The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery.

OBJECTIVE: To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis posthypophysectomy. DESIGN: Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4-6 weeks after pituitary surgery. SUBJECTS: Thirty-two patients with known pituitary disease. None with present or previous Cushing's syndrome. OUTCOME MEASUREMENTS: Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11-deoxycortisol level following a weight related oral dose of metyrapone at 0000 h. RESULTS: One of the 32 patients required further surgery and was studied twice after each operation. Thirty-three results are therefore compared. Twenty-six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11-deoxycortisol level less than 200 nmol/l). After 3-40 months (median 20 months) of follow-up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test. CONCLUSIONS: The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow-up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow-up to date would not support this.

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

OBJECTIVE: 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. PATIENTS: 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). MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Assessment of the hypothalamic-pituitary-adrenal axis function after corticosteroid therapy for MS relapses.

Doses of corticosteroids usually given for relapses of MS are able to suppress the hypothalamic-pituitary-adrenal (HPA) axis. We evaluated HPA axis function using rapid ACTH stimulation and rapid overnight metyrapone tests, just after cessation of regular oral prednisone therapy for relapses in 14 MS patients. Nine additional patients treated with i.v. boluses of methylprednisolone before beginning conventional oral therapy were also evaluated. Sixteen patients had normal response to both tests and 6 patients had only a discordant response to one test. These data indicate that most patients had normal HPA axis function, which make corticosteroid replacement unnecessary after cessation of therapy for relapses.

Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone.

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose metyrapone test at 06.00 h: an accurate method for assessment of pituitary-adrenal reserve.

One dose of metyrapone (1.5g) administered at 06.00 h, with subsequent measurement of 11-deoxycortisol and 17-hydroxycorticosteroid (17-OHCS) levels in plasma at 12.00 and 14.00 h, allowed accurate assessment of the pituitary-adrenal reserve. Normal response was defined as achieving a serum 17-OHCS level of more than 10.0 micrograms/100 ml and a 11-deoxycortisol level of more than 6.0 micrograms/100 ml at either 12.00 or 14.00 h. These criteria are based on a group of 18 persons with normal pituitary-adrenal axis, and 86 additional cases responded in this normal range. In this group of 104 subjects, 11-deoxycortisol levels rose to 9.2 +/- 3.5 micrograms/100 ml at noon and 17-OHCS levels to 15.4 +/- 4.7 micrograms/100 ml at 14.00 h. Post-metyrapone 17-OHCS levels were significantly higher than normal cortisol levels at these times (P less than 0.001) and than those observed at 08.00 h on the day of the test, demonstrating stimulation of adrenal corticoid production in addition to blockade of cortisol production by metyrapone. Thirty-one patients found to suffer from secondary adrenal failure showed impaired response. All these patients had limited pituitary-adrenal reserve, either proven by other pituitary-adrenal tests or implicated by severe pituitary disease.

Assessment of 11beta-hydroxylase activity with plasma corticosterone, deoxycorticosterone, cortisol, and deoxycortisol: role of ACTH and angiotensin.

UNLABELLED: In this study we evaluated the role of ACTH and angiotensin on regulation of activities of 11beta-hydroxylases of the adrenal cortex. The ratio of the plasma concentrations of 11 deoxycorticosterone (DOC) to plasma corticosterone (B) reflected the activity of the enzyme of the B and/or aldosterone pathways, and the ratio of plasma 11-deoxycortisol (S) to plasma cortisol (F) as the activity of the enzyme in the F pathway. In normal subjects, both ratios were significantly lower at 0800-0900 h (Doc to B, .01+/-.004, mean+/-SE, n=10; and S to F, .01+/-.003) than at 2000 h (DOC to B, .028+/-.024 and S to F, .015+/-.005). The plasma levels of DOC, B, S and F were all significantly lower at 2000-2100 h than at 0800-0900 h. In contrast 9 patients with Cushing's syndrome exhibited no diurnal change in the ratios. The ratios increased substantially following dexamethasone or metyrapone administration. A high or low salt diet and an angiotensin infusion produced no significant effect on the ratios. The plasma concentration of all four steroids was increased by more than 50% by an infusion of angiotensin. Four hours after administration of 80 mg of Lasix at 0800 h to 10 normal subjects, the ratios of DOC to B and S to F increased significantly (P less than .02), an effect possibly related to a decreased secretion of ACTH. CONCLUSIONS: 1) 11beta-hydroxylase activity of the B and/or aldosterone and F pathways appears to change in parallel with ACTH secretion, and 2) although angiotensin stimulates steroidogenesis of the pathways, it has no apparent effect on 11beta-hydroxylase activity.