patients and Methods: LDAT (0.5 µg/m²), SDAT (250 µg/m²) and overnight metyrapone (30 mg/kg) tests were carried out in 29 patients with suspected adrenal insufficiency. LDAT and SDAT were also performed in 36 control subjects. Results: 18 of 29 patients were grouped in the adrenal-sufficient (AS) group and 11 of 29 patients in the adrenal-deficient (AD) group according to the metyrapone test results. The control group had significantly higher cortisol responses than the AS and AD groups during LDAT. The control group had similar cortisol responses to the AS group but higher cortisol responses than the AD group during SDAT. The AS group was divided into 2 subgroups: AS patients with multiple pituitary hormone deficiencies (AS-multiple) and AS patients with idiopathic growth hormone deficiencies (AS-isolated). The AS-multiple group had statistically lower cortisol responses than the control group during LDAT. Receiver-operating characteristics analysis revealed that the cortisol cutoff value in LDAT was 19.8 µg/dl (100% sensitivity, 89% specificity) and 30.4 µg/dl in SDAT (82% sensitivity, 78% specificity). Conclusion: LDAT is capable of identifying patients with adrenal insufficiency more effectively than SDAT. The cortisol cutoff value in LDAT was calculated as 19.8 µg/dl with 100% sensitivity. AS patients with multiple pituitary hormone deficiencies had lower cortisol responses to LDAT than the control group implying that these patients might have a lower cortisol secretory capacity than healthy subjects.

Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function

Purpose : To prospectively evaluate pediatric patients with localized primary brain tumors for evidence of endocrinopathy before radiotherapy (RT). Methods and Materials : Seventy-five pediatric patients were evaluated with the arginine tolerance test and l-dopa test for growth hormone secretory capacity and activity; thyroid-stimulating hormone surge and thyrotropin-releasing hormone stimulation test for the hypothalamic-thyroid axis; the 1-μg adrenocorticotropin hormone (ACTH) and metyrapone test for ACTH reserve; and, depending on age, a gonadotropin-releasing hormone stimulation test to determine gonadotropin response. The study included 38 male and 37 female patients, age 1–21 years with ependymoma ( n = 35), World Health Organization (WHO) Grade I–II astrocytoma ( n = 18), WHO Grade III–IV astrocytoma ( n = 10), craniopharyngioma ( n = 7), optic pathway tumor ( n = 4), and germinoma ( n = 1). Seven patients receiving dexamethasone at the time of the evaluation were excluded from the final analysis. Results : Of 68 assessable patient, 45 (66%) had evidence of endocrinopathy before RT, including 15 of 32 patients (47%) with posterior fossa tumors. Of the 45 patients, 38% had growth hormone deficiency, 43% had thyroid-stimulating hormone secretion abnormality, 22% had an abnormality in ACTH reserve, and 13% had an abnormality in age-dependent gonadotropin secretion. Conclusion : The incidence of pre-RT endocrinopathy in pediatric brain tumor patients is high, including patients with tumors not adjacent to the hypothalamic-pituitary unit. These data suggest an overestimation in the incidence of radiation-induced endocrinopathy. Baseline endocrine function should be determined for brain tumor patients before therapy. The potential for radiation-induced endocrinopathy alone cannot be used as an argument for alternatives to RT for most patients. Pre-RT endocrinopathy may be an early indicator of central nervous system damage that will influence the functional outcome unrelated to RT.

Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management.

Patients undergoing surgical resection of pituitary adenomas are frequently given perioperative glucocorticoid therapy. There are no randomized controlled studies assessing the need for such steroids; however, several studies have documented changes in the hypothalamic-pituitary-adrenal (HPA) axis associated with pituitary surgery. Based on the evidence available, this article details recommendations for the perioperative management of glucocorticoid therapy in patients with pituitary tumors. For patients with proven ACTH deficiency preoperatively [usually based on response to a short ACTH 1-24 (Synacthen) test], 48 hours of supraphysiological glucocorticoid therapy should be administered perioperatively (e.g. hydrocortisone, 50 mg every 8 hours on day 0, 25 mg every 8 hours on day 1, and 25 mg at 0800 h on day 2). For patients with intact HPA function preoperatively, and in whom selective adenomectomy is possible, perioperative glucocorticoids are not necessary. Early postoperative assessment depends on daily clinical assessment of the patient and 0800 h plasma cortisol levels. Cortisol levels over 450 nM (16 microg/dl) reflect normal HPA function, and levels less than 100 nM (3.6 microg/dl) are consistent with ACTH deficiency. Cortisol levels between 100 and 250 nM (3.6-9 microg/dl) may be ACTH deficient and should receive morning hydrocortisone replacement until definitive HPA axis testing. Cortisol levels between 250 and 450 nM (9-16 microg/dl) are unlikely to be ACTH deficient but should receive additional steroids for stress until a definitive test is performed. For those requiring definitive testing, the insulin tolerance test, the overnight metyrapone test, or the glucagon stimulation test are appropriate and may be performed as early as d 7-10 or, if more convenient, wk 4-6. Following the guidelines suggested here should reduce the use of unnecessary glucocorticoids, while ensuring the safety of patients is not compromised.

Glucocorticoid Replacement in Pituitary Surgery: Guidelines for Perioperative Assessment and Management

Patients undergoing surgical resection of pituitary adenomas are frequently given perioperative glucocorticoid therapy. There are no randomized controlled studies assessing the need for such steroids; however, several studies have documented changes in the hypothalamic-pituitary-adrenal (HPA) axis associated with pituitary surgery. Based on the evidence available, this article details recommendations for the perioperative management of glucocorticoid therapy in patients with pituitary tumors. For patients with proven ACTH deficiency preoperatively [usually based on response to a short ACTH 1–24 (Synacthen) test], 48 h of supraphysiological glucocorticoid therapy should be administered perioperatively (e.g. hydrocortisone, 50 mg every 8 h on d 0, 25 mg every 8 h on d 1, and 25 mg at 0800 h on d 2). For patients with intact HPA function preoperatively, and in whom selective adenomectomy is possible, perioperative glucocorticoids are not necessary. Early postoperative assessment depends on daily clinical assessment of the patient and 0800 h plasma cortisol levels. Cortisol levels over 450 nm (16 μg/dl) reflect normal HPA function, and levels less than 100 nm (3.6 μg/dl) are consistent with ACTH deficiency. Cortisol levels between 100 and 250 nm (3.6–9 μg/dl) may be ACTH deficient and should receive morning hydrocortisone replacement until definitive HPA axis testing. Cortisol levels between 250 and 450 nm (9–16 μg/dl) are unlikely to be ACTH deficient but should receive additional steroids for stress until a definitive test is performed. For those requiring definitive testing, the insulin tolerance test, the overnight metyrapone test, or the glucagon stimulation test are appropriate and may be performed as early as d 7–10 or, if more convenient, wk 4–6. Following the guidelines suggested here should reduce the use of unnecessary glucocorticoids, while ensuring the safety of patients is not compromised.

Altered HPA axis responsivity to metyrapone testing in methadone maintained former heroin addicts with ongoing cocaine addiction.

Metyrapone testing, a provocation of hypothalamic-pituitary-adrenocortical (HPA) axis function, was performed in 39 in-patient subjects: 10 stable methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM), eight methadone- maintained former heroin addicts without ongoing drug or alcohol abuse or dependence other than ongoing cocaine dependence (C-MM), and 21 normal volunteers (NV). Plasma adrenocorticotrophic hormone (ACTH) levels were determined in samples drawn at 9A.M., just before administration of 2.25 g metyrapone orally and 4 and 8 hours afterward. Following metyrapone, C-MM had levels of ACTH that were significantly higher than both MM (p < .05) and NV (p < .01); whereas, MM and NV had levels that were comparable. Area under the plasma ACTH curves yielded similar results. This study documents hyper-responsivity to removal of glucocorticoid negative feedback associated with cocaine addiction, even in the setting of methadone maintenance for heroin addiction, which here and previously has been shown to be associated with normalization of HPA axis function.

Adrenal suppression versus clinical glucocorticoid deficiency in the premature infant: no simple answers.

In a recent issue of the journal, Karlsson et al. (1) reported their results of a study on the adrenal function of mostly premature infants by means of a low dose (1 mg/1.73 m) ACTH test and a standard, human (h) CRH (CRH) test (1 mg/kg). Infants studied varied in gestational age, exposure to antenatal glucocorticoid therapy, quantity of dexamethasone received postnatally, interval between the last dose of dexamethasone and the time of testing, and presence or not of concurrent hydrocortisone replacement. They concluded that the hCRH test was superior to the low dose ACTH test in detecting adrenal suppression on the basis of being abnormal more frequently than the latter in the same population of patients. By definition, adrenal suppression denotes sustained deficiency of hypothalamic-pituitary-adrenal (HPA) axis function ensuing exposure of the organism to excessive and prolonged administration of exogenous glucocorticoids (2). The mechanism is suprapituitary, and the condition has no real rodent model equivalent, as adrenal suppression in rats has a very limited duration of 1–2 days (3). Generally, clinically important adrenal suppression in children and adults occurs after 2 or more weeks of glucocorticoid therapy, depends on the type of and the schedule of glucocorticoid administration and lasts from days, to weeks, months or, rarely, infinity (2). The susceptibility of human beings to the development of adrenal suppression varies widely, as does the sensitivity of their different tissues to glucocorticoids (4). When one thinks of glucocorticoid suppression, one should clarify an important issue. The HPA axis, through several feedback control loops that influence its regulatory centers in the brain, is constantly attempting to maintain the day-to-day exposure of tissues to cortisol normal. This results in an intraindividual variability of HPA axis activity that is quite narrow, in contrast to the wide interindividual variability of this system. This means that decreased cortisol secretion a day or two after administration of a large dose of glucocorticoid is not but a corrective action of the organism. Such a change would not qualify as adrenal suppression, which is the sustained, risky glucocorticoid deficiency that ensues prolonged, excessive exposure to exogenous or endogenous glucocorticoids (2). The latter has significant morbidity, ranging from hypoglycemia to hypotension, as well as mortality, usually as a result of circulatory collapsus. The third trimester fetus and the premature and full-term infants have a functional HPA axis that responds to the negative feedback by glucocorticoids and can develop clinically significant adrenal suppression (5–7). Our ability to recognize adrenal suppression in infants is a prerequisite to decide whether or not to administer daily and stress-appropriate glucocorticoid coverage. In a full-term infant in which suppression is not complicated by concurrent systemic inflammation, one could employ the tests and criteria established for older children and adults. The rapid standard ACTH test (250 mg/1.75 m BSA) would be the procedure of choice in such an instance, and the criterion of a cortisol response greater than the value of 1.96 sd below the normal child/adult mean at 30 or 60 min would suggest no need for coverage. In the uncomplicated premature infant, a 40% lowering of these limits has been proposed because of a relative hypoactivity of the premie HPA axis when compared with that of full-term neonates (6). An insulin tolerance or a metyrapone test should not be used in these frail populations, as they provide no advantage over the standard ACTH test and might have serious complications. There is very little experience with the low dose ACTH test in infants and its clinical utility in children and adults remains controversial. Although, admittedly, it may be more sensitive than the standard ACTH test in detecting subtler abnormalities of the HPA axis, its true pertinence in helping treat patients that would not be treated on the basis of a standard ACTH test is uncertain. The same is true for the human or ovine CRH tests. Both appear to be more sensitive than the standard ACTH test in detecting subtle HPA axis abnormalities, but again, are such mild disturbances clinically relevant to dictate medical intervention? The study of Karlsson et al. (1) shows that the hCRH test is more sensitive than the low dose ACTH test but the question is: will such data change our approach to treatment? The usefulness of the standard ACTH test goes beyond detecting adrenal suppression in the premature infant after the remission of a disease for which glucocorticoid therapy was administered in the first place. Infants with the systemic inflammation that accompanies the respiratory distress synReceived October 30, 2000. Accepted October 30, 2000. Address correspondence and requests for reprints to: George Chrousos, M.D., National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583. 0021-972X/01/$03.00/0 Vol. 86, No. 2 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoasrenalism.

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoasrenalism.

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoasrenalism

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoasrenalism

Diagnosis of ACTH Deficiency

Test sensitivity and accuracy of 250 μg/m² ACTH test, 1 μg/m² ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.

The Use of Naloxone for Investigating Disorders of the Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis forms an integral and vital part of the stress response system. Pituitary ACTH secretion is regulated by two hypothalamic peptides, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), with CRH being the primary mediator in humans. Numerous neuronal circuits within the brain influence the activity of the CRH neurons in the paraventricular nuclei of the hypothalamus, including endogenous opioid systems. Opioid receptors are widely distributed in the brain but have a particular association with three major neural networks: the sensory, limbic and neuroendocrine systems. Opioidergic agents affect HPA activity in humans and animals, al though important species differences exist. In vitro and in vivo studies provide considerable evidence for a centrally mediated effect of opioidergic agents on the HPA axis, most likely by direct action on the hypothalamus. Naloxone is a competitive antagonist at multiple opioid receptor subtypes. Clinical investigations utilizing naloxone administration in humans have had three primary aims:1) to elucidate the role of endogenous opioid systems in the normal physiology of the HPA axis; 2) to study the pathophysiology of disorders associated with or caused by dysfunction of the HPA axis; 3) to develop new diagnostic tests. High doses of naloxone stimulate the human HPA ards causing rises in plasma ACTH and cortisol concentrations. Pharmacological stud ies strongly suggest that naloxone blocks a tonic inhibitory effect of endogenous opioids on central alpha-adrenergic pathways, which in turn stimulate ACTH secretion via CRH release from the hypothalamus. Therefore, the naloxone test provides a means of evaluating hypothalamic CRH reserve and assesses the integrity of the entire HPA axis. Several disorders are associated with dysregulation of the HPA axis including major depression, post-traumatic stress disorder, alcoholism, chronic fatigue syndrome, Cushing's syndrome, and obesity. Major depression is a condition often associated with clinical and biochemical evidence of hypercortisolism (pseudo-Cushing's syndrome) and may be very difficult to distinguish from patients with true Cushing's syndrome. Patients with pseudo-Cushing's syndrome are postulated to have hypersecretion of hypothalamic CRH producing an upregulation of an otherwise normal HPA axis. Patients with major depression have an ACTH hyperresponse to naloxone compared with healthy subjects and patients with Cushing's disease. This increased ACTH response is further exaggerated by combining naloxone administration with the direct corticotrope stimulation provided by exogenous AVP. The naloxone test also has potential diagnostic utility-when central adrenal insufficiency is suspected. Naloxone applies a specific pharmacological stimulus at the hypothalamic level, therefore a normal ACTH and cortisol response implies functional integrity of all three components of the HPA axis. Preliminary studies comparing naloxone administration with the insulin hypoglycemia and metyrapone tests are promising. The naloxone test may provide an alternative in patients with suspected central adrenal insufficiency who are unable to undergo an insulin hypoglycemia test or a metyrapone test because of safety issues.

Effect of Endogenous Cortisol Levels on Natural Killer Cell Activity in Healthy Humans

The aim of this study was to examine the effects of increasing and decreasing endogenous cortisol levels on natural killer (NK) cell activityin vivo.Normal healthy volunteers participated in the following studies: baseline (n= 27), metyrapone challenge test (n= 10), dexamethasone suppression test (n= 10), and adrenocorticotropic hormone (ACTH) stimulation test (n= 8). Each subject served as his own control for each study. Each subject was tested for NK activity and plasma cortisol levels at 9a.m., just before the challenge drug administration, and at 10a.m., except for the dexamethasone study, in which only the 9a.m.blood was drawn, 10 h after the dexamethasone administration. On the baseline study day, a significant decrease in plasma cortisol levels was found from 9 to 10a.m.(p< .02) along with a significant increase in NK activity (p< .001). On the metyrapone test day, plasma cortisol levels at 10a.m.were significantly reduced (p< .005) as expected, while NK activity at the same time point was not affected and was increased to an extent equivalent to the baseline study day. On the dexamethasone test day, plasma cortisol concentrations were significantly decreased (p< .0001) as compared to the same time point on the baseline day, without any significant change in the NK activity. On the ACTH test day, plasma cortisol rose significantly at 10a.m.(p< .02), with no change in NK activity. We conclude that plasma cortisol alone has no significant effect on NK activityin vivo.

Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases.

Addison's disease is frequently a component of autoimmune polyendocrinopathies while secondary adrenal insufficiency associated with autoimmune disorders is believed to be a rare event. We present a series of patients with secondary adrenal insufficiency coexisting with autoimmune diseases and/or antithyroid autoantibodies. Among a group of 102 patients with secondary adrenal failure of unknown origin diagnosed at the Department of Endocrinology of the Centre for Postgraduate Medical Education (Warsaw, Poland) we have identified a group with associated autoimmune disorders. Thyroid abnormalities occurred most frequently. Other diseases included insulin-dependent diabetes mellitus, pernicious anaemia, vitiligo, premature ovarian failure and autoimmune thrombocytopaenia. There were 23 women and one man aged 17-72 years at the time of investigation. Additionally, we included a woman with Addison's disease in whom the ACTH deficiency appeared 18 years after the onset of primary adrenal hypofunction. Pituitary-adrenal function tests comprised urinary excretion of 17-hydroxycorticosteroids in basal conditions and during a 2-day tetracosactrin test, plasma concentrations of ACTH and cortisol, and a 2-day metyrapone test (in eight cases). Thyroid function and immunity tests were: TSH, thyroxine, the antithyroglobulin, antimicrosomal and anti-peroxidase autoantibodies. Other endocrine studies included: serum LH, FSH and PRL. The 17-hydroxycorticosteroid values, both basally and during stimulation tests were consistent with a diagnosis of secondary adrenal insufficiency. Serum cortisol and plasma ACTH concentrations were low. In 14 patients primary hypothyroidism was confirmed by low T4 levels. In three patients subclinical primary hypothyroidism was revealed (elevated TSH levels). Three patients who had a past history of Graves' disease were euthyroid at the time of investigation. Twenty-three patients had antibodies against peroxidase. Most patients had gonadotrophins and PRL values within normal limits. The co-existence of autoimmune disorders with secondary adrenal insufficiency suggests an autoimmune aetiology for the ACTH deficiency.

PITUITARY AND ADRENAL RESERVE: EFFECTS OF TRAINING AND ACUTE EXERCISE.

1564 We examined the effect of training status and acute exercise on pituitary and adrenal reserve and the impact of reduced plasma cortisol on VO2max in 8 trained (T) and 8 untrained (UT) males. Subjects completed 2 graded maximal exercise tests (GXT) each preceded by either an overnight metyrapone(MET) test or placebo (PLA) administration. Blood samples were collected before (PRE) and after (POST) GXT. PRE-PLA plasma adrenocorticotropin (ACTH) was higher in T compared to UT subjects, whereas POST-PLA plasma ACTH increased only in UT (P< 0.05). Additionally, T subjects had higher PRE-MET ACTH levels compared with POST-PLA values. PRE-MET plasma cortisol was attenuated ≈ 70% in both groups compared to PRE-PLA, whereas plasma 11-deoxycortisol and ACTH increased (P<0.05). POST-MET 11-deoxycortisol and ACTH increased compared to PRE-MET in both groups ( P <0.05), whereas plasma cortisol remained unchanged. Further, the POST-MET ACTH response was greater in T than in UT subjects. VO2max was not altered by MET in either group. We conclude that: 1) at rest training does not alter pituitary or adrenal reserve; 2) individually the GXT and MET provide a similar ACTH response in UT but not in T subjects; 3) when these two tests are superimposed, greater ACTH and glucocorticoid responses result compared to either test alone; and 4) an acute reduction in plasma cortisol does not alter VO2max.

Normal Short Synacthen Test in Patients with Secondary Adrenal Failure

The short synacthen test (SST), first introduced by Wood et al. 1 in 1965, is widely used to confirm the diagnosis of primary adrenal insufficiency. The optimum method for the diagnosis of secondary adrenal insufficiency remains controversial. The insulin tolerance test (ITT) is accepted by most endocrinologists as the gold standard 2 for the assessment of the hypothalamic-pituitary-adrenal (HPA) axis, but is hazardous at times, with some morbidity and occasional mortality. The short synacthen test is gaining popularity, and by 1994, up to 50% of UK endocrinologists were using it to assess the HPA axis. 3 We describe two cases presenting with hyponatremia in whom hypoadrenalism was suspected, but with normal SST. The secondary adrenal insufficiency was later confirmed in these cases on clinical features, associated hormonal deficiencies, ancillary investigations and most important of all, the therapeutic response to replacement steroids. Case 1 A 63-year-old male presented with a history of six to seven episodes of fainting/loss of consciousness over the previous year-and-a-half. These episodes were never preceded by any palpitations or associated with seizure activity and/or incontinence of urine or feces. He also experienced occasional nausea with vomiting. He was labelled to have ischemic heart disease on the basis of ECG changes, but did not have angina and was taking diltiazem, moduretic (amiloride and hydrochlorothiazide), ranitidine and amitriptyline regularly. He appeared unwell upon admission, and was pale-looking, with a pulse of 90/min. His blood pressure was in the range of 120-140 mm Hg systolic and 70 mm Hg diastolic, but with a significant postural drop of 20 mm Hg. The rest of the examination was unremarkable. Routine investigations revealed serum sodium of 112 mmol/L, potassium of 3.3 mmol/L, and creatinine of 1.0 mg/dL. It was thought that electrolyte imbalance was due to diuretics and associated vomiting. He was rehydrated with normal saline and the

Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease.

The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation. From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8-118 months). Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 x 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol < 140 nmol/l and/or 24-hour urinary cortisol excretion < 250 nmol. During follow-up: serum cortisol, as well as serum cortisol in the 1 mg overnight dexamethasone-suppression test was measured in order to detect relapse of Cushing's disease. Twelve of 29 patients were not in remission after surgery. These patients all had serum 11-deoxycortisol levels > 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient's experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol < 150 nmol/l after metyrapone, no relapse occurred. The metyrapone test is a useful test in the assessment of outcome of pituitary surgery for Cushing's disease, with a sensitivity of 100% and a specificity of 75% for the early detection of patients at risk of a relapse. Patients in whom a serum 11-deoxycortisol > 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

Testing the hypothalamic-pituitary-adrenal axis in survivors of childhood brain and skull-based tumors.

The objective of this study was to determine whether a low dose of ACTH (0.2 microg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors. Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-microg i.v. bolus), a low dose ACTH test (0.2 microg/kg i.v. bolus), an insulin tolerance test, and a single dose metyrapone test. Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion. In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.

Failure of the short ACTH test to unequivocally diagnose long‐standing symptomatic secondary hypoadrenalism

Recent guidelines propose that secondary hypoadrenalism can be reliably diagnosed, in the absence of acute ACTH deficiency or glucocorticoid use, by means of the short ACTH test (Synacthen). We report a patient who maintained a normal response to exogenous ACTH stimulation despite symptomatic chronic ACTH deficiency proven by the insulin tolerance and overnight metyrapone tests. It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation. A normal cortisol response in the short ACTH test does not therefore exclude the possibility of clinically relevant ACTH deficiency.