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Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing., Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018., Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients)., Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

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Context: There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder., Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing's disease., Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study., Patients: Thirty-nine patients with either de novo Cushing's disease who were candidates for pituitary surgery or with persistent or recurrent Cushing's disease after surgery without having received prior pituitary irradiation., Intervention: Patients self-administered sc pasireotide 600 microg twice daily for 15 d., Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure., Results: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders., Conclusions: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

Urinary free cortisol (UFC) excretion over 24 h reflects the production rate of cortisol and is used commonly in the diagnosis of Cushing syndrome. We report on two patients evaluated for Cushing syndrome who had elevated UFC when analyzed by HPLC but normal values for the analysis performed by RIA and HPLC-mass spectrometry/mass spectrometry (HPLC-MS/MS). Other laboratory testing was inconsistent with the diagnosis of Cushing syndrome and raised doubts about the diagnosis. We identified a probable cause of analytical interference as coming from fenofibrate (Tricor), medication taken by the patients. Fenofibrate peak overlapped with the HPLC peak of cortisol and produced an MS/MS transition overlapping the major transition of cortisol. A second MS/MS transition was free from interference. In summary, fenofibrate administration may cause false elevation of UFC values determined by HPLC or HPLC-MS/MS in patients evaluated for Cushing syndrome. An HPLC-MS/MS method using multiple mass transitions, rather than a single transition, allows accurate quantitation of urinary cortisol in patients taking fenofibrate.

Determination of the etiology of primary aldosteronism remains a diagnostic challenge. The most common types of primary aldosteronism are bilateral adrenal hyperplasia (BAH), aldosterone-producing adenomas (APA), and primary adrenal hyperplasia. Computed tomography (CT) and adrenal vein sampling (AVS) are the primary modalities used to differentiate these subtypes. The purpose of this study was to compare AVS and CT imaging of the adrenal glands in patients with hyperaldosteronism in whom CT imaging was normal or in whom focal unilateral or bilateral adrenal abnormalities were detected. The diagnosis of primary aldosteronism was made in 62 patients based on an elevated plasma aldosterone to PRA ratio and an elevated urinary aldosterone excretion rate. Thirty-eight patients had CT imaging and successful bilateral adrenal vein sampling and were included in the final analysis. AVS was considered the gold standard in determining the specific subtype of primary aldosteronism. There were 15 patients with APA, 21 patients with BAH, and 2 patients with primary adrenal hyperplasia. Plasma aldosterone was significantly higher in patients with APA (46.3 +/- 8.5 ng/dL; 1284 +/- 235 pmol/L) than in those with BAH (29.3 +/- 2.4 ng/dL; 813 +/- 11 pmol/L; P < 0.05). Plasma potassium was significantly lower in patients with APA (3.1 +/- 0.1 mmol/L) than in patients with BAH (3.5 +/- 0.1 mmol/L; P < 0.02). There was considerable overlap in the other biochemical indices (e.g. PRA and urinary aldosterone) in patients with the different subtypes. In patients with APA proven by AVS, eight had concordant findings with CT imaging, four had discordant findings, and three had normal CT imaging. In patients with BAH proven by AVS, four had concordant findings with CT imaging, eight had discordant findings, and nine had normal CT imaging. Compared with AVS, CT imaging was either inaccurate or provided no additional information in 68% of the patients with primary aldosteronism. We conclude that adrenal CT imaging is not a reliable method to differentiate primary aldosteronism. Adrenal vein sampling is essential to establish the correct diagnosis of primary aldosteronism.

The clinical features of Cushing's syndrome (such as obesity, hypertension, and diabetes) are commonly encountered in clinical practice. Patients with Cushing's syndrome have been identified by an abnormal low-dose dexamethasone suppression test, elevated urine free cortisol (UFC), an absence of diurnal rhythm of plasma cortisol, or an elevated late-night plasma cortisol. Because the concentration of cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma, measurement of salivary cortisol in the evening (nadir) and morning (peak) may be a simple and convenient screening test for Cushing's syndrome. The purpose of this study was to evaluate the usefulness of the measurement of late-night and morning salivary cortisol in the diagnosis of Cushing's syndrome. We studied 73 normal subjects and 78 patients referred for the diagnosis of Cushing's syndrome. Salivary cortisol was measured at 2300 h and 0700 h using a simple, commercially-available saliva collection device and a modification of a standard cortisol RIA. In addition, 24-h UFC was measured within 1 month of saliva sampling. Patients with proven Cushing's syndrome (N = 39) had significantly elevated 2300-h salivary cortisol (24.0 +/- 4.5 nmol/L), as compared with normal subjects (1.2 +/- 0.1 nmol/L) or with patients referred with the clinical features of hypercortisolism in whom the diagnosis was excluded or not firmly established (1.6 +/- 0.2 nmol/L; N = 39). Three of 39 patients with proven Cushing's had 2300-h salivary cortisol less than the calculated upper limit of the reference range (3.6 nmol/L), yielding a sensitivity of 92%; one of these 3 patients had intermittent hypercortisolism, and one had an abnormal diurnal rhythm (salivary cortisol 0700-h to 2300-h ratio <2). An elevated 2300-h salivary cortisol and/or an elevated UFC identified all 39 patients with proven Cushing's syndrome (100% sensitivity). Salivary cortisol measured at 0700 h demonstrated significant overlap between groups, even though it was significantly elevated in patients with proven Cushing's syndrome (23.0 +/- 4.2 nmol/L), as compared with normal subjects (14.5 +/- 0.8 nmol/L) or with patients in whom Cushing's was excluded or not firmly established (15.3 +/- 1.5 nmol/L). Late-night salivary cortisol measurement is a simple and reliable screening test for spontaneous Cushing's syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus).

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

Liddle's syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of the beta- or gamma-subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxy-corticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the beta-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle's syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of diabetes insipidus due to progressive vasopressin deficiency with onset typically at 1-6 yr of age. Affected individuals demonstrate specific degeneration of the vasopressinergic magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei and loss of the posterior pituitary bright spot on magnetic resonance imaging. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. Mutations that cause ADNDI have been found to occur both within the signal peptide of the prepro-AVP-NPII precursor and within the coding sequence for neurophysin II, but not within the coding sequence for AVP itself. We evaluated the AVP-NPII genes in two independent families with ADNDI and identified a mutation (C280-->T) in the coding sequence for the signal peptide of the prepro-AVP-NPII precursor in both families. This mutation encodes an Ala-->Val substitution at the C-terminus of the signal peptide (-1 amino acid). This mutation predicts the complete inability of signal peptidase to cleave the signal peptide from the preproprecursor and supports the hypothesis that the progressive neural degeneration that underlies ADNDI is caused by accumulation of malprocessed precursor. However, considerable heterogeneity in the age of onset (1-28 yr of age) and the severity of diabetes insipidus among affected members of these two families suggests that additional factors modulate the rate and extent of progression of the neurodegeneration that results from this one specific ADNDI mutation.

The optimal treatment for ectopic ACTH syndrome is the complete removal of the tumor secreting ACTH. These tumors are often occult, with their location suggested but not proven with imaging techniques. The intraoperative measurement of ACTH by immunoradiometric assay in five patients with the occult ectopic ACTH syndrome during removal of suspicious intrapulmonary lesions is reported. A significant ACTH gradient was detected in the pulmonary veins of the affected lobes in two patients. ACTH had decreased significantly in all five patients by 10 and 15 min after tumor removal. All five patients had histologically proven ACTH-secreting bronchial carcinoid tumors, suppressed plasma ACTH by 24 h after tumor removal, and subsequent secondary adrenal insufficiency indicating successful surgical therapy (five of five true-positive). In one patient, previous surgery was not curative and did not result in a decrease in intraoperative measurement of ACTH (one of one true-negative). It was demonstrated that a rapid ACTH immunochemiluminescence assay with a 15-min incubation time has sufficient sensitivity and precision to detect decreases in ACTH described above. These results demonstrate that complete removal of ACTH-secreting bronchial carcinoid tumors can be detected intraoperatively by a decrease in arterial ACTH by 15 min. The modification of the ACTH immunochemiluminescence assay to 15 min incubation allows the documentation of a successful tumor removal in the operating room. It may also be used to locate the tumor intraoperatively by selective pulmonary vein sampling. This protocol may be applicable to the intraoperative measurement of ACTH during pituitary microadenomectomy for Cushing's disease.

Adrenal dysfunction has been reported in patients infected with the human immunodeficiency virus (HIV). To evaluate the prevalence and degree of adrenal dysfunction in HIV-infected patients, we performed a longitudinal study in 53 ambulatory HIV patients. The plasma cortisol, aldosterone, and dehydroepiandrosterone (DHEA) responses to cosyntropin (250 micrograms, i.v.) were evaluated at 6-month intervals for 24 months and compared to those of normal subjects. The basal and peak cortisol responses to cosyntropin were normal in all HIV patients during the study. There was no difference in the mean basal or stimulated cortisol measurements between Center for Disease Control (CDC) class II-III and CDC class IV patients. Although the mean peak aldosterone response to cosyntropin in HIV patients did not differ from that in normal subjects during the study, the aldosterone secretory capacity was significantly less in CDC class IV than CDC class II-III patients at 6- and 18-month intervals. In addition, there was an impaired aldosterone response to cosyntropin in 31-53% of CDC class IV patients and in only 0-26% of CDC class II-III patients. The mean peak DHEA response to cosyntropin in HIV patients was significantly less than that in normal subjects during the entire study. Basal plasma aldosterone, PRA, cortisol, and DHEA levels did not change in 25 HIV patients who were followed for the entire 24-month period. However, plasma ACTH in these 25 patients was significantly increased at 24 months (9.7 +/- 0.9 pmol/L) compared to that at study entry (7.0 +/- 0.7 pmol/L). Of these 25 patients, 8 had plasma ACTH concentrations that exceeded the normal range at 24 months. The subnormal aldosterone and DHEA secretion with normal cortisol production in these HIV patients is similar to the alterations in adrenal function reported in seriously ill patients without HIV infection. Although we found that clinically significant adrenal insufficiency is uncommon, the elevations in plasma ACTH in several patients at the end of our 2-yr study suggest that adrenocortical capacity may become compromised.

The clinical, biochemical, and radiographic features of ectopic ACTH-dependent Cushing's syndrome are often indistinguishable from those of pituitary ACTH-dependent hypercortisolism (Cushing's disease). We prospectively evaluated 29 patients with ACTH-dependent hypercortisolism by means of bilateral inferior petrosal sinus ACTH sampling with ovine CRH (oCRH) stimulation. Patients with Cushing's disease (n = 20), had a maximal basal inferior petrosal sinus to peripheral ACTH ratio (IPS:P-ACTH) of 11.7 +/- 4.4 (+/- SE) from the dominant IPS, which increased to 50.8 +/- 18.3 after oCRH administration. Bilateral IPS sampling was necessary to correctly identify patients with Cushing's disease, since the maximal basal nondominant IPS:P-ACTH was less than 2.0 in over 50% of the patients and remained less than 2.0 after oCRH administration in one third. In contrast, patients with occult ectopic ACTH-secreting neoplasms (n = 9) had maximal basal IPS:P-ACTH of 1.2 +/- 0.1 that did not change after oCRH administration. Occult ectopic ACTH-secreting neoplasms were found in 7 of 9 patients from 0.4-14 yr after the recognition of Cushing's syndrome, and 4 of these patients had intermittent hypercortisolism with prolonged periods of remission. Selective endobronchial lavage for ACTH correctly localized a radiologically occult ACTH-secreting bronchial carcinoid in 1 patient, and magnetic resonance imaging identified a similar neoplasm in a patient with a normal chest computed tomographic scan. Basal ACTH and urinary free cortisol excretion were significantly higher in patients with ectopic ACTH than in those with Cushing's disease, but overlap existed between groups. High dose dexamethasone suppression testing inaccurately classified 24% of patients, and radiological imaging of the pituitary and adrenal glands was misleading. The occult ectopic ACTH syndrome is a common form of ACTH-dependent hypercortisolism that cannot be distinguished from Cushing's disease with routine clinical studies. The accurate differential diagnosis of ACTH-dependent Cushing's syndrome requires bilateral inferior petrosal sinus ACTH sampling with oCRH stimulation.

We report a postmenopausal woman with primary hyperparathyroidism (PHPT) and severe hypercalcemia while her total calcium intake was more than 2 g daily. Despite a markedly elevated intact PTH level, her serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was low (17 pmol/L; 7 pg/mL). With reduced calcium intake, her serum calcium normalized, and 1,25-(OH)2D increased to 122 pmol/L (51 pg/mL). At the same time, intact PTH decreased to 32% of the initial value. PHPT may be associated with low circulating 1,25-(OH)2D levels. Furthermore, low 1,25-(OH)2D levels in PHPT may be due to a direct effect of severe hypercalcemia and be reversible with correction of hypercalcemia.

A young woman developed intermittent headaches and progressive hyperpigmentation after bilateral adrenalectomy for Cushing's disease. Results of sellar polytomography were abnormal. Her plasma ACTH levels increased to 4750-7340 pg/ml and did not rise with insulin-induced hypoglycemia. Although she experienced no clinical features associated with spontaneous infarction of a pituitary tumor, plasma ACTH levels fell to 474-575 pg/ml, and hemorrhagic necrosis was found in a 5-mm chromophobe adenoma at transsphenoidal surgery. Postoperatively, ACTH levels returned to normal (51-88 pg/ml), with the rest of her anterior pituitary function remaining intact 4 yr later. Spontaneous infarction of pituitary microadenomas may be subclinical, resulting in improvement of pituitary hormone hypersecretion without impairment of other anterior pituitary hormone secretion.

We studied the effects of glucocorticoid excess on calcium and phosphorus homeostasis in relation to vitamin D metabolites and parathyroid hormone (PTH) in seven patients with spontaneous ACTH-dependent Cushing's syndrome. Remission of hypercortisolism resulted in a significant increase in tubular reabsorption of phosphate [from 76 +/- 4% to 89 +/- 2% (mean +/- SEM); P less than 0.01] and serum phosphorus (from 3.1 +/- 0.1 to 4.2 +/- 0.2 mg/dl; P less than 0.005). Serum calcium did not change, although there was a reduction in daily urinary calcium excretion from 0.23 +/- 0.02 to 0.107 +/- 0.02 mg calcium/mg creatinine. Serum immunoreactive PTH (iPTH) levels were normal during Cushing's syndrome (34 +/- 5 microleq/ml), but fell significantly after remission to 22 +/- 2 microleq/ml (P less than 0.05). This small decrease in iPTH did not correlate with the improvement of phosphate homeostasis. Plasma 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH2)D] concentrations in Cushing's syndrome did not differ from measurements in 97 normal subjects. After treatment, 25OHD did not change, but 1,25-(OH)2D fell in each patient from a mean of 44 to 22 pg/ml (P less than 0.02). 1,25-(OH)2D was inversely correlated with serum phosphorus (r = 0.59; P less than 0.01), but did not correlate with iPTH. The known impairment of intestinal calcium absorption in Cushing's syndrome cannot be attributed to a decrease in the circulating levels of 1,25-(OH)2D. Endogenous hypercortisolism decreases tubular phosphate reabsorption and serum phosphorus, increase tubular phosphate reabsorption and serum phosphorus, increases iPTH, and results in an increase in 1,25-(OH)2D. These events may contribute to the severe loss of bone mass in such patients and may account for the calciuria and phosphaturia of Cushing's syndrome.

Glucocorticoid negative feedback is exerted in at least two time domains: fast feedback (within minutes of the feedback signal) and delayed feedback (within hours of the feedback signal). Although delayed feedback is known to inhibit ACTH responses to a variety of stimuli in humans, whether there is fast feedback inhibition of the ACTH responses to such stimuli is not known. The purpose of this study was to evaluate the efficacy of a pharmacological injection of cortisol sodium succinate (CORT) as a rapid inhibitor of the ACTH response to surgery in patients undergoing thoracotomy for myocardial revascularization. Thirty patients were premedicated with diazepam and induced with thiopental sodium. They were assigned to one of four groups: group I, general anesthesia was maintained with enflurane (n = 8); group II, patients were anesthetized as in group I, but received a bolus injection of 500 mg CORT within 5 s of the start of surgery (n = 7); group III, anesthesia was maintained with 50-100 mg fentanyl (FENT; n = 8); and group IV, patients were anesthetized as in group III and given CORT as in group II (n = 7). Surgery induced a large increase in plasma ACTH in group I (no CORT, no FENT); the mean plasma ACTH level was 57 +/- 14 (+/- SE) pmol/L 10 min after the start of surgery, and it peaked at 92 +/- 18 pmol/L 50 min after the start of surgery. Administration of CORT at time zero (group II) resulted in a significant but attenuated ACTH response to surgery both 10 min (36.5 +/- 9.7 pmol/L) and 50 min (42.5 +/- 7.3 pmol/L) after the start of surgery. FENT per se (group III) significantly attenuated the ACTH response to surgery (e.g. plasma ACTH was 13 +/- 5 pmol/L 10 min and 21 +/- 7 pmol/L 50 min after the start of surgery). The combination of CORT and FENT (group IV) eliminated the ACTH response to surgery at all time points. In fact, plasma ACTH levels became undetectable (less than 4.4 pmol/L) from 30-50 min after the start of surgery. We conclude that a pharmacological dose of CORT administered at the time of stimulus introduction significantly attenuated the ACTH response to the stimulus (surgery). FENT not only inhibited the ACTH response to surgery per se, but amplified the effect of CORT, such that ACTH actually declined even during a large surgical stimulus. CORT clearly attenuates the ACTH response to surgery in humans in the fast feedback time domain.

CS comprises a group of disorders characterized by hypercortisolism. The variety of causes--pituitary-dependent CS (CD), adrenal tumor, and the ectopic ACTH syndrome--necessitates a variety of therapies--surgical, radiotherapeutic, and medical. Once a specific diagnosis is made, specific therapy can be instituted. Although some controversy persists regarding treatment, particularly that of CD, for most patients it is straightforward. However, in our experience with more than 60 patients, therapeutic dilemmas can arise in a number of circumstances, e.g. the patient with the radiologically normal sella or recurrent CD after adrenalectomy. In addition, the treatment of such conditions as the large ACTH-producing pituitary tumor, Nelson's syndrome, the malignant ectopic ACTH syndrome, and adrenal carcinoma is not entirely satisfactory. Our approach to these problems is illustrated by seven cases, and we emphasize that the proper management of CS requires both correct diagnosis and the logical application of all available therapies.

We examined the plasma ACTH and cortisol responses to surgery in 25 patients with atherosclerotic heart disease undergoing myocardial revascularization. The patients were all premedicated with diazepam, and general anesthesia was induced with thiopental. They were randomly assigned to one of four groups: I) no dexamethasone (DEX), enflurane anesthesia, II) 40 mg DEX, iv, 45-60 min before sternotomy, enflurane anesthesia, III) no DEX, fentanyl [N-(1-phenethyl-4-piperidyl)propionanilide] anesthesia (50-100 micrograms/kg), and IV) DEX, fentanyl anesthesia. Isokalemic hemodilution of significant magnitude occurred during cardiopulmonary bypass. All groups had significant increases in plasma ACTH during surgery, which returned to control levels 22 h after the bypass. Group I (no DEX, no fentanyl) and group III (no DEX, fentanyl) patients had large similar increases in plasma ACTH, which peaked 2-4 h postbypass [400 +/- 83 (+/- SEM) pg/mL; 88 +/- 18 pmol/L]. The group II (DEX, no fentanyl) patients also had large increases in ACTH which were similar to those in groups I and III, except 2-4 h postbypass (183 +/- 91 pg/mL; 40 +/- 20 pmol/L). The group IV (DEX, fentanyl) patients had a significantly attenuated ACTH response to surgery; the mean plasma ACTH level 2-4 h postbypass was only 54 +/- 21 pg/mL (12 +/- 5 pmol/L). Therefore, although DEX or fentanyl alone had a minimal effect on the ACTH response to surgery, a significant attenuation occurred when DEX and fentanyl were used in combination. We conclude that glucocorticoids and morphine agonists exert interactive inhibitory effects on ACTH release in humans, probably by virtue of their suppression of CRH release from the hypothalamus.

A recent report measured a decrease in plasma ACTH concentration by immunoradiometric assay (IRMA) during infusion of ACTH-(1-24) in humans. It was concluded that this decrease in ACTH concentration was due to short loop ACTH autoregulation. The present study demonstrates that the decrease in ACTH concentration measured by IRMA was due to an artifact of the IRMA. We injected 250 micrograms ACTH-(1-24), iv, into five normal male volunteers after overnight 2.5-g metyrapone administration. The ACTH concentration measured by IRMA decreased from 59.6 +/- 9.7 pmol/L before to 4.8 +/- 2.0 pmol/L 1 min after ACTH-(1-24) injection. The ACTH concentration measured by IRMA increased thereafter in a mirror image of the decline in ACTH-(1-24) measured by RIA. Addition of ACTH-(1-24) to plasma in vitro resulted in a decrease in the ACTH concentration measured by IRMA which was of similar magnitude to that observed in vivo. ACTH-(1-24) infusion in vivo or addition to ACTH-(1-39)-containing plasma in vitro decreased ACTH-(1-39) measured by IRMA by binding to N- but not C-terminal antibody without forming a detectable sandwich complex. We conclude that although ACTH short loop feedback may exist, it cannot be detected after ACTH-(1-24) injection with the use of a two-site IRMA.

A syndrome of elevated PRA accompanied by inappropriately low plasma aldosterone (ALDO) levels has been identified in some critically ill patients. To determine whether this phenomenon is due to a disturbance in factors that stimulate ALDO, we measured PRA, angiotensin II (AII), potassium (K+), and ACTH levels in 83 patients admitted to an intensive care unit. In 59 patients, PRA was greater than 2.0 ng/ml X h. Of these, 24 had an ALDO to PRA ratio (ALDO/PRA) below 2 (group I), and 35 had an ALDO/PRA ratio of 2 or more (group II). An ALDO/PRA ratio below 2 was deemed inappropriately low. Despite markedly elevated PRA [34 +/- 12 (+/- SE) ng/ml X h], the group I patients had inappropriately low ALDO levels (19 +/- 5 ng/dL). Patients in group II had significantly higher ALDO levels (48 +/- 6 ng/dL) despite lower PRA (9 +/- 1 ng/ml X h). AII levels were appropriately elevated in group I (39 +/- 26 pg/mL) and significantly greater (P less than 0.5) than those in group II. PRA correlated well with AII in both groups. There were no differences in plasma ACTH or K+ in these 2 groups, and plasma cortisol levels were similarly elevated in both groups of patients. Of 66 consecutively studied patients, 14 (21%) had inappropriate ALDO (group I). Mortality was significantly greater in group I (75%) than in group II (46%; P less than 0.001). In summary, a significant subset (21%) of seriously ill patients have inappropriately low ALDO levels despite elevated PRA. This dissociation is not due to an impairment of AII production or changes in plasma ACTH or K+. This phenomenon is associated with a higher mortality during critical illness. In light of evidence of decreased adrenal androgen secretion during severe illness, this dissociation of renin and aldosterone may represent an additional adrenal adaptation designed to promote cortisol production in critically ill patients.

We evaluated a new, commercially available two-site immunoradiometric assay (IRMA) for corticotropin (ACTH) in human plasma. The precision and detection limit were an improvement over radioimmunoassay (RIA). Addition of ACTH 1-24 or ACTH 18-39 to plasma containing ACTH 1-39 resulted in a decrease in measured ACTH. Results by both IRMA and RIA are reported and compared for normal subjects, patients with Cushing's disease, and patients with ectopic ACTH. Effects of administering dexamethasone, metyrapone, ACTH 1-24, and corticoliberin were evaluated. The present assay is more sensitive, specific, and reproducible than RIA. The presence of fragments of ACTH or "big" ACTH that are reactive in RIA may lead to artifactually low ACTH concentrations by IRMA. Therefore, RIA may still be necessary for differential diagnosis of ectopic ACTH syndromes. However, the IRMA is an improvement for evaluating pituitary--adrenal function in patients with low concentrations of ACTH in plasma.