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We performed selective venous catheterization and sampling for ACTH in six patients with ACTH-secreting pituitary adenomas (Cushing's disease) and four patients with occult ectopic ACTH-secreting neoplasms. In five patients with Cushing's disease in whom the inferior petrosal sinus could be catheterized, ACTH levels were unequivocally higher than simultaneous peripheral values: The ratio was greater than 2.0, with a range of 2.2 to 16.7. In contrast, the inferior petrosal sinus-to-peripheral ACTH ratio in three patients with ectopic ACTH secretion was less than 1.5. In the fourth patient, an arteriovenous gradient of 6.8 was shown 2 years before a bronchial carcinoid tumor was clinically apparent. Central-to-peripheral ACTH ratios at the level of the jugular bulb and jugular vein were not diagnostic. We conclude that selective venous ACTH sampling from the inferior petrosal sinus is a reliable and useful aid in the differential diagnosis of Cushing's syndrome when standard clinical and biochemical studies are inconclusive.

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushing's syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushing's disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushing's disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushing's syndrome.

Cushing's syndrome, an unusual group of disorders characterized by hypercortisolism, must be considered in the differential diagnosis of such common clinical problems as hirsutism, menstrual irregularity, hypertension, diabetes mellitus, and obesity. Its distinct forms--pituitary-dependent Cushing's syndrome (Cushing's disease), adrenal tumor and ectopic ACTH syndrome--must be identified correctly so that specific therapy can be administered. In the majority of cases, use of a relatively simple diagnostic sequence will provide accurate and rapid diagnosis. However, in our experience with more than 60 patients, diagnostic difficulties may arise from a variety of conditions (e.g., drug interference, alcohol ingestion, and depression). In addition, unusual circumstances, such as unexpected responses to dexamethasone, may complicate the diagnosis. Our approach to these problems is illustrated through a report of seven cases, and we emphasize that the proper management of Cushing's syndrome mandates a thorough marshalling of all the available data.

A 40-year-old woman had visual loss and a large nonfunctioning pituitary tumor. After partial surgical resection and radiation treatment, clinical and biochemical evidence of Cushing's disease developed. The pituitary source of her adrenocorticotropic hormone hypersecretion was documented on selective venous sampling. After 18 months of medical therapy with metyrapone and aminoglutethimide, the patient experienced a spontaneous remission of her hypercortisolism. A "nonfunctioning" pituitary tumor has a hypersecretory potential.

The objective of this study was to determine the effects of transient aortic valve occlusion (balloon valvuloplasty) on vasoactive hormones in patients with heart failure. Plasma atrial natriuretic peptide, vasopressin, aldosterone, adrenocorticotropic hormone (ACTH), and plasma renin activity were measured before, immediately after, and 30 minutes and 18 to 24 hours following balloon inflation in 18 patients. Mean right atrial and pulmonary wedge pressures were 6 and 18 mm Hg before inflations, respectively, and were unchanged after balloon inflations (5 and 13 mm Hg, respectively). Systemic systolic/diastolic pressures were 139 +/- 8/65 +/- 4 mm Hg before occlusion, decreased to 47 +/- 5/34 +/- 3 mm Hg during occlusion, and returned to baseline after occlusions. Baseline atrial natriuretic peptide levels were 267 +/- 43 pg/ml and increased to 513 +/- 71 pg/ml after balloon inflations. Vasopressin levels before occlusion were 9.1 +/- 2.2 pg/ml and increased to 21.4 +/- 4.8 pg/ml after balloon inflations. Plasma renin activity was 5.4 +/- 1.4 ng/ml/hr before inflations and was not significantly changed after balloon inflations. No clinically significant changes in plasma sodium, potassium, creatinine, and osmolality were observed after the procedure. Aldosterone increased from 23 +/- 4 to 40 +/- 7 ng/dl 10 minutes after the last inflation. Plasma ACTH measured in seven patients with increased aldosterone was 28 +/- 8 pg/ml before and increased to 295 +/- 157 pg/ml 10 minutes after balloon inflations. The increases in natriuretic peptide and vasopressin were likely due to elevated intracardiac and decreased arterial pressures, respectively; they persisted in spite of no clinically significant changes in filling pressures 12 to 24 hours after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Cushing's disease is a form of Cushing's syndrome, persistent inappropriate hypercortisolism, that results from pituitary ACTH hypersecretion. It currently accounts for 70 per cent of adult cases of Cushing's syndrome and affects mainly women of childbearing age. The pathology, cause, and clinical and laboratory features of the disease are discussed. The initial step in diagnosis is documentation of endogenous hypercortisolism, which is followed by identification of the cause. Selective transsphenoidal resection of ACTH-producing pituitary adenomas is the initial treatment of choice. The roles of radiotherapy and medical therapy are discussed.

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.

In a 56 year old woman, shock, disseminated intravascular coagulation, symmetrical peripheral gangrene and the adult respiratory distress syndrome developed following a dog bite. She suffered from chronic alcoholism and was asplenic. The newly described gram-negative bacillus (DF-2) was isolated from the initial blood cultures on the eighth hospital day when she was recovering from the illness. Penicillin G, clindamycin, or both (administered intravenously in large doses), and therapy directed toward the severe complications appeared responsible for her successful outcome.

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.

Fine needle aspiration of the thyroid has achieved increasing acceptance as a valuable diagnostic aid in the evaluation of nodular thyroid disease. It has been suggested, however, that this procedure should be performed only in major medical centers. We report our experience with thyroid needle aspiration in 400 consecutive patients seen in the ambulatory setting of a community hospital. Benign cytology was found in 80% of patients. Surgery was recommended in 51 patients (12.8%) with either suspicious or malignant cytology, and cancer was found in 31 (61%) of these patients. Non-diagnostic aspirates accounted for 7.2% of patients. Thyroid imaging failed to add anything to the diagnostic evaluation. Our results compare favorably to those from university centers and show that thyroid needle aspiration can be performed well in a community hospital setting. We believe that it should be the initial study in patients with nodular goiter.

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.