Studies on the pathogenesis of hypertension in Cushing's disease and acromegaly

The pathogenesis of the hypertension associated with Cushing's syndrome and with acromegaly is poorly understood. We have investigated the possible roles of sodium retention, activation of the renin-angiotensin system and increased sympathetic nervous system activity in untreated patients. In 11 patients with Cushing's disease, seven of whom were hypertensive, total exchangeable sodium was normal despite increased levels of the mineralocorticoid hormones, 11-deoxy-corticosterone and corticosterone. The renin-angiotensin system was also normal. Cardiac sensitivity to the beta-receptor agonist isoprenaline was increased, but this was not due to an increase in beta-adrenoceptor density. Hypertension in Cushing's disease is neither sodium-dependent nor angiotensin II-mediated, but increased cardiac sensitivity to catecholamines, by increasing cardiac output, may contribute to the pathogenesis of hypertension. In nine patients with acromegaly (three of whom were hypertensive) total exchangeable sodium was elevated. Although no correlation between blood pressure and exchangeable sodium was found, hypertension in acromegaly is probably sodium dependent. No evidence was found for a pathogenetic role for either the renin-angiotensin-aldosterone or the sympathetic nervous system.     

Studies on the Pathogenesis of Hypertension in Cushing's Disease and Acromegaly

The pathogenesis of the hypertension associated with Cushing'ssyndrome and with acromegaly is poorly understood. We have investigatedthe possible roles of sodium retention, activation of the renin-angiotensinsystem and increased sympathetic nervous system activity inuntreated patients. In 11 patients with Cushing's disease, seven of whom were hypertensive,total exchangeable sodium was normal despite increased levelsof the mineralocorticoid hormones, 11-deoxycorticosterone andcorticosterone. The renin-angiotensin system was also normal.Cardiac sensitivity to the ß-receptor agonist isoprenalinewas increased, but this was not due to an increase in ß-adrenoceptordensity. Hypertension in Cushing's disease is neither sodium-dependentnor angiotensin II-mediated, but increased cardiac sensitivityto catecholamines, by increasing cardiac output, may contributeto the pathogenesis of hypertension. In nine patients with acromegaly (three of whom were hypertensive)total exchangeable sodium was elevated. Although no correlationbetween blood pressure and exchangeable sodium was found, hypertensionin acromegaly is probably sodium dependent. No evidence wasfound for a pathogenetic role for either the renin-angiotensin-aldosteroneor the sympathetic nervous system.     

An evaluation of the distinction of ectopic and pituitary ACTH dependent Cushing's syndrome by clinical features, biochemical tests and radiological findings

The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied, based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test, suppression by less than 50 per cent of 9 a.m. serum cortisol, urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome, but in none of the 23 patients with Cushing's disease. For urine free cortisol, a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group, all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.     

Normal and abnormal regulation of β-MSH in man

The regulation of plasma beta-melanocyte-stimulating hormone (beta-MSH) in man has been studied utilizing a radioimmunoassay previously described (1). In normal subjects plasma beta-MSH values ranged from 20 to 110 pg/ml. Metyrapone increased and dexamethasone decreased plasma beta-MSH levels. Surgical stress stimulated beta-MSH secretion. Plasma beta-MSH levels were elevated in patients with untreated Addison's disease and untreated congenital adrenal hyperplasia, and these levels fell to normal during glucocorticoid therapy. In patients with Cushing's syndrome due to pituitary adrenocorticotropic hormone (ACTH) excess, plasma beta-MSH was slightly elevated before treatment. In those patients who developed pituitary tumors and hyperpigmentation after bilateral adrenalectomy, plasma beta-MSH was greatly elevated. In patients with Cushing's syndrome due to adrenal tumor, plasma beta-MSH was subnormal. In patients with the ectopic ACTH syndrome, the levels of plasma beta-MSH were high. Plasma beta-MSH had a diurnal variation in normal subjects, patients with Addison's disease, and patients with congenital adrenal hyperplasia; but the normal diurnal variation was lost in patients with Cushing's disease. In patients with high plasma beta-MSH, simultaneous determinations of plasma ACTH showed close correlation between the degree of elevation of ACTH and that of beta-MSH. In extracts of tumors from patients with the ectopic ACTH-MSH syndrome the quantities of the two hormones were roughly equivalent. In patients with hyperpigmentation due to a variety of disorders other than pituitary-adrenal abnormalities, plasma beta-MSH was normal. It is concluded that the secretion of beta-MSH is regulated by the same factors that regulate ACTH.     

Medical treatment for Cushing's syndrome

Systemic cortisol plays an important role in the metabolism of glucose, lipids and proteins, as well as in the regulation of electrolyte balance. It is well known that the development of the microvascular disease of various organs such as the heart and kidney, in patients with diabetes mellitus, hyperlipidemia and hypertension of which disorders are frequently associated with Cushing's syndrome. Thus, we should treat Cushing's syndrome as soon as possible, since many complications, including cardiovascular diseases and infections, will soon occur when the definite diagnosis is delayed. Adrenalectomy is essential for treatment for Cushing's syndrome even in the patients with pituitary or ectopic ACTH-producing tumor. Some case can not be treated with surgical procedures because of worsened conditions with several complications of infection and diabetes. Then we choose medical treatment. Medical adrenalectomy is achieved by using with mitotane which is usually used for adrenocortical cancer. We commonly treat the patients with Cushing's syndrome due to adrenal tumor and pituitary or ectopic ACTH producing tumor by using metyrapone which mainly inhibits 11-hydroxylase. Metyrapone is also recommended to treat the patients who are not well differentiated Cushing's disease from ectopic ACTH syndrome. We rarely use trilostane which is an inhibitor against 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Replacement therapy with hydrocortisone should be considered if adrenal failure will occur during treatment with those drugs.     

Single determination of plasma ACTH using an immunoradiometric assay with high detectability differentiates between ACTH-dependent and -independent Cushing's syndrome

The purpose of this retrospective study was to elucidate the value of an ACTH assay with high detectability to differentiate between ACTH-dependent and -independent Cushing's syndrome. The study was based on the case records of 56 patients with Cushing's syndrome comprising 34 patients with ACTH-dependent Cushing's syndrome and 22 patients with ACTH-independent Cushing's syndrome. Basal morning plasma 1-39 ACTH was measured using an immunoradiometric assay (IRMA) with a normal range of 1.8-11 pmol/L. Peripheral corticotrophin-releasing hormone (CRH) tests were performed in 24 and 17 patients with ACTH-dependent and -independent Cushing's syndrome, respectively. Using a single ACTH measurement, a complete separation was observed between the two defined groups, with a cut-off value of 2.4 pmol/L. Mean ACTH concentration was 14.4 pmol L (range 2.5-47.7 pmol/L) in ACTH-dependent Cushing's syndrome and 0.6 pmol/L (range 0.2-2.2 pmol/L) in ACTH-independent Cushing's syndrome. The range of separation between the two groups was further increased by using two ACTH measurements in each patient or peripheral stimulation with CRH. It is concluded that in the majority of patients with Cushing's syndrome a single basal morning ACTH determination is sufficient to discriminate between ACTH-dependent and ACTH-independent Cushing's syndrome. In borderline cases with ACTH in the range 2-3 pmol/L, repeated measurements might be necessary. The peripheral CRH test was not superior to repeated ACTH measurements.     

Normal menstruation and pregnancy in a patient with Nelson's syndrome

The patient with Nelson's syndrome in this report represents an unusual case in which regular cyclic menstruation was preserved even though a large ACTH-producing pituitary adenoma was present. Despite normal menses and pregnancy, the radiologic findings of an enlarged sella turcica and an enhanced lesion on CAT scan were identified. This case demonstrates that patients with normal menstruation can have significant pituitary disease, and it exemplifies the need for regular follow-up examination to look for radiologic abnormalities in patients who have had adrenalectomy for treatment of Cushing's disease.     

Radioimmunoassay of ACTH in plasma

Techniques are described in detail for a radioimmunoassay of plasma adrenocorticotropin (ACTH) that is capable of detecting hormone in unextracted normal human plasma at 1:5 dilution under the conditions described. The sensitivity of the assay is at the level of 1 mumug/ml (equivalent to 0.014 mU/100 ml).In normal subjects ACTH concentrations averaged 22 mumug/ml (equivalent to 0.308 mU/100 ml) plasma at 8-10 a.m. In a smaller group the concentrations averaged 9.6 mumug/ml (equivalent to 0.134 mU/100 ml) at 10-11 p.m. Although a circadian rhythm in normal subjects was not always well marked throughout the daytime hours, plasma ACTH usually fell to its lowest value in the late evening. In hospital patients who were not acutely ill, concentrations were infrequently above 100 mumug/ml in the morning and usually fell to significantly lower levels in the late evening. Severely ill hospital patients occasionally exhibited a.m. concentrations above 200 mumug/ml.In a group of subjects showing frequent spiking of plasma 17-OHCS concentrations throughout the day parallel spiking of plasma ACTH as well was generally observed.Metyrapone produced marked increases in plasma ACTH within 24 hr in all cases and generally within 3-6 hr except when started late in the day. Dexamethasone brought about a persistent reduction in plasma ACTH in a patient under continued treatment with metyrapone.Hypoglycemia, electroshock, surgery under general anesthesia, histalog and vasopressin administration were usually followed by significant increases in plasma ACTH concentration. Prior administration of dexamethasone blocked the response to hypoglycemia.Marked elevations in plasma ACTH were observed in patients with adrenal insufficiency off steroid therapy, in Cushing's disease after adrenalectomy even in the presence of persistent hypercortisolemia, and in some untreated patients with Cushing's disease.Umbilical cord blood contained higher plasma ACTH concentrations than maternal blood at delivery in seven of eight cases.After suppression of ACTH secretion by dexamethasone or cortisol. ACTH disappeared from plasma with half-times ranging from 22 min to 30 min in three cases studied.     

Cushing's disease treated by total adrenalectomy: long-term observations of 43 patients

Forty-three patients were treated by total adrenalectomy for pituitary-dependent Cushing's disease. The median period of observation was 10 years (range one to 20 years). Thirty-eight patients (88 per cent) had rapid and lasting remissions. Of the 38 in remission, 21 became pigmented but without pituitary enlargement, 11 became pigmented with evidence of further pituitary expansion (Nelson's syndrome) and six neither became pigmented nor showed pituitary expansion. Pituitary expansion was associated with high plasma ACTH values, and treatment of pituitary tumours by surgery or radiotherapy gave poor results. However, when compared with alternative methods of treatment, total adrenalectomy for Cushing's disease is still satisfactory for many patients, despite advances in pituitary surgery, and has advantages over 'medical adrenalectomy' with drugs.     

Cushing's Disease: TREATMENT BY PITUITARY IMPLANTATION OF RADIOACTIVE GOLD OR YTTRIUM SEEDS

Fifty-seven patients with Cushing's disease (pituitary-dependentCushing's syndrome), and four with Nelson's syndrome followingadrenalectomy, have been treated by implantation of ¹⁹⁸Au or⁹⁰Y seeds into the pituitary gland. Fifty-five of the Cushing'sdisease patients have been fully followed up with steroid testsfor 1 to 12 years after implant. They have been categorizedaccording to the X-ray appearance of the fossa before implant,which was the most important factor in predicting the outcome.The results were as follows: 1. Cushing's disease without evidence of pituitary tumour onX-ray (31 patients). One year after implant, 65 per cent ofthese patients were in complete remission and a further 16 percent in partial remission—a total of 81 per cent improved,without any other treatment. Only 34 per cent required replacementcorticosteroids, and 30 per cent replacement thyroxine. 52 percent needed no replacement hormone treatment. Only one patienthad relapsed more than 2 years after implant. 2. Cushing's disease with possible pituitary tumour on X-ray(10 patients). One year after implant, five of these were incomplete and one in partial remission. These remissions weremaintained. 60 per cent required replacement steroids or thyroxine. 3. Cushing's disease with definite X-ray evidence of pituitarytumour (14 cases). In only two of these was permanent remissionobtained by implant alone, despite the use of higher radiationdoses in most of them. In four the tumour showed X-ray or clinicalevidence of local invasion after implant, and three subsequentlyneeded surgical hypophysectomy. A combination of implant, adrenalectomy,hypophysectomy, or external irradiation was needed to controlthe disease in most of these patients; 10 required surgery ofpituitary or adrenals. Some degree of hypopituitarism occurredin them all and 64 per cent required replacement hormones asa result of pituitary or adrenal ablation. In the whole series of 61 patients implanted for either Cushing'sor Nelson's syndrome, there were six who developed serious problemsfrom local invasion by pituitary tumours despite various formsof treatment of the pituitary. This invasion contributed tothe deaths of four. 4. In all four cases of Nelson's syndrome, clinical remissionof pigmentation was evident within a year of implant. One patientlater required external pituitary irradiation and craniotomyto control his pituitary tumour, but survived 13 years. Theothers have been followed for three, four, and nine years withoutrecurrence. 5. Pituitary implant for Cushing's disease appears to be atleast as effective in producing remission as other treatmentsdirected at the pituitary, and is as effective in restraininggrowth of pituitary tumours. It is much more effective thanexternal irradiation. Though the cure of the Cushing's syndromeis not as certain as with adrenalectomy, the proportion of patientsrequiring replacement hormone therapy is approximately half,and the procedure of implant is a smaller surgical undertaking.The technical complications of implants, particularly cerebrospinalfluid rhinorrhoea, are minimal (5 per cent) and readily treatable.     

Hepatotoxicity of a synthetic cortisol antagonist: OP'DDD (mitotane)

The adrenolytic agent, Op'DDD (Mitotane) has been employed for almost 50 years for treatment of Cushing's syndrome. Despite clinical observations of elevation of hepatic enzymes encountered in patients taking the drug, there are few published data regarding the frequency, time course and factors that might influence hepatic toxicity of Mitotane. We analysed 10 patients consecutively treated with Mitotane for Cushing's syndrome. We measured hepatic transaminase and gamma glutamyl transferase before, during and after treatment. The study population included 6 women and 4 males, with a mean age of 41 years. Seven patients presented Cushing's disease while two had adrenal tumours and one had an undetermined origin of Cushing's syndrome. After a progressive increase, patients were being treated with a mean dosage of 9 g per day. All patients had elevation of either GGT or ALAT and all but one had elevation of transaminase (the maximum increase was sixfold the basal value). The only variable correlated with hepatic increase was the body mass index. In contrast, the severity of the disease, alcohol intake, and other biological characteristics were not correlated with transaminase elevations. We conclude that transaminase increase is encountered in the vast majority of patients treated with Mitotane. Levels at which the drug should be withdrawn remain to be established.     

Variable hormonogenesis in Cushing's syndrome.

Four patients with Cushing's syndrome and variable cyclic hormonogenesis are reported and 40 other cases from the literature are reviewed. These cases were divided into four categories depending on regular or irregular cyclic adrenal hypersecretion and presence or absence of concomitant fluctuations in the clinical course. The manifestations of cyclic adrenal hypersecretion in these patients varied from daily to yearly intervals. Cyclic activity persisted for as long as 25 years, with cycle lengths varying from 12 hours to 85 days. Some patients demonstrated complex biochemical cyclic patterns. Clinical presentations varied from a single outstanding symptom, such as recurring oedema, to a complex clinical syndrome. The aetiology in these patients varied: 12 appeared to be pituitary dependent, 11 had corticotropin-producing tumours and another eight were described as showing 'adrenal hyperplasia'. A hypothalamic disorder was found in four, a benign adrenal adenoma in two, and an adrenal 'mass' and adrenocortical nodular dysplasia in single patients. Evaluation during the intercyclic phase may reveal normal pituitary function. Inconsistent responsiveness to administration of dexamethasone in different phases of cyclic activities may suggest the presence of cyclic Cushing's syndrome.     

Influence of Glucocorticoids on Glucagon Secretion and Plasma Amino Acid Concentrations in Man

Plasma concentrations of glucagon, insulin, glucose, and individual plasma amino acids were measured in normal nonobese and obese subjects before and after 3 days of dexamethasone treatment (2 mg/day) and in patients with Cushing's syndrome. The subjects were studied in the basal postabsorptive state and following the infusion of alanine (0.15 g/kg) or ingestion of a protein meal.In nonobese subjects dexamethasone treatment resulted in a 55% increment in basal glucagon levels and in a 60-100% increase in the maximal glucagon response to alanine infusion or protein ingestion. In obese subjects, basal glucagon rose by 110% following dexamethasone, while the response to alanine increased fourfold. In patients with Cushing's syndrome basal glucagon levels were 100% higher and the glucagon response to alanine infusion was 170% greater than in normal controls.Dexamethasone treatment in normal subjects resulted in a 40% rise in plasma alanine concentration which was directly proportional to the rise in basal glucagon. The remaining 14 amino acids were unchanged. In the patients with Cushing's syndrome alanine levels were 40% higher than in normal controls and were directly proportional to basal glucagon concentrations. No other plasma amino acids were significantly altered in the group with Cushing's syndrome.It is concluded that (a) glucocorticoids increase plasma glucagon concentration in the basal state and in response to protein ingestion or aminogenic stimulation; (b) this effect of glucocorticoids occurs in the face of obesity and persists in chronic hypercorticism; (c) hyperalaninemia is a characteristic of acute and chronic glucocorticoid excess, and may in turn contribute to steroid-induced hyperglucagonemia; and (d) increased alpha cell secretion may be a contributory factor in the gluconeogenic and diabetogenic effects of glucocorticoids.     

Psychiatric aspects of Cushing's syndrome

Patients with Cushing's syndrome were studied (n=209, 78% females). Control patients had pituitary adenomas secreting growth hormone or prolactin. Age at diagnosis of Cushing's syndrome was 8-74 (mean 39) years. Duration of symptoms was 0.2-9 (median 2.0) years. Adverse life events within the 2 years preceding the onset of Cushing's syndrome were not significantly commoner than in controls. Depressive illnesses were associated with the presence of adverse life events (p<0.001). Depressive illness was more common in females (p<0.01). There were no significant differences in the severity of depression in the different types of Cushing's syndrome. Pathological anxiety had been diagnosed in 26 patients (12%), mania or hypomania in six patients (3%) and confusion in three patients (1%). Psychotic illness had been diagnosed in 16 patients (8%) and was more common in adrenal carcinomas (p<0.01). Significant psychiatric illness, usually depressive preceded the onset of all symptoms and signs of Cushing's syndrome in 25 patients (12%); 23 of these developed pituitary Cushing's disease, and two adrenal adenomas. When Cushing's syndrome was diagnosed, significant psychiatric illness, usually depression, was present or had been a feature of Cushing's syndrome in 120 (57%) patients.      

Parallel assays of beta-endorphin and ACTH in Cushing's patients undergoing petrosal sinus sampling

This study explores the possibility of improving endocrinologic testing during petrosal sinus catheterization by determining both beta-endorphin and corticotropin (ACTH). We studied 14 patients with Cushing's disease, two with adrenal tumor, and three with ectopic tumors secreting ACTH. In patients with Cushing's disease, beta-endorphin concentrations paralleled those of ACTH in all basal plasma samples collected either from petrosal sinuses or peripheral veins. Individual responses of beta-endorphin and ACTH to corticotropin releasing hormone (CRH) were closely related to the presence of a corticotroph adenoma. In such patients, a consistently higher concentration of beta-endorphin over ACTH was observed in all samples collected either from petrosal sinuses or peripheral veins; the ratios were unchanged after the administration of CRH. In patients with ectopic ACTH secretion, the mean ratio of beta-endorphin over ACTH (with both values expressed in pmol/L) was significantly higher (3.5) than that of patients with Cushing's disease (2.9) or Cushing's syndrome due to adrenal tumor (2.7).     

Cushing's Syndrome: AN EVALUATION OF THE CLINICAL USEFULNESS OF URINARY FREE CORTISOL AND OTHER URINARY STEROID MEASUREMENTS IN DIAGNOSIS

Urinary free cortisol excretion has been measured in a groupof 40 patients with Cushing's syndrome and in 34 patients inwhom this diagnosis was suspected on clinical grounds, but inwhom it was later disproved. Measurements were made in the basal state, during dexamethasonesuppression, and after metyrapone (when free cortisol and 11-deoxycortisolwere measured together) and the results compared with thoseof 17 oxogenic steroid measurements. In the basal state no normal or ‘suspected’ patientexcreted more than 106 µg/24 h of free cortisol whilethe lowest value seen in any patient with Cushing's syndromewas 110 µg/24 h. In 25 per cent of the patients with hyperadrenalism17 OGS excretion was within the normal range. Three patientswith ectopic ACTH produc tion all excreted more than 1000 µgof free cortisol in 24 h and in two of the three 17 OGS excretionwas greater than 100 mg/ h. During low-dose dexamethasone suppression (2 mg daily) freecortisol excretion fell to very low levels in normal and suspectedsubjects but failed to do so in patients with Cushing's syndrome,although a few patients did show suppression almost to withinthe normal range. In no patient with Cushing's syndrome did17 OGS excretion fall to less than 5 mg/24 h. However, it alsofailed to do this in 43 per cent of the ‘suspected’subjects. High-dose dexamethasone suppression (8 mg/day) failed to providea clear differentiation between patients with pituitary-dependentdisease and those with autonomous adrenal lesions or ACTH-producingtumours in terms of change in either free cortisol or 17 OGSexcretion. On metyrapone testing 96 per cent of pituitary-dependent patientsshowed a definite rise in 17 OGS excretion. We have not yetseen such a response in a patient with a non-pituitary-dependentlesion. Measurement of free F+S excretion was not ¹Present address: Department of Medicine, University Hospitalof South Manchester, Withington     

Steroid 21-hydroxylase and 17 alpha-hydroxylase in microsomal fraction of functioning adrenocortical tumors

In order to survey the enzymic activities of steroidogenesis in functioning adrenocortical tumors, we investigated the activities of steroid 21-hydroxylase and 17 alpha-hydroxylase in microsomal fractions of 12 surgically resected adrenocortical tumors associated with Cushing's syndrome (5 adenomas and one carcinoma), primary aldosteronism (5 adenomas) and adrenogenital syndrome (AGS) (one carcinoma), and one adrenocortical hyperplasia resulting from Cushing's disease. Seven adrenal cortices from the patients with mammary carcinoma, renal cell carcinoma or pheochromocytoma were used for normal control. In normal controls 21-hydroxylase activities with progesterone as a substrate were 1.61 +/- 0.25 nmole/min/mg protein and those with 17 alpha-hydroxyprogesterone were 5.22 +/- 1.06 nmole/min/mg protein. The activity of 21-hydroxylase was higher in four cases of 5 aldosteronomas than in normal controls. Those activities in Cushing's adenomas were in the range of normal controls in this study. 17 alpha-hydroxylase activities were much variable from case to case even though in normal controls (4.50 +/- 2.40 nmole/min/mg protein), and in most cases of adenomas 17 alpha-hydroxylase activities were in the range of normal controls. Activities of both hydroxylase in carcinomas were lower than in normal controls. The present paper showed the abnormal steroidogenic enzyme activities in aldosteronomas and adrenocortical carcinomas.     

Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro.

To differentiate between ectopic ACTH syndrome and Cushing's disease, gene expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and glucocorticoid receptor was examined in 10 pituitary adenomas (Cushing's disease) and in 10 ectopic ACTH-producing tumors. CRH increased plasma ACTH levels in all patients with Cushing's disease and in five patients with ectopic ACTH syndrome whose tumors contained CRH and CRH mRNA. In five CRH nonresponders, CRH was not detected in tumors that contained no CRH mRNA or that contained only long-size CRH mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in three patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRH mRNA and PMA-induced POMC gene expression. In addition, there are two ectopic ACTH syndrome subtypes: tumors containing ACTH with CRH (CRH responder) and tumors without CRH. Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids. Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome.     

In vitro cellular cytotoxicity in Crohn's disease and ulcerative colitis: relation with disease activity and treatment, and the effect of recombinant gamma-interferon

In a previous study using total mononuclear cells and lymphocytes, enriched by elutriation centrifugation, of patients with Crohn's disease and ulcerative colitis were found to have a decreased NK cell activity. In the present study the relation with disease activity and treatment, and the effect of recombinant gamma-interferon (gamma-IFN) on NK cell and monocyte cytotoxicity has been studied in 19 patients with Crohn's disease, 11 with ulcerative colitis, two with indeterminate colitis and 12 healthy controls. Patients with active Crohn's disease and active ulcerative colitis were shown to have an impaired NK cell activity compared to the control group. However, no difference was found in the percentage of CD16 (Leu 11+) cells, as determined by fluorocytometry, between patients with active or inactive disease. Moreover, the NK cell impairment was not related to corticosteroid treatment. Recombinant gamma-interferon (gamma-IFN) stimulated significantly the cytotoxic activity of the total mononuclear cells and the monocyte-enriched fraction against all target cell lines, both in patients and controls. No relation was found between the increase in cytotoxicity by gamma-IFN and disease activity in the patients. Stimulation with gamma-IFN demonstrated that the monocyte cytotoxic response of inflammatory bowel disease patients is normal. The present study reveals that the impairment in NK cell activity in patients with inflammatory bowel disease is related to disease activity and therefore suggests to be secondary to the inflammatory process.     

An Evaluation of the Distinction of Ectopic and Pituitary ACTH Dependent Cushing's Syndrome by Clinical Features, Biochemical Tests and Radiological Findings

The efficiency of various laboratory and radiological investigationsin the differentiation of ectopic from pituitary dependent Cushing'ssyndrome was studied, based on findings in 23 patients withverified Cushing's disease and seven patients with the ectopicACTH syndrome. Clinical features strongly favouring the ectopic type were malesex and history for less than 18 months. Basal biochemical featuresstrongly indicating the ectopic syndrome included plasma K⁺<3.0 mmol/l and HCO₃ >30 mmol/l; serum cortisol at 9 a.m.or midnight of > 800 nmol/l; urine free cortisol > 1300nmol/24 hours; plasma ACTH > 100 ng/1. In the high-dose dexamethasone suppression test, suppressionby < 50 per cent of 9 a. m. serum cortisol, urine free cortisolor 17-oxogenic steroids was usually indicative of an ectopicsource of ACTH. A mean suppressed value of > 450nmol/l forthe 9 a.m. and midnight cortisol combined occurred in all ofthose with the ectopic syndrome, but in none of the 23 patientswith Cushing's disease. For urine free cortisol, a mean suppressedvalue of < 1000 nmol/24 hours was found in all patients withCushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of