Food-dependent Cushing's syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide.

BACKGROUND. Some patients with Cushing's syndrome have nodular adrenal hyperplasia. In most the disease is corticotropin-dependent, but in others it is corticotropin-independent. The cause of the adrenal hyperplasia in the latter patients is not known. METHODS. We studied a 49-year-old woman with Cushing's syndrome and nodular adrenal hyperplasia in whom food stimulated cortisol secretion. Plasma cortisol concentrations were measured in response to the ingestion of mixed meals, glucose, protein, and fat and after the administration of various gastrointestinal and other types of hormones. We also studied the ability of the long-acting somatostatin analogue octreotide to prevent the food-induced increase in plasma cortisol concentrations and to ameliorate the clinical manifestations of Cushing's syndrome in this patient. RESULTS. The patient's fasting plasma cortisol concentrations were subnormal, ranging from 3.0 to 7.5 micrograms per deciliter (83 to 207 nmol per liter), and they increased to as high as 16.5 micrograms per deciliter (455 nmol per liter) after a mixed meal. Her urinary cortisol excretion ranged from 164 to 250 micrograms per day (453 to 690 nmol per day) and could not be suppressed by a large dose of dexamethasone. Plasma corticotropin concentrations were virtually undetectable at all times. The ingestion of glucose, protein, and fat increased plasma cortisol concentrations to 3.6, 2.2, and 4 times the base-line value, respectively; the meal-induced and glucose-induced increases were inhibited by octreotide. The infusion of gastric inhibitory polypeptide (GIP) increased the patient's plasma cortisol concentration to 3.7 times the base-line value, but had no effect in normal subjects. The patient's fasting plasma GIP concentrations were normal both before and after a meal, and there was a close correlation between her plasma cortisol and GIP concentrations. Treatment with octreotide decreased urinary cortisol excretion and ameliorated the clinical manifestations of Cushing's syndrome. CONCLUSIONS. The development of aberrant adrenal sensitivity to GIP can result in food-dependent adrenal hyperplasia and therefore in Cushing's syndrome.     

Effects of synthetic corticotropin-releasing factor in normal individuals and in patients with hypothalamic-pituitary-adrenocortical disorders

Plasma adrenocortical hormone (ACTH) and cortisol response to four dose levels (25, 50, 100 and 300 micrograms) corticotropin-releasing factor (CRF) were studied in 5 healthy men, and the response to 100 micrograms CRF in 12 patients with various disorders of the hypothalamic-pituitary-adrenocortical function. In normals, mean plasma ACTH and cortisol concentration rose at all dose levels of CRF and peaked at 30 and 60 min respectively. The increment in plasma cortisol at 60 and 90 min was significantly higher on 100 and 300 micrograms CRF than on 25 micrograms, but the total cortisol concentration was not. Seven patients had Cushing's syndrome. In 2 patients with adrenocortical carcinoma the basal plasma ACTH was suppressed. After CRF a small increase was seen in plasma ACTH and cortisol in one patient successfully treated with mitotane, while the other patient did not respond. In 1 patient with ectopic ACTH syndrome an increase in plasma ACTH 15 min after CRF was not accompanied by any increase in plasma cortisol. One patient with bilateral multinodular adrenocortical hyperplasia did not respond to CRF. The plasma ACTH and cortisol response to CRF was supernormal in 2 patients with Cushing's disease, while a third patient responded in the normal range. In 2 patients with Nelson's syndrome the plasma ACTH response was excessive. Two out of three hypophysectomized patients did not respond to CRF, while one patient with a slightly positive response to hypoglycemia also responded (subnormally) to CRF. Our data indicate that CRF in doses of 50-100 micrograms will be a valuable substance in the differential diagnosis of Cushing's syndrome. Some overlap in the response is, however, seen between patients with Cushing's disease and other patients with Cushing' syndrome. CRF will possibly be of value also for the diagnosis of secondary adrenocortical failure.     

Different therapeutic efficacy of ketoconazole in patients with Cushing's syndrome

Summary The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease,n=10; adrenocortical adenoma,n=2; adrenocortical carcinoma,n=1; ectopic ACTH syndrome,n=1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We concluded from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11- and 17-hydroxylase activity. This effect was compensated in part by a rebound increase of pituitary ACTH secretion in most patients with Cushing's disease. Therefore, ketoconazole treatment is above all effective in patients with Cushing's syndrome due to an adrenal tumor or in patients with ectopic ACTH syndrome, who cannot respond with an increased pituitary ACTH secretion.Abbreviations ACTH Adrenocorticotropic hormone - AA Adrenocortical adenoma - AC Adrenocortical carcinoma - B Corticosterone - CRH Corticotropin-releasing hormone - EAS Ectopic ACTH syndrome - PDCD Pituitary-dependent Cushing's disease - P Progesterone - 17OH-P 17-hydroxyprogesterone - RIA Radioimmunoassay - S 11-deoxycortisol - DOC 11-deoxycorticosterone     

The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushing's disease) and in 9 patients with other forms of Cushing's syndrome. In all patients with Cushing's disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushing's syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushing's syndrome.     

Case Report: Adrenal LH/hCG Receptor Overexpression and Gene Amplification Causing Pregnancy-Induced Cushing’s Syndrome

Transient pregnancy-induced Cushing’s syndrome (CS) is extremely rare, with only several cases reported in the literature. Ectopic LH/hCG-receptors (LHCGR) in the adrenal gland have been suggested to be involved in the pathogenesis of this condition. We report the clinical, molecular, and genetic features of a patient with pregnancy-induced CS. A 29-year-old female patient developed CS during multiple pregnancies, leading to repeated miscarriage. Signs and symptoms of hypercortisolism resolved soon after delivery or abortion, only to recur in subsequent pregnancies. In the non-pregnant state, hCG stimulation testing resulted in elevated cortisol levels. Serum cortisol was not suppressible with dexamethasone. The adrenals exhibited bilateral adrenal cortical nodular hyperplasia. Quantitative RT-PCR revealed a 2-fold increase in LHCGR and progesterone receptor mRNA expression and decreased estrogen receptor-beta expression in the patient’s adrenal tissue relative to normal adrenals. Higher intensity of immunostaining for LHCGR was observed, particularly within the nodular lesions, compared to controls. Quantitative PCR revealed a LHCGR-to-β-actin ratio of 1.5 in genomic DNA from adrenal and peripheral leukocytes, suggesting the presence of a germline duplication of the LHCGR gene. LHCGR overexpression resulting from germline gene duplication may be a potential pathogenic mechanism underlying this case of pregnancy-induced CS.     

The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls.

The aims of this study were to determine whether the administration of cortisol has a significant effect on mood in patients with depression and whether the effects of cortisol on changes in plasma hormone concentrations are like those of synthetic corticosteroids. Twelve patients had major depression and one each had dysthymic disorder and a depressive adjustment disorder. Five were male and nine were female. All were in-patients. Eight normal subjects, two females and six males, were used as controls. Basal beta-endorphin concentrations were 2- to 3-fold higher in depressed patients than in control subjects, but there were no significant differences between the patient and control groups in the basal (pre-infusion) plasma concentrations of ACTH, cortisol, growth hormone or prolactin. Cortisol, but not saline infusion resulted in a significant improvement in self rated mood. Surprisingly, cortisol infusion at first increased plasma beta-endorphin concentrations. At later times after cortisol infusion, plasma beta-endorphin concentrations decreased as did the plasma concentrations of ACTH and growth hormone; prolactin levels were increased. These results show (i) that cortisol infusion raises mood significantly in major depression, (ii) that plasma beta-endorphin concentration is a potential marker of major depression (iii) that rather than blunting of corticosteroid effects, responses to cortisol may even be enhanced in depressive illness. The unexpected, initial increase in beta-endorphin stimulated by cortisol, suggests that the action of cortisol is not simply one of negative feedback inhibition, but may involve mineralocorticoid, as well as glucocorticoid receptors.     

Evidence for two subtypes of Cushing's disease based on the analysis of episodic cortisol secretion

To investigate the pathogenetic mechanisms of Cushing's syndrome, we studied variations in plasma cortisol levels (episodic variations, or pulses) over 24 hours in 51 normal subjects, 14 patients with adrenal adenoma, and 46 patients with Cushing's disease. Data were obtained both from our patients and from the literature. As compared with normal subjects, patients with adrenal adenoma had fewer spikes in cortisol levels (defined as an elevation of at least 10 per cent and no less than 1 microgram per deciliter), and the spikes were lower both in absolute terms (4.0 +/- 1.8 vs. 5.1 +/- 2.2 micrograms per deciliter, P less than 0.05) and in terms of the percentage of the preceding trough concentration (23 +/- 7 vs. 123 +/- 74 per cent, P less than 0.001). Patients with Cushing's disease seemed to fall into two groups: those with hypopulsatile and those with hyperpulsatile secretion. The hypopulsatile group had a normal number and absolute height of spikes, but their height relative to the preceding trough concentration was lower than in controls (42 +/- 16 vs. 123 +/- 74 per cent, P less than 0.005). In contrast, the hyperpulsatile group had a similar number of spikes as the hypopulsatile group, but their absolute and relative heights were twice as great (12.7 +/- 2.3 vs. 6.0 +/- 1.6 micrograms per deciliter and 84 +/- 40 vs. 42 +/- 16 per cent, respectively; P less than 0.001 for both). We hypothesize that the Cushing's disease in the second group of patients may have been caused by increased hypothalamic release of, or pituitary responsiveness to, corticotropin-releasing factor, whereas that in the first group may represent pituitary oversecretion of corticotropin that is relatively independent of corticotropin-releasing factor.     

Combined aldosterone and cortisol secretion by adrenal incidentaloma

A 70-year-old woman was referred to the authors' unit following hospitalization for cardiac failure, high urinary free cortisol concentrations and severe hypokaliemia. A computed tomography scan of the abdomen showed an adrenal adenoma. The 24-hour urinary free cortisol values were high and plasma cortisol levels failed to suppress following 1 mg dexamethasone test. Aldosterone to plasma renin activity ratio was also pathologic, confirmed by saline load. She showed no symptoms of glucocorticoid excess. She was diagnosed with combined primary hyperaldosteronism and Cushing's syndrome. Cases of adrenal incidentalomas co-secreting cortisol and aldosterone are rare; they should be addressed in patients undergoing adrenal surgery for Conn's syndrome to avoid adrenal insufficiency after removal of the tumor.     

Combined adrenal myelolipoma and adenoma associated with Cushing's syndrome

A case of Cushing's syndrome in a 31-year-old woman is presented. The resected left adrenal gland revealed a tumor consisting of cortical cells intermingled with myelolipomatous tissue comparable to that of normal bone marrow. The adjacent cortex was atrophic. Postoperative plasma cortisol concentrations have remained quite low. Previously, 28 cases of surgically removed adrenocortical tumors with a main diagnosis of myelolipoma have been published. Of these, three cases (two pituitary Cushing's disease, one steroid 21-hydroxylase deficiency) were associated with endocrine dysfunction. The combination of a myelolipoma and a true adenoma has only been described once before (in a case of virilization) and never in connection with Cushing's syndrome. The etiology of myelolipoma is discussed, and a local trigger mechanism related to adrenocortical growth disturbances is suggested.     

Cushing's syndrome and autoimmunity.

Is Cushing's syndrome ever caused by adrenal stimulating autoantibodies? Specific antiadrenal antibodies were found in the serum of three of seven patients with Cushing's syndrome. The immunologic techniques that showed positive results were complement fixation, tanned RBC hemagglutination, and immunofluorescence. Lymphocytic infiltration of the adrenal was present in two cases, in one of which nodular hyperplasia seemed to be of primary adrenal origin with autoimmunity as a possible cause. However, in cases with clear-cut pituitary origin, the lymphocytic adrenalitis and circulating adrenal antibodies are likely secondary to antigen leaking from damaged tissue.     

Adrenocarticotropic hormone-independent bilateral macronodular adrenocortical hyperplasia associated with Cushing's syndrome

A case of adrenocorticotropic hormone independent bilateral adrenocortical macronodular hyperplasia (AIMAH) is reported. A 59 year old male was admitted to hospital because of hypertension. Subsequently, hypercortisolism, low plasma adrenocorticotropic hormone (ACTH), loss of diurnal rhythm of ACTH, lack of suppression with high dose dexa-methasone were found and bilateral adrenal enlargement was detected by abdominal computerized tomography and adrenal scintlgraphy. Bilateral total adrenalectomy was performed under a diagnosis of bilateral adrenal hyperplasia associated with Cushing's syndrome. Both adrenal glands were enlarged in size and weight. Bulging nodules were found at the cut section. Microscopically, a variegated histologic pattern including trabecular, adenoid and zona glomerulosa-like (ZG-like) structures was revealed in the nodules. lmnunohistochemical examination disclosed positive staining of cytochrome P-450 1701, negative of 3p-HSD in the ZG-like structure. Ultrastructurally, the cells composing the ZG-like structure were similar to those of the ZG in normal adrenal cortex. The authors agree that AIMAH is one of the entiiies causing Cushing's syndrome, and advise patholo-gists to keep this disorder in mind when they examine the adrenals in Cushing's syndrome.     

Problems of cortisol assay: confusion in the diagnosis of preclinical Cushing's syndorme

Cortisol assay is used for the diagnosis of hypothalamo-pituitary adrenal disorders. The Incidence of adrenal incidentaloma has been increasing with advances in imaging tools. The criteria for the diagnosis of preclinical Cushing's syndrome in Japan was made by the Nawata group supported by the Ministry of Health and Welfare in 1995. The presence of adrenal adenoma, a lack of overt signs of Cushing's syndrome and autonomic cortisol secretion are essential for the diagnosis of preclinical Cushing's syndrome. For the diagnosis of autonomy of cortisol secretion, cortisol should not be suppressed by either low dose dexamethasone (DEX) of 1 mg (cortisol > or =3 microg/dl) or high dose DEX of 8 mg (cortisol > or =1 microg/dl). We have reported that two doses of DEX suppression tests revealed a discrepancy in several cases of adrenal incidentaloma; therefore, we studied the cortisol values of DEX suppression tests in 47 cases with adrenal incidentaloma using four different cortisol kits (TFB, SPAC, TDX and TOSOH). Correlation between the kits was good; however, correlation coefficient in the low range (< or =5 microg/dl) among kits declined. In the inter assay, discrepant results of the cortisol level were seen in six cases after 1 mg of DEX and 18 cases after 8 mg of DEX. In the intra assay, discrepant results of cortisol after 1 mg of DEX and 8 mg of DEX were seen in 31 in TFB, 23 in SPAC, 24 in TDX and 25 in TOSOH. These results revealed that the clinical diagnosis varies according to the cortisol kit used. It is suggested that standardization of the cortisol assay is necessary for the accurate diagnosis of adrenal incidentaloma.     

Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing's syndrome. Enzyme histochemical and ultrastructural study of four cases with a review of the literature.

Four patients with adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) were examined. All of them were men whose ages ranged from 37 to 52 years. Plasma cortisol levels were high, with a loss of diurnal rhythmicity, and plasma ACTH was undetectable. Adrenal cortisol secretion was not suppressed by dexamethasone, but it was ACTH responsive. Test results for corticotropin-releasing hormone (CRH) also were negative. Image analyses revealed a normal sella turcica and significantly enlarged adrenal glands, which showed enhanced uptake of isotope. Both adrenal glands in all cases were between 72 and 176 g in combined weight and were composed of, and distorted by, yellow nodules. Histologically, small cortical cells with or without lipid, occasional clear cells, and rare compact cells of the usual size were increased in number in the glandular cords. Enzyme histochemically, cortical cells showed weaker activity for 3 beta hydroxysteroid dehydrogenase and other enzymes than did usual cortisol-producing adenomas. Ultrastructurally, they had moderately to poorly developed smooth endoplasmic reticulum. Nonnodular areas of the cortex consisting of nonproliferating cells were atrophic and contained no compact cell zone. This is similar to the adrenal cortices attached to cortisol-producing adenomas. These features are unique to AIMAH and suggest the presence of a distinct subtype of Cushing's syndrome.     

Corticotropin production by tumors of the autonomic nervous system

Cushing's syndrome in association with a tumor of the autonomic nervous system (ANS) has been reported occasionally. We studied a patient who had an intra-adrenal paraganglioma (pheochromocytoma), and whose plasma corticotropin level was elevated prior to surgery but dropped to a low value following removal of the tumor. Catecholamine levels were elevated preoperatively and catecholamines were extracted from the tumor tissue. Corticotropin was identified in the tumor by immunoperoxidase staining. We also compared the endocrine data of 16 previously reported cases of Cushing's syndrome secondary to the release of ectopic corticotropin from ANS tumors. We concluded that in these patients, the plasma corticotropin level is only modestly elevated but indexes of steroid production frequently are markedly elevated. Also, discrepant responses to dexamethasone suppression tests occur, perhaps via sporadic release of corticotropin. These factors complicate evaluation of the cause of Cushing's syndrome in these patients.     

Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency

BACKGROUND: Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. METHODS: We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. RESULTS: Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P<0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells. CONCLUSIONS: Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.     

Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to measure 6 metabolic compounds of the adrenocorticosteroid pathway simultaneously on residual specimens from patients who had previously been previously diagnosed, on the basis of immunoassays, as having congenital adrenal hyperplasia (CAH), 11 beta-hydroxylase deficiency, 21-hydroxylase deficiency, or Addison disease (adrenal insufficiency). Two subjects with normal adrenal function had serum cortisol values of 13.6 and 8.9 micrograms/dL and serum cortisone values of 2.1 and 0.6 microgram/dL, but the rest of the compounds were undetectable. Two patients with 11 beta-hydroxylase deficiency had serum 11 beta-deoxycortisol values of 14.9 and 10.0 micrograms/dL and serum 11-deoxycorticosterone values of 3.9 and 1.0 microgram/dL, but their serum levels of cortisol and cortisone were diminished. A patient with 21-hydroxylase deficiency had a highly increased serum 17-hydroxyprogesterone concentration of 28.5 micrograms/dL (or 28,500 ng/dL, the traditional unit to report this assay) and a serum 21-deoxycortisol concentration of 6.9 ug/dL (this is a pathologic marker of 21-hydroxylase deficiency that is nondetectable in sera of healthy subjects). This patient also had diminished concentrations of serum cortisol and cortisone (0.9 and 0.3 microgram/dL, respectively). At 30 and 60 min after corticotropin (ACTH) stimulation, serum cortisol was the only compound that showed a dramatic increase in the normal subjects; the patient with 21-hydroxylase deficiency showed an increase of serum 17-hydroxyprogesterone level, but no increase of serum cortisol level; the patient with Addison disease showed no increase in the levels of serum cortisol or other compounds. Metyprapone, which blocks 11 beta-hydroxylase activity, increased the serum 11-deoxycorticosteroid levels and decreased the serum cortisol level. This pilot study demonstrates that it is feasible to use LC-MS/MS for the laboratory diagnosis of adrenal cortical dysfunction. The authors envision that LC-MS/MS may soon become an ideal analytical technique for the diagnosis of such endocrine diseases.     

CUSHING'S SYNDROME WITH BILATERAL MULTINODULAR ADRENAL HYPERPLASIA

An unusual case of Cushing's syndrome of a 59-year-old man with bilateral multinodular adrenal hyperplasia and microadenoma of the pituitary gland is presented. Failure to suppress plasma Cortisol with large doses of dexamethasone may suggest autonomous growth of hyperplastic nodules of the adrenals, which were at first induced by prolonged stimuli of ACTH from the microadenoma of the pituitary gland. ACTH could not be detected in the microadenoma cells on paraffin sections, while Crooke's cells were strongly positive for ACTH. The interrelation between bilateral multinodular adrenal hyperplasia and pituitary microadenoma is discussed.     

Multiple pigmented adrenal cortical nodules associated with Cushing's syndrome. Histochemical, ultrastructural and quantitative studies

Multiple pigmented adrenocortical nodules were found in a 25-year-old woman associated with Cushing's syndrome, whose laboratory data indicated that the adrenal cortex had been functioning autonomously and adrenocorticotrophic hormone (ACTH) from the pituitary gland as suppressed. The surgically removed left adrenal gland disclosed multiple black nodules measuring up to 3 mm in diameter and histologically consisting of large "compact cells" which contained numerous yellow-brown pigments, but adjacent cortical cells were not atrophied. This kind of adrenal lesion is generally regarded as nodular hyperplasia of the cortex. The present case revealed scanty lipid and markedly increased activity of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and glucose-6-phosphate-dehydrogenase (G6PD). Ultrastructural study showed abundant cytoplasm with a large number of mitochondria, well-developed smooth-surfaced endoplasmic reticulum (SER), less rough-surfaced endoplasmic reticulum (RER), lysosomes, and numerous granules in cells of the nodules. Mitochondria varied in size and shape up to occasional giant mitochondria. SER was vesicular or tubular forming a network of anastomosing tubules. Granules varied greatly in size from 400 millimicrons to 6 microns in diameter, with diverse electron densities, mostly exhibiting the structural features of lipofuscin. The ultrastructural features resembled those in black adenoma associated with Cushing's syndrome ever reported. Concentration of cortisol was increased in the tissue where numerous black nodules were contained.     

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

Summary We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism.Abbreviations ACTH adrenocorticotrophic hormone - CD Cushing's disease - CS Cushing's syndrome     

Gastrointestinal regulatory peptides during oxytocin infusion in post-term pregnancies

The plasma concentrations of the gastrointestinal regulatory peptides vasoactive intestinal polypeptide (VIP), insulin, secretin, somatostatin, motilin, pancreatic polypeptide (PP) and gastric inhibitory polypeptide (GIP), as well as blood glucose, were measured in eight healthy women before, during and after oxytocin infusion in post-term pregnancies. Plasma VIP increased significantly (P less than 0.01) during oxytocin infusion. Plasma secretin showed a significant (P less than 0.05) decrease during oxytocin infusion. Plasma somatostatin remained unchanged during oxytocin infusion, but thereafter a significant (P less than 0.05) increase occurred. Both plasma motilin and plasma PP showed a non-significant increase during oxytocin infusion with sustained levels thereafter. No changes were found for plasma insulin, GIP and blood glucose.