Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes.

Subclinical Cushing's syndrome (SCS) is being detected with increased frequency in patients with adrenal incidentaloma. In the current study, we evaluated the prevalence of SCS in 70 patients with adrenal incidentaloma and compared the main findings on them with other patients with nonfunctional adrenal incidentaloma (NFA). Overnight 3 mg dexamethasone (DXM) suppression test to exclude cortisol hypersecretion, and high dose DXM suppression test to find out patients with SCS, were applied to all subjects. Afterwards, biochemical and clinical findings of patients with SCS were compared with the other patients with NFA. Four of the 70 patients with adrenal incidentaloma were found to have SCS, with a prevalence of 5.7%. Basal ACTH and DHEA-S levels were significantly lower (p < 0.05 and p < 0.01, respectively), and midnight cortisol and 24-hour urinary free cortisol levels were significantly higher in patients with SCS (p < 0.001 and p < 0.05, respectively). Biochemical and metabolic bone parameters were similar in patients with SCS and in patients with NFA. Hypertension, diabetes mellitus, and obesity were more common in patients with SCS. One of the patients with SCS developed adrenocortical insufficiency following unilateral adrenalectomy which lasted for about 6 months. Suppressed ACTH and DHEA-S levels, and high midnight cortisol levels may be some clues for SCS in patients with adrenal incidentaloma. Since patients with SCS frequently have risk factors for atherosclerosis such as hypertension, diabetes, and obesity, and the surgical management of SCS with adrenalectomy may offer an advantage. Patients undergoing adrenalectomy should be followed for the development of adrenal insufficiency.

Subclinical Cushing's syndrome.

Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (< 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome.

Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia.

We present two patients with Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia who showed marked plasma cortisol response to lysine-8-vasopressin (LVP) injection (from 930 and 731 pmol/L to 2177 and 1920 pmol/L, respectively), while plasma ACTH levels remained undetectable. The ACTH independence of cortisol secretion in the two patients was determined from the following endocrinological findings. Plasma cortisol levels were not increased by corticotropin-releasing hormone injections and were not suppressed by high dose (16 mg) dexamethasone administrations. The plasma ACTH levels, measured by two independent sensitive immunoassays, were persistently undetectable even after corticotropin-releasing hormone injection, metyrapone administration, and bilateral adrenalectomy. The particular pathological finding of the two cases, atrophic lesions in nonnodular parts of the adrenal cortexes, also indicated ACTH independence of the macronodular hyperplasia. In vitro examination revealed a direct effect of LVP on cortisol secretion from the adrenal cells of the macronodules. We also examined seven patients with Cushing's syndrome caused by adrenal adenoma and found a statistically significant plasma cortisol response to LVP injection. The direct effect of LVP was also demonstrated in cultured adenoma cells. In conclusion, we discovered a direct adrenal effect of LVP on cortisol secretion in patients with ACTH-independent macronodular hyperplasia and, to a lesser extent, in patients with cortisol-producing adrenal adenoma. The cortisol response to LVP may serve to facilitate their diagnosis and choice of therapy.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple forms of immunoreactive growth hormone-releasing hormone in human plasma, hypothalamus, and tumor tissues.

We examined the nature of GHRH in plasma of normal subjects and patients with acromegaly, hypothalamic tissue, pheochromocytoma, and GHRH-producing pancreatic tumor tissue using two RIAs of different specificity. One assay was a N-terminal assay that recognized GHRH-(1-44)-NH2, GHRH-(1-40)-OH, and GHRH-(1-37)-OH equally, and the other was a C-terminal assay that recognized only the COOH-terminal amidated sequence of GHRH-(1-44)-NH2. GHRH immunoreactivity was detectable in all samples in both assay systems, but the ratios of C- to N-terminal activity differed. The gel filtration profiles of plasma and tumor tissue revealed one peak in (or near) the position of synthetic GHRH-(1-44)-NH2. In contrast, two peaks were found in hypothalamic tissue; a major peak in the position of synthetic GHRH-(1-44)-NH2 and a higher mol wt peak. Ion exchange chromatography of the immunoreactive GHRH material from gel filtration of pooled plasma from normal subjects revealed three components of immunoreactive GHRH, one major peak in the position of GHRH-(1-40)-OH and two minor peaks in the positions of GHRH-(1-44)-NH2 and GHRH-(1-37)-OH. Two components of immunoreactive GHRH, a major peak in the position of GHRH-(1-44)-NH2 and a minor peak in the position of GHRH-(1-40)-OH, were found in hypothalamic tissue and pheochromocytomas. In the two ectopic GHRH-producing pancreatic tumors, three components of immunoreactive GHRH were detected: a major peak in the position of GHRH-(1-40)-OH, a smaller peak in the position of GHRH-(1-37)-OH, and a very small peak of GHRH-(1-44)-NH2. Synthetic GHRH-(1-44)-NH2 was not degraded by plasma during the extraction procedures. These results suggest that 1) the measured immunoreactive GHRH concentration differs when the same samples are measured by RIAs using antisera with different specificities; 2) such differences may be due to the presence of microheterogeneity of immunoreactive GHRH; 3) the microheterogeneity of immunoreactive GHRH in plasma is different from that in the hypothalamus; and 4) the posttranslational processing of GHRH in human hypothalamus is similar to that of pheochromocytomas but different from that of ectopic GHRH-producing pancreatic tumors.

Preoperative management of pheochromocytoma with the calcium-antagonist nifedipine.

Labile high blood pressure and associated complaints (eg, severe headache, palpitation, and vague discomfort in the chest) in a 28-year-old woman with pheochromocytoma were stabilized by adding nifedipine to the conventional regimen of alpha- and beta-blocking agents. Electrocardiographic (ECG) data (ST depressions, prolonged QT intervals, and giant negative T waves during a hypertensive attack) and findings in biopsied myocardial specimens (slight cell infiltration composed mainly of lymphocytes associated with interstitial fibrosis) had suggested the presence of catecholamine cardiomyopathy. Oral administration of 10 mg of nifedipine alone had rapidly resulted in normalization of blood pressure and complete relief from associated signs and symptoms. Because conventional preoperative treatment with alpha- and beta-blockers did not alleviate the hypertensive attacks, a 20-mg long-acting nifedipine tablet was added to the regimen. The effect of twice-daily administration of a 20-mg long-acting nifedipine tablet (combined with alpha- and beta-blockers) was so prominent that it was possible for the patient to undergo surgery for removal of the right adrenal gland and a 4-cm tumor at the gland. After surgery there were no abnormal ECG findings.

Adrenergic regulation of insulin release.

Insulin release is influenced by the autonomic nervous system. In the periphery the regulation occurs via both alpha-adrenergic and beta-adrenergic receptors. The parasympathetic nervous system is important in the central regulation of insulin secretion. Nevertheless, adrenergic mechanisms are also concerned. This review discusses the mechanisms for the adrenergic regulation of insulin release and some clinical conditions where these mechanisms are concerned.

[Problem of autonomy of adrenal cortex adenomas of different histological structures in Cushing's syndrome]. / Problema avtonomnosti adenom kory nadpochechnikov razlichnogo gistologicheskogo stroeniia u bolnykh s sindromom Itsenko-Kushinga.

The authors analyzed the results of examination of 69 patients operated on for Itsenko-Cushing's syndrome (ICS); in 32 cases tumours of the adrenal cortex were revealed during the operation. Two histological forms of adenoma of the adrenal cortex were distinguished, i.e. adenomas of mono- and polymorphous structure. Increased background urinary excretion of 17-oxycorticosteroids (17-OCS) in patients with ICS suffering from tumours of polymorphous structure persisted at the former level or increased in the tests with 8 mg of dexamethazone (DMZ). The character of tests with 8 mg of DMZ in patients with ICS having adenomas of monomorphous structure was analogous to such in patients with ICS, but without any adrenal gland tumours--urinary 17-OCS excretion was either decreased or suppressed by 50 or more per cent of the initial level. A suggestion is put forward on functional dependence of the adrenal cortex of monomorphous structure on the hypothalamo-hypophysial control.