Acute effects of acylated and unacylated ghrelin on total and high molecular weight adiponectin inmorbidly obese subjects.

BACKGROUND: Energy homeostasis and body weight are regulated by a highly complex network involving the brain, the digestive tract, and white adipose tissue (WAT). Knowledge about signaling pathways connecting digestive tract and WAT is limited. Gut hormone ghrelin and adipokine adiponectin are both decreased in obesity and they share a potent effect on insulin sensitivity: both adiponectin and the combination of acylated (AG) and unacylated ghrelin (UAG) improve insulin sensitivity. AIM: In the present study, we evaluated whether acute administration of UAG alone or combined with AG affects adiponectin concentrations. SUBJECTS AND METHODS: Eight morbidly obese non-diabetic subjects were treated with either UAG 200 µg, UAG 100 µg + AG 100 µg (Comb), or placebo in 3 episodes in a double blind randomized cross-over design. Study medication was administered as single iv bolus injections at 09:00 h after an overnight fast. High molecular weight (HMW) and total adiponectin, glucose, insulin, and total ghrelin and AG were measured up to 1 h after administration. RESULTS: HMW and total adiponectin concentrations did not change after administration of either UAG or Comb, nor were they different from placebo. Insulin concentrations decreased significantly after acute administration of Comb, reaching a minimum at 20 min: 58.2 ± 3.9% of baseline. CONCLUSIONS: Acute iv administration of UAG and the combination of UAG and AG in morbidly obese non-diabetic subjects without overt diabetes does not affect total or HMW adiponectin concentrations, neither directly nor indirectly by changing insulin concentrations.

Biochemical predictors of outcome of pituitary surgery for Cushing's disease.

OBJECTIVE: Transsphenoidal surgery (TS) is the primary therapy for Cushing's disease (CD). The aims of this retrospective study were twofold: (i) investigate early and late results of TS for CD, and (ii) evaluate various postoperative tests in order to predict the outcome of TS. METHODS: We reviewed the long-term outcome in 79 patients with CD who underwent TS (median follow-up 84 months, range 6-197). Within 2 weeks after surgery, morning serum cortisol concentrations were obtained (n = 78) and corticotropin-releasing hormone (CRH) (n = 53) and metyrapone tests (n = 72) were performed. Three groups of outcome were identified: sustained remission, early failure (persistent CD), and late relapse. RESULTS: Immediate postoperative remission was achieved in 51 patients (65%), whereas 28 patients (35%) had persistent CD after TS. Ten patients developed recurrent CD after initial remission (20%). Morning cortisol: all relapses but one recorded serum cortisol >50 nmol/l. A cortisol threshold value of 200 nmol/l has a positive predictive value of 79% for immediate surgical failure (negative predictive failure [NPV] 97%). CRH test: CRH-stimulated peak cortisol > or =600 nmol/l predicted early failure in 78% (NPV 100%). All relapses recorded CRH-stimulated peak cortisol >or =485 nmol/l. Metyrapone test: 11-deoxycortisol >or =345 nmol/l predicted an early failure in 86% of cases (NPV 94%). CONCLUSION: Predictive factors of surgical failure are morning cortisol >or =200 nmol/l, 11-deoxycortisol >or =345 nmol/l after metyrapone and CRH-stimulated cortisol >or =600 nmol/l. CRH and/or metyrapone testing are not superior to morning cortisol concentration in the prediction of outcome of TS. Careful long-term follow-up remains necessary independent of the outcome of biochemical testing.

Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma.

Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.

Salivary cortisol is related to atherosclerosis of carotid arteries.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population. METHODS AND RESULTS: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline. RESULTS: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (beta = 0.08 per sd of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score. CONCLUSION: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant.

OBJECTIVE: The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment. DESIGN: This was a prospective, investigator-initiated, double blind, placebo-controlled, crossover study. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 wk, separated by a washout period of 4 wk. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ). RESULTS: The AcroQoL (P = 0.008) and AcroQoL physical (P = 0.002) improved significantly after PEG-V was added. The addition of PEG-V also significantly improved the PASQ (P = 0.038) and the single PASQ questions, perspiration (P = 0.024), soft tissue swelling (P = 0.036), and overall health status (P = 0.035). No significant change in Z-score of IGF-I (P = 0.34) was observed during addition of PEG-V. Transient liver enzyme elevations were observed in five subjects (25%). CONCLUSION: Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.

Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire.

UNLABELLED: Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL). OBJECTIVE: Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions. DESIGN: Observational, international, cross-sectional study. METHODS: A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score. RESULTS: A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20-73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's alpha=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient > or =0.597). Patients with current hypercortisolism scored worse (lower) than those without (44+/-22 vs 56+/-21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL. CONCLUSION: CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.

Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma.

CONTEXT: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. OBJECTIVE: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs). DESIGN: This was a follow-up study. PATIENTS: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort. OUTCOME MEASURES: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients. RESULTS: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008). CONCLUSIONS: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.

[Cushing's syndrome. I. New diagnostic developments]. / Syndroom van Cushing. I. Nieuwe ontwikkelingen in de diagnostiek.

Over the past few years, new diagnostic tests for Cushing's syndrome have become available. Some of the other, older diagnostic tests have fallen into discredit as they could not distinguish conditions from one another sufficiently well. New biochemical tests include midnight salivary cortisol measurement and the combined dexamethasone-corticotropin releasing hormone (CRH) test. The high dose dexamethasone test and the CRH-stimulation test have been abandoned as they were unable to differentiate between hypophysial and ectopic secretion of adrenocorticotropic hormone (ACTH). For the detection of ectopic ACTH-secreting tumours new imaging techniques, such as somatostatin receptor scintigraphy and positron emission tomography with 5-hydroxytryptophan, have become available.

[Cushing's syndrome. II. New forms of treatment]. / Syndroom van Cushing. II. Nieuwe behandelingen.

Several new therapeutic options both medicinal and surgical, have emerged for the treatment of Cushing's syndrome. In Cushing's disease caused by an adrenocorticotropin (ACTH) secreting pituitary adenoma, the introduction ofendoscopic pituitary surgery offers better visualization of the sella than does the traditional explorative surgery. However, at present it is unclear whether this will result in a better outcome. New drugs under investigation include universal somatostatin analogues such as SOM230, and a combination of a somatostatin analogue and dopamine agonist known as dopastatin. These agents may also be effective for the medicinal treatment of ectopic ACTH-secretion. Treatment with radioactive-labelled somatostatin-analogues such as 177lutetium octreotate is another option for these patients. The primary treatment for ACTH-independent Cushing's syndrome is laparoscopic adrenalectomy. In rare cases of bilateral adrenal hyperplasia, medicinal treatment aimed at new regulatory pathways of cortisol secretion can be applied.

Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant.

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.

Quality of life in patients after long-term biochemical cure of Cushing's disease.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

Neuroendocrine tumors and somatostatin: imaging techniques.

Tumors and metastases bearing the somatostatin receptor subtypes 2 (SSTR2) or SSTR5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs like 111In-pentetreotide. The sensitivity of 111In-pentetreotide scintigraphy for the detection of carcinoid tumors is 86-95%. The sensitivity of 111In-pentetreotide scintigraphy for the detection of gastrinomas, vasoactive intestinal polypeptide-secreting tumors, and glucagonomas as well as clinically non-functioning lesions is 75-100%. However, for insulinoma this is 50-60%. 111In-pentetreotide scintigraphy generally has a lower detection rate for benign pheochromocytomas than 123I-MIBG scintigraphy, but it can have a complementary role for the staging of malignant pheochromocytomas. It can also be used for the detection of extra-adrenal pheochromocytomas and paragangliomas. Most GH- and TSH-secreting pituitary adenomas can be visualized using 111In-pentetreotide. 111In-pentetreotide scintigraphy is negative in microprolactinomas and ACTH-secreting pituitary microadenomas. 111In-pentetreotide scintigraphy has been successful for the localization of extra-pituitary ACTH-secreting tumors and their metastases, and especially for occult tumors. A large variety of lesions in and around the pituitary region express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.

Diagnosis and treatment of hypopituitarism: an update.

Diagnosis and treatment of patients with hypopituitarism needs careful clinical evaluation and individual optimization. Symptoms of hypopituitarism are variable, often insidious in onset and dependent on the degree of hormone deficiency. Diagnosis of hypopituitarism can be straightforward by measuring reduced basal hormone levels. Frequently, dynamic stimulation tests are indicated in equivocal basal hormone levels or to diagnose partial hormone deficiencies. Knowledge of the use and limitations of these dynamic tests is mandatory for proper interpretation. Hormone replacement therapy should be individualized, taking into account possible interactions. Persisting symptoms and reduced quality of life are frequently reported, explained by, at least in part, intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. In the present overview, the principles of diagnosis and treatment of hypopituitarism are discussed.

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Cerebrospinal fluid leakage during transsphenoidal surgery: postoperative external lumbar drainage reduces the risk for meningitis.

Postoperative meningitis is a well known complication of transsphenoidal surgery (TSS). The objective of this study was to evaluate whether postoperative external cerobrospinal fluid (CSF) drainage in case of intraoperative CSF-leakage, reduces the risk of postoperative meningitis. We retrospectively reviewed a series of 278 consecutive transsphenoidal operations. In all operations with intraoperative CSF leakage, an external lumbar drain (ELD) was inserted directly postoperatively, and removed after at least 5 days. The incidence of postoperative meningitis was compared with that in a previously studied series of 228 consecutive transsphenoidal operations, without insertion of an ELD in cases with intraoperative CSF leakage. In the present series, postoperative meningitis occurred in 2/278 (0.7%) operations, compared to 7/228 (3.1%) operations in the previous study period (P < 0.05). Intraoperative CSF leakage was noted in 70/278 (25.2%) operations. All these patients received an ELD immediately after surgery for at least 5 days. There were no reported complications of ELD insertion. In the present series, 1 of 70 (1.4%) patients with intraoperative CSF leakage developed meningitis, compared to 3 of 22 (13.6%) patients in the previous study (P < 0.05). The present report on 278 consecutive transsphenoidal operations shows that the routine insertion of an ELD in patients in whom intraoperative CSF leakage is observed significantly reduces the incidence of postoperative meningitis. Possibly, diversion of CSF prevents the formation of a CSF fistula and thereby the risk of infection. The role of prophylactic antibiotic treatment in patients with CSF rhinorrhea after TSS remains to be established.

[The prioritisation of genetic screening with primary haemochromatosis as an example]. / Prioritering van criteria voor genetische screening, toegelicht aan de hand van de ziekte primaire hemochromatose.

In 1994, the Health Council of the Netherlands published a report entitled 'Genetic screening' which contained 12 criteria for genetic screening programmes. However, the list does not prioritize the various criteria. From the list we have selected two criteria that we consider to be the most important. Firstly, the genetic screening test should be able to discriminate between subjects who are likely to develop the disease and those who are not. Secondly, there should be an effective treatment for subjects with the genetic defect. From this point of view, for example, screening for the C282Y mutation is not a suitable approach for detecting primary haemochromatosis. Although 85-90% of the patients with this disease are homozygous for this mutation, the majority of the carriers will not develop the disease. The 12 criteria of the Health Council of the Netherlands are still applicable. However, when taking a decision as to whether or not genetic screening is useful, we recommend that priority be given to the two primary criteria.

No increase in mortality and morbidity among carriers of the C282Y mutation of the hereditary haemochromatosis gene in the oldest old: the Leiden 85-plus study.

BACKGROUND: The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85-plus. STUDY DESIGN: A cross-sectional comparison and prospective follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all-cause and specific causes of death. RESULTS: Prevalence of C282Y homozygosity in both cohorts was 0.2% (1/661 and 1/552, respectively) and of C282Y heterozygosity was 12.4% (82/661) and 11.4% (63/552), respectively. These estimates coincide exactly with reported estimates in younger age groups. Median ferritin level was 97 microg L-1 (IQR 39-162) for heterozygous carriers and 89 microg L-1 (IQR 41-157) for noncarriers (P = 0.66). The serum ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at the time of enrollment in 1986, was 392 microg L-1. Cardiovascular morbidity was comparable between the C282Y heterozygous subjects and the noncarriers in both study cohorts. All-cause and cardiovascular mortality of carriers of the C282Y mutation was similar to that in noncarriers. CONCLUSIONS: We found two C282Y homozygous subjects, illustrating that homozygosity can be compatible with survival in very old ages. C282Y heterozygosity was not associated with history of cardiovascular disease morbidity, all cause mortality, cardiovascular mortality, or biochemical phenotype of haemochromatosis at old age.

Risk factors for meningitis after transsphenoidal surgery.

To evaluate possible risk factors for meningitis, we retrospectively reviewed 228 transsphenoidal operations (in which a standard regimen of amoxicillin prophylaxis was used) for sellar pathology. The incidence of meningitis was 3.1% (seven of 228 cases). Cultures of preoperative specimens from the anterior nasal vestibule in three of seven patients yielded Staphylococcus aureus, but none of these patients developed S. aureus meningitis. Two of three patients with significant preoperative paranasal sinus abnormalities developed meningitis compared with only five of 225 patients without significant paranasal sinus abnormalities (P < .005). Three of 22 patients with intraoperative cerebrospinal fluid (CSF) leakage developed meningitis compared with four of 206 patients without intraoperative CSF leakage (P < .05). Six of seven patients with postoperative CSF rhinorrhea and only one of 221 patients without postoperative CSF rhinorrhea developed meningitis (P < .00001). In conclusion, postoperative CSF leakage is an important risk factor for meningitis after transsphenoidal surgery. Cultures of preoperative specimens from the anterior nasal vestibule did not have any predictive value in our study.

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.