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     

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.     

The effect of magnesium valproate on plasma ACTH concentrations in Nelson's syndrome

Sodium valproate, a gamma-aminobutyric acid (GABA) agonist, was found to decrease plasma ACTH concentration in some cases of Cushing's disease and Nelson's syndrome. In this study we have investigated the influence of magnesium valproate (MV), a newly introduced salt of valproic acid, on plasma ACTH levels in 8 patients with Nelson's syndrome. The daily dose, 1200 mg of MV, significantly decreased plasma ACTH level at 10 p.m. compared with placebo. A single dose of 400 mg of MV, led to a reduction in plasma ACTH concentration only in two out of seven patients during a four-hour observation. The fall in plasma ACTH level in the same patients at 10 p.m., after the next two doses of this drug, suggests that single dose may be insufficient for introducing GABA-dependent reduction in ACTH release. During a long-term therapy with MV, in all three patients investigated a marked decrease in plasma ACTH was observed. Our results suggest that magnesium valproate may be useful during chronic therapy in some patients with ACTH hypersecretion.     

Cyclical Cushing's disease. A case report.

A 41-year-old man with clinical Cushing's syndrome and intermittent central ACTH hypersecretion for a period of 9 1/2 years follow-up is described. Episodes of biochemical and clinical remission alternated with periods of florid Cushing's disease, characterized by circadian hyperpulsatile ACTH and cortisol secretion. Responses to metyrapone and inhibition of ACTH and cortisol hypersecretion after high dose dexamethasone during active phases of the disease favored a central origin of ACTH hypersecretion, confirmed by simultaneous bilateral venous sampling of the sinus petrosus inferior. Prolonged clinical remission followed near total anterior hypophysectomy. However, on anatomopathological examination of the pituitary neither corticotroph cell hyperplasia nor a microadenoma could be documented. The possibility of a functional ACTH hypersecretion is discussed.     

Electron microscopical morphometry of well-differentiated and undifferentiated ACTH secreting adenomas in Cushing's disease and Nelson's syndrome

Summary Adrenocorticotrophic hormone (ACTH)-secreting adenomas of patients with Cushing's disease (undifferentiated and well-differentiated ACTH-cell adenomas) were studied ultrastructurally and analysed morphometrically by a computer-supported quantitative image-analysing system. They were compared with identically prepared ACTH tumours (undifferentiated and well-differentiated ACTH-cell adenomas) of pituitaries from bilateral adrenalectomised patients with Nelson's syndrome. The aim of our study was to look for significant differences in ultrastructure and to evaluate these findings statistically regarding adenoma types and clinical syndromes. Clinical syndromes aside, more secretory granules and larger-sized prosecretory granules were measured in the well-differentiated ACTH-cell adenomas. The undifferentiated adenomas showed a greater content of nucleoli and prosecretory granules. Within the adenoma types, comparison of well-differentiated ACTH-cell adenomas showed that the clinical group of Cushing's disease contained larger areas of cytofilaments, whereas the clinical group of Nelson's syndrome had a larger tumour size and more lysosomes. Comparing the undifferentiated adenomas of both clinical groups the adenomas in Cushing's disease contained larger nuclei and more lysosomes, whereas the adenomas in Nelson's syndrome were larger in tumour size and contained larger prosecretory granules. Comparison of well-differentiated and undifferentiated adenomas in Cushing's disease showed more secretory granules and bigger prosecretory granules in well-differentiated adenomas whereas in undifferentiated adenomas the total area of the nuclei is larger, the nucleoli increase in number and size and the lysosomes are more frequent. Comparison of well-differentiated and undifferentiated adenomas in Nelson's syndrome demonstrated more lysosomes in well-differentiated adenomas and a larger total area of the nuclei in undifferentiated adenomas. The differences between the well-differentiated adenomas (mainly more secretory granules and larger prosecretory granules) and undifferentiated adenomas (mainly more and larger nuclei and nucleoli and more prosecretory granules) prove the clear separability between the adenoma types, not demonstrated in the literature up to now. The significant differences between adenomas in Cushing's disease (mainly more cytofilaments) and Nelson's syndrome (mainly more ribosomes and larger prosecretory granules) may be interpreted as different cell reactions due to the hypercortisolism present in Cushing's disease and lacking in Nelson's syndrome following adrenalectomy. Despite the fact that both clinical syndromes are based on the same adenoma types, indistinguishable by light microscopy, significant morphometrical findings in ultrastructure allow a clear discrimination of both clinical types.Dedicated to Prof. Gerhard Seifert on the occasion of his 70th birthdayPresented at the 5th European Workshop on Pituitary Adenomas, Venice, March 1991     

Ectopic ACTH syndrome and severe hypokalaemia

Cushing's syndrome is rare and remains a challenge to diagnose. Particularly difficult are the differentiation between Cushing's syndrome and Pseudo-Cushing's states and between the two forms of ACTH dependent Cushing's: Cushing's disease and ectopic ACTH syndrome. We report the case of a patient diagnosed with a metastatic small cells lung carcinoma associated with ectopic ACTH-syndrome. Hypokalaemia was a clue to diagnosis. We focus on critical questions addressing diagnosis and differential diagnosis of Cushing's syndrome and we explain the mechanism of hypokalaemia.     

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.     

Application of adrenocorticotropin assays in a routine clinical laboratory.

The radioimmunoassay of ACTH was used in a routine laboratory to localize the site of the lesion in 20 patients with Cushing's syndrome. Eight of the patients had no detectable circulating ACTH and had adrenal tumors removed, 12 had high levels and were diagnosed as having pituitary Cushing's syndrome. Very high levels of plasma ACTH were found in eight patients who had primary adrenal insufficiency, while ACTH was undetectable in ten patients with secondary hypoadrenalism. The routine use of this assay in endocrinology should reduce the hospitalization of patients under investigation for disorders of the pituitary--adrenal axis. Eight patients who had the ectopic ACTH syndrome and carcinoma of the lung were found to have very high levels of ACTH with no diurnal variation. Forty-seven patients with oat-cell carcinoma but without evidence of the ectopic ACTH syndrome had normal ACTH levels. A possible role of ACTH and other peptide hormones as tumor markers is mentioned.     

Pituitary pathology in Cushing's disease

Pituitaries of 137 cases with Cushing's disease were microscopically and immunohistologically studied. Many alterations and parameters (sex, age, anamnesis, cortisol plasma levels, tumor size, invasiveness, localization, differentiation of adenomas, immunohistological hormone content, capillarity, recurrences, peritumorous ACTH cell hyperplasia, and Crooke's cells) were analyzed and compared. Whereas most parameters were not correlated, we found some important statistically significant correlations: Undifferentiated adenomas are more frequently invasive than differentiated ones. Invasive adenomas recur more frequently than non-invasive adenomas. Extremely laterally localized adenomas are more often invasive. Larger adenomas are more frequently invasive than micro-adenomas. ACTH cell hyperplasia are more often demonstrable in specimens from total hypophysectomies (confined to our earlier series) than from partial hypophysectomies and adenomectomies. Recurrences of adenomas are more frequent in pituitaries with periadenomous ACTH cell hyperplasia. Very rarely ACTH cell hyperplasia are the only source of ACTH hyperfunction. The more Crooke's cells are demonstrable, the longer the post-operative replacement dose of Cortisol is required. Adenomas in Cushing's disease and adenomas in Nelson's syndrome differ significantly in the following points: Adenomas in Nelson's syndrome are larger and contain more plurinuclear cells. In the ultrastructure, adenomas in Cushing's disease show more cytofilaments. Paraadenomous Crooke's cells are lacking in Nelson's syndrome.     

Pituitary tumors containing cholecystokinin

We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained increased amounts of cholecystokinin, the concentrations being extremely high in two: 8281 and 13,453 pmol per gram as compared with less than 30 pmol per gram in normal pituitary glands. The cholecystokinin concentrations were moderately increased in adenomas from another 12 patients, of whom 5 had Cushing's disease and 7 acromegaly with adenomas containing ACTH. The cholecystokinin peptides from the tumors were smaller and less sulfated than cholecystokinin from normal pituitary glands. We conclude that ACTH-producing pituitary cells may also produce an altered form of cholecystokinin.     

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     

垂体ACTH细胞腺瘤的免疫电镜研究

5 cases of pituitary adenomas associated with Cushing's disease or Nelson's syndrome were studied with electron microscopy and immunoelectron microscopy by using protein A--gold complex. Diversified ultrastructure was displayed in these tumors, among which 4 revealed presence of ACTH positive secretory granules. These granules were round or polyhedric in shape, varied in number, size and electronic density. Bundles of microfilaments could be seen in the tumor cells frequently, which were of the highest diagnostic value. There was no significant difference found in ultrastructure and immunocytochemical reaction of adenomas in Cushing's disease and Nelson's syndrome.     

Small cell neuroendocrine carcinoma of the thymus complicated by Cushing's syndrome. Report of a 58-year-old woman with a 3-year history of hypertension

A 58-year-old woman with a history of Cushing's syndrome for three years presented with a mediastinal mass and received the diagnosis of small cell neuroendocrine carcinoma of the thymus invading the pericardium. On immunohistochemical study, the neoplastic cells reacted with antibodies against cytokeratin, epithelial membrane antigen, neuron-specific enolase, chromogranin, synaptophysin, and ACTH. Clinicopathologic findings of this rare case of ectopic adrenocorticotropic hormone (ACTH) syndrome are discussed with a literature review.     

Inhibition of human adrenal androgen secretion by ketoconazole

Summary The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens. In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all measured androgens. The mean reduction in serum levels of dehydroepiandrosterone sulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43%; mean serum levels of cortisol only fell by 19%. The reduction in serum androgen levels was first significant 24 h after beginning of treatment and persisted as long as the drug was administered. We conclude that ketoconazole inhibits adrenal androgen biosynthesis more pronouncedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion.Abbreviations CV coefficient of variation - MV mean value - SEM standard error of the mean - f female - m male - K ketoconazole - ACTH adrenocorticotropic hormone - DHEA dehydroepiandrosterone - DHEAS dehydroepiandrosterone sulfate - A androstenedione - T testosterone - F cortisol - P progesterone - H hirsutism - C Cushing's disease - EAS ectopic ACTH syndrome - ATU adrenal tumor     

Multiple cellular forms of corticotrophs in surgically removed pituitary adenomas and periadenomatous tissue in Cushing''s disease.

Transsphenoidally removed samples of pituitary adenomas from 14 patients with Cushing's disease and 5 patients with Nelson's syndrome always contained groups of uniform small ACTH-cells. Antibodies against the pro-opiocortin precursor fragments beta-endorphin, ACTH, and 16k-peptide recognized material in typical adenoma cells. A subpopulation of these cells, varying in number from sample to sample, specifically exhibited alpha-melanotropin immunoreactivity. Most periadenomatous samples showed signs of severe degeneration. Typical Crooke cells only occurred in samples from patients with Cushing's syndrome, but, with this exception, no clear differences between pituitaries of patients with Cushing's and Nelson's syndromes could be discerned. Two other forms of ACTH-immunoreactive cells were observed: rare, single, highly immunoreactive cells, with characteristics of both normal and Crooke cells, and numerous syncytial groups of cells in an advanced state of disintegration, presumably the remnants of hyperplastic follicles. The four different corticotrophs are characterized according to their fine structure and immunoreactivity in this study.     

Failure of Partial Hypophysectomy as Definitive Treatment in Cushing's Disease Owing to Nodular Corticotrope Hyperplasia: Report of Four Cases

Nodular corticotrope hyperplasia is a rare pathology causing Cushing's syndrome owing to a primary pituitary disease or ectopic CRH production. In this study, we evaluated the laboratory and pathological findings and results of transsphenoidal pituitary surgery in four patients with Cushing's disease. Dynamic tests of pituitary-adrenal function (dexamethasone suppression, metyrapone, CRH, and DDAVP tests) were done before and after transsphenoidal pituitary surgery. Plasma and total urinary cortisol, serum 11-deoxycortisol, and plasma ACTH were determined by RIA. Hormonal dynamic tests and radiologic studies were compatible with a pituitary ACTH source. The transsphenoidal surgery revealed the presence of corticotrope hyperplasia confirmed by immunoperoxidase stain and a preserved reticulum framework in the removed pituitary tissue of these four patients. The pituitary surgery led to a short period of improvement in two of the patients (1 and 4), a 3-yr remission in one patient (patient 2), and no improvement in one (patient 3). We conclude that although our patients appear to have inadequate suppression with high-dose dexamethasone, there is no way to diagnose this pathology presurgically, and that total hypophysectomy, bilateral adrenalectomy, and irradiation are the only alternatives for definitive treatment. A CRH-secreting ectopic tumor could not be found in our patients either before or after surgery in the follow-up period.     

Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome.

BACKGROUND. Measurement of adrenocorticotropin levels in plasma from the inferior petrosal sinuses of patients with Cushing's syndrome can distinguish adrenocorticotropin-secreting pituitary tumors (Cushing's disease) from other causes of the syndrome, principally ectopic adrenocorticotropin secretion from an occult tumor. However, it is unknown whether such measurement consistently identifies patients with Cushing's disease and whether testing with corticotropin-releasing hormone (CRH) enhances the value of the procedure. METHODS. We prospectively studied 281 patients with Cushing's syndrome to evaluate the diagnostic efficacy of the procedure. Bilateral sampling was successfully accomplished in 278 patients, with no major morbidity; 262 of these patients underwent sampling before and after administration of ovine CRH. The adrenocorticotropin levels in the samples were used to calculate the ratio of the concentration in plasma from the inferior petrosal sinuses to the concentration in peripheral-blood plasma (the IPS:P ratio). RESULTS. The diagnosis of 246 patients was confirmed surgically as Cushing's disease in 215, as ectopic adrenocorticotropin syndrome in 20, and as primary adrenal disease in 11. An IPS:P ratio greater than or equal to 2.0 in basal samples identified 205 of the 215 patients with Cushing's disease (sensitivity, 95 percent), with no false positive results (specificity, 100 percent). A peak IPS:P ratio greater than or equal to 3.0 after CRH administration identified all 203 of the patients with Cushing's disease who received CRH (sensitivity, 100 percent), with no false positive results (specificity, 100 percent). The sensitivity was much lower when the adrenocorticotropin concentrations in the samples from one sinus were considered alone. In patients with Cushing's disease a difference of greater than or equal to 1.4-fold between the concentrations in the two sinuses (the adrenocorticotropin gradient) predicted the location of the microadenoma in 68 percent of 104 patients during basal sampling and in 71 percent of 105 patients after CRH administration. CONCLUSIONS. Simultaneous bilateral sampling of plasma from the inferior petrosal sinuses, with the adjunctive use of CRH, distinguishes patients with Cushing's disease from those with ectopic adrenocorticotropin secretion with high diagnostic accuracy.     

Medullary carcinoma of the thyroid as a cause of Cushing's syndrome: a case with ectopic adrenocorticotropin secretion characterized by double enzyme immunostaining.

A case of a medullary carcinoma of the thyroid gland that secreted both calcitonin and adrenocorticotropin (ACTH) is reported. The patient was a 32-year-old man who was referred to the Clinical Center of the National Institutes of Health with radiologic evidence of intrathoracic and hepatic masses accompanied by florid Cushing's syndrome. Serum levels of calcitonin and ACTH were elevated. The thoracic and hepatic masses were resected. The histologic findings were typical of medullary carcinoma of the thyroid with extensive metastases to the liver. The neoplasm had a predominantly solid pattern, and the neoplastic cells were either round or spindled, many with cytologic atypia. Immunohistochemical analysis of fixed, paraffin-embedded sections demonstrated chromogranin, calcitonin, and ACTH in the neoplastic cells. The immunostaining for chromogranin was intense in all of the cells, whereas weaker staining for calcitonin and ACTH was present in scattered cells. Electron microscopy revealed sparse secretory granules in the majority of tumor cells; a minority of neoplastic cells contained numerous granules. We further characterized this neoplasm by performing dual immunohistochemical analysis. This technique clearly demonstrated the presence of ACTH and calcitonin within the same neoplastic cells. Thus, the medullary carcinoma of the thyroid in this patient was the source of ectopic ACTH secretion causing Cushing's syndrome. In addition, this report highlights the value of using double immunostaining to localize both the ACTH and calcitonin within the same cells.     

Steroid biosynthesis inhibitors in Cushing's syndrome

Conclusions About one-third of all patients with Cushing's syndrome cannot be cured by surgery (at the pituitary or adrenal level) or radiation therapy and are therefore candidates for medical treatment. As a conservative therapeutic approach to lower hypercortisolism, the use of steroid biosynthesis blocking substances has the greatest importance. Trilostane, an inhibitor of the adrenal 3-hydroxysteroid dehydrogenase 5,4-isomerase system, has been studied in only a few patients with Cushing's syndrome and was not potent enough to normalize hypercortisolism, especially in patients with pituitary-dependent Cushing's disease.Aminoglutethimide, predominantly blocking side-chain cleavage, normalized elevated serum or urinary cortisol levels in only a minority of patients with Cushing's disease and showed adverse reactions in the majority.Metyrapone, a strong inhibitor of adrenal 11-hydroxylase activity, has only an insufficient blocking effect on elevated cortisol levels in some patients with various forms of Cushing's syndrome and shows side effects in a significant number of patients.Ketoconazole in vitro blocks predominantly adrenal 17,20-desmolase activity and to a lesser extent 17- and 11-hydroxylase activity. Therefore the substance in vivo more markedly suppresses serum androgen levels (dehydroepiandrosterone sulfate, androstenedione, testosterone) than cortisol. However, clinical data from several groups show that the administration of ketoconazole normalizes the urinary excretion of cortisol in the mean in about 70% of patients with Cushing's disease. Furthermore, the antimycotic drug was effective in many patients with a benign primary adrenal form of Cushing's syndrome, in about 50% of patients with ectopic ACTH syndrome, but rarely in patients with adrenocortical carcinoma. The main side effect of ketoconazole is liver toxicity, in about 10% of all cases.Etomidate has strong inhibiting properties on adrenal 11-hydroxylase activity and in vivo is the most potent substance to normalize hypercortisolism. However, its widespread use is prevented by the necessity of intravenous administration.Mitotane inhibits various pathways of adrenal steroid biosynthesis, but its main effect is a cytolytic effect especially on adrenocortical cells. It is therefore a special cytostatic drug for patients with adrenocortical carcinoma. High doses of the substance lower or normalize elevated cortisol parameters in the majority of these patients, but objective tumor regression has been documented in only in few cases.Abbreviation ACTH adrenocortropic hormone     

Human corticotroph cell adenomas

Sixty-one pituitary corticotroph adenomas from 47 patients with Cushing's disease, 10 with Nelson's syndrome, and four eucorticoid patients were studied by light microscopy, immunoperoxidase, and electron microscopy. Seventy nine percent of all tumors and 70% of Nelson's cases were microadenomas, sometimes minute. A contiguity between the posterior lobe and the adenoma was seen in ten cases. Spontaneous infarction of the tumor with remission of Cushing's syndrome occurred in one case. Light microscopy revealed that the adenoma cells were basophilic and contained PAS-positive granules also staining with Herlant tetrachrome and lead-hematoxylin. The granules stained positively with antiserum to adrenocorticotrophic hormone (ACTH), beta-lipotropic hormones (beta-LPH) and beta-endorphin. The most characteristic ultrastructural finding was the presence of perinuclear bundles of microfilaments found in all our cases. Oncocytic changes were seen in three tumors. Four silent corticotroph adenomas, two of them originally microadenomas that had enlarged to enclosed adenomas while being treated with bromocriptine for hyperprolactinemia and one a large diffuse invasive tumor, did not differ in their microscopic, immunocytological, or ultrastructural features.