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Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12-15 kg that were treated daily with Mitometh or Mitotane (50-100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line, NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action. [ABSTRACT FROM AUTHOR]

Low doses of mitotane were given orally to 36 patients with Cushing's disease, concurrently with or after pituitary cobalt irradiation. Clinical and biochemical remission occurred in 29. The response to treatment occurred early in 17 patients and late in 12. The different pattern of response to mitotane was not related to the dose given or to its serum level. Early biochemical indicators of adrenal suppression with mitotane were a sharp decrease in adrenal response to the infusion of ACTH and in plasma levels of dehydroepiandrosterone sulfate. Although mitotane was given together with pituitary irradiation, initial remission was due mainly to the adrenal effect of mitotane. Plasma ACTH levels were still elevated when cortisol had returned to normal. In seventeen of the 29 patients who responded to treatment drug therapy has been discontinued, and they remain in remission of Cushing's syndrome. Side-effects have been dose dependent, with anorexia, nausea, decreased memory, and gynecomastia in men being the commonest. [ABSTRACT FROM AUTHOR]

Study Objective: To assess the efficacy of 131I-6-beta-iodomethylnorcholesterol scintigraphy in the adrenocorticotropic hormone-independent Cushing syndrome and to compare this with computed tomography.Design: Retrospective analysis of case series from 1977 to 1987.Setting: Referral to the Division of Nuclear Medicine at a tertiary-care university medical center.Patients: Twenty-four patients with a pathologically-confirmed diagnosis of the adrenocorticotropic hormone-independent Cushing syndrome had 131I-6-beta-iodomethylnorcholesterol scintigraphy and, in most cases, computed tomography.Measurements and Main Results: Using 131I-6-beta-iodomethylnorcholesterol scintigraphy, adenomas were accurately seen as focal, unilateral tracer uptake in 14 of 14 patients. In carcinoma, the classic scintigraphic pattern of bilateral nonvisualization was observed in 3 of 4 patients, with ipsilateral uptake of tracer in 1 patient with a histologically well-differentiated malignancy. Computed tomography done during the same interval depicted abnormal adrenals in all cases of adenoma and carcinoma. In cortical nodular hyperplasia, however, computed tomography identified abnormal pairs of adrenals in only one of four cases studied, whereas scintigraphy showed typical patterns of bilateral increased uptake in all of the cases.Conclusion: 131I-6-beta-iodomethylnorcholesterol scintigraphy accurately shows the location and nature of adrenal dysfunction in the adrenocorticotropic hormone-independent Cushing syndrome and may be particularly useful in identifying the bilateral adrenal involvement in cortical nodular hyperplasia. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Given the limited number of patients seen in most medical centers with this diagnosis, series usually reported are small and clinical trials not randomized or blinded. In an attempt to answer important questions concerning the management of patients with adrenal cancer, a consensus conference was organized and held at the University of Michigan in Ann Arbor, MI, 11-13 September 2003, with the participation of an international group of physicians who had reported on the largest series of patients with this disease and who had recognized basic and clinical research expertise in adrenal cortical cancer. Totally 43 questions were addressed by the presenters and recommendations discussed in plenary and breakout sessions. Evidence for the recommendations of this conference was at the 2-4+ level and based on available literature and participants' experience. In addition to setting up guidelines in specific areas of the diagnosis and treatment of adrenal cancer, the conference recommended and initiated the planning of an international prospective trial for treatment of patients with adrenal cancer in stages III and IV. In terms of new therapies, first trials of dendritic cell therapy in human subjects with adrenal cancer have been started, but it is too early to comment on efficacy. Different strategies of immunotherapy, including DNA vaccination are currently being tried in animal models. There are no clinical gene therapy trials for human adrenal cortical cancer. The adrenals are a preferred target for adenovirus and the results of gene therapy in preclinical studies are promising. In addition, there is evidence that histone deacetylase inhibitors can further enhance the rate of adenoviral infectivity in human adrenal cancer cells. Testing of retroviral vectors, non-viral vectors, small interfering RNA technology, and combined approaches could be performed in various laboratories. Anti-angiogenic substances have only been applied in preclinical studies. The use of these and other agents in the treatment of adrenal cancer should be hypothesis-driven and based on a thorough analysis of tumor biology.

A patient with adrenocortical carcinoma presented with fever, leukocytosis, and increased acute phase reactants. The tumor was infiltrated with neutrophils. Immunohistochemical staining of the tumor showed positive signal for epithelial neutrophil-activating protein-78, an angiogenic and chemotactic CXC chemokine. Conditioned medium from tumor-derived cells (RL-251) showed high concentration of IL-8, epithelial neutrophil-activating protein-78, Gro alpha, and Gro gamma, angiogenic CXC chemokines with a potential role in tumorigenesis. An adrenal cancer/severe combined immunodeficiency mouse chimera was developed. Mice grew tumors rapidly, and circulating levels of IL-8 and epithelial neutrophil-activating protein-78 were detected. In contrast, animals transplanted with NCI-H295 cells, a nonchemokine-secreting cell line, grew tumors more slowly and did not have detectable chemokine levels. Similar to the patient, mice with RL-251 tumors developed marked leukocytosis and neutrophilia, and their tumors were infiltrated with neutrophils. Mice were passively immunized with epithelial neutrophil-activating protein-78 antisera. A marked decrease in tumor growth was observed. Potential for chemokine production by other adrenocortical tumors was investigated by RT-PCR in archival material. Six of seven adrenal carcinomas and one of three adenomas had cDNA for IL-8; six of seven carcinomas and the three adenomas had cDNA for epithelial neutrophil-activating protein-78. We concluded that the clinical presentation of this case resulted from increased tumor production of chemotactic chemokines. Through their angiogenic and chemotactic properties these chemokines may play an important role in adrenal tumorigenesis.

Adrenocortical carcinoma is a highly malignant neoplasm with an incidence of two per million people per year. Several treatment strategies have resulted in temporary or partial tumor regression but very few cases have attained long survival. Surgical resection of the primary tumor and metastases is most effective. Several chemotherapeutic protocols have been employed with variable success. Mitotane (o,p'-DDD) is an adrenalytic drug effective in inducing a tumor response in 33% of patients treated. Mitotane requires metabolic transformation for therapeutic action. Tumors may vary in their ability to metabolize mitotane and the ability of tumors to transform mitotane may predict the clinical response to the drug. Preliminary data show a possible correlation between metabolic activity of neoplastic adrenocortical tissue and response to mitotane. We have attempted to develop mitotane analogs with enhanced adrenalytic effect. Compared to mitotane, a di-chloro compound, the bromo-chloro and di-bromo analogs appear to have a greater effect. Future approaches to the treatment of adrenocortical carcinoma are likely to be based on blocking or reversing the biological mechanisms of tumorigenesis. Angiogenic and chemotactic mechanisms may play a role in adrenal tumor growth and inhibition of these mechanisms may result in inhibition of tumor growth. New mitotane analogs with greater adrenalytic potential could be a promising approach to developing more effective and selective therapies for adrenal cancer. Alternative approaches should attempt to suppress tumor growth by means of compounds with anti-angiogenic and anti-chemotactic activity.

Adrenal masses are discovered incidentally in 1 to 3% of abdominal CT scans performed for investigation of nonadrenal-related abdominal complaints. Although most incidentally discovered masses are clinically silent, 10% are hormone-secreting and are associated with subtle symptoms of hormone excess. The major concern is the possibility that such a mass is malignant and requires surgical intervention. Benign adrenal cortical adenomas are 60 times more common than primary adrenal cortical carcinomas, which are rare, and many of the lesions that are malignant are metastatic from extra-adrenal neoplasms. Size is a significant factor in determining the probability that the lesion is benign or malignant, and there is concensus that most benign lesions are smaller than 3 cm, whereas most malignant lesions are larger than 6 cm. Uncertainty remains, however, as to the potential malignant character of masses measuring 3 to 6 cm; thus, size alone is insufficient for determining if an incidentally-found adrenal mass is benign or malignant, and information obtained from other diagnostic techniques, such as CT, MR imaging, and adrenal scintigraphy with 131I 6 beta-iodomethylnorcholesterol, should be considered. Fine needle biopsy of an adrenal mass is not recommended unless there is strong suspicion that the mass is metastatic from an extra-adrenal neoplasm.

Background: Decreased hippocampal volume is observed in patients with Cushing's syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy., Methods: The study included 22 patients with Cushing's disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment., Results: Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease., Conclusions: Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

Purpose: Mitotane (o,p'-DDD), is the only adrenolytic agent available for the treatment of adrenocortical carcinoma. Previous studies have shown that mitotane covalently binds to adrenal proteins following its metabolism in adrenocortical tissue to a reactive acyl chloride intermediate. It was the objective of this study to compare the electrophoresis separation patterns of such adducts following activation of mitotane by various adrenocortical sources., Methods: With the use of a 125I-labeled analog of mitotane, 1-(2-chlorophenyl)-1-(4-iodophenyl)-2,2-dichloroethane, gel electrophoresis patterns were obtained for homogenates from bovine, canine and human adrenocortical preparations as well as from a human adrenal preparation. Western immunoblotting analysis was used to test the resulting patterns for adducts of cytochrome P-450scc and adrenodoxin., Results: The electrophoresis separations were similar for all preparations, with bands at apparent molecular weights of 49.5 and 11.5 kDa being the most pronounced. Radiolabeling of the proteins of a human adrenal cancer cell line NCI H-295 was weak, but a band at 11.5 kDa was detected. Western immunoblotting analyses indicated that the band at 49.5 kDa corresponded in molecular weight to that of adrenal cytochrome P-450scc, but the band at 11.5 kDa did not correspond to adrenodoxin., Conclusions: The similarity of the results with canine and bovine adrenal preparations to that of human material offers useful systems for studying mitotane and its analogs. This should aid in understanding the mechanism of action of mitotane and in the design of compounds for the treatment of adrenocortical carcinoma.

Hormones of the hypothalamic-pituitary-adrenal (HPA) axis are connected closely with immune measures. To investigate whether Cushing's syndrome (CS) is associated with immune dysregulation, we compared the percentage of specific lymphocyte subsets as well as natural cell activity (NKCA) in 48 patients with Cushing's syndrome and 48 age- and sex-matched normal controls. Lymphocyte subset analysis included the percentage of lymphocytes expressing CD3 (total T), CD4 (T helper/inducer), CD8 (T suppressor/cytotoxic) and CD56 (NK cell) antigens. Baseline plasma concentrations of cortisol, ACTH and beta-endorphin as well as 24 h urinary-free cortisol (UFC) levels also were determined. Results indicated a decrease in the percentage of CD4+ cells (p < 0.05), an increase in percentage of CD8+ cells (p < 0.05), a decrease in CD4/CD8 ratios (p < 0.01), and a reduction in NKCA (p < 0.05) in patients with CS compared to matched controls. We also found significant negative correlations between NKCA on the one hand and 24 h UFC (p < 0.05) and plasma beta-endorphin (p < 0.05) on the other. These results indicate there is immune dysregulation in CS patients which can be explained in part by an increase in HPA-axis hormones.

This study explored the effect of elevated systemic cortisol levels on plasma epinephrine and norepinephrine, and hemodynamic variables, in patients with active Cushing's syndrome; ratings of depressed mood were also obtained. Norepinephrine levels were significantly negatively correlated with 24 h urinary free cortisol levels. Cushing's patients without depressed mood showed more robust negative correlations than those with depressed mood. The inverse relationship between norepinephrine and cortisol is consistent with data obtained previously in acute studies of normal subjects. Mechanisms which might explain these relationships include changes in control of catecholamine production, release, and or metabolic clearance in Cushing's patients. The decrease in the strength of association in depressed Cushing's patients is consistent with prior studies that suggest abnormal relationships between hypothalamic-pituitary-adrenocortical activity and noradrenergic function in major depressive disorder.

The adrenalytic activity of mitotane (o,p'-DDD) has made it useful in the treatment of adrenocortical carcinoma and Cushing's syndrome. In support of a study to develop mitotane analogs as more effective therapeutic agents and as a basis for understanding the toxicity of related compounds in the adrenals, the biotransformations of o,p'-DDD in adrenocortical homogenate preparations have been studied and compared with those of its m,p'- and p,p'-isomers. Aliphatic oxidation to the corresponding acetic acid derivative, o,p'-, m,p'- or p,p'-DDA, was the major transformation for all the preparations. In the comparisons of the DDD isomers, the order of both DDA formation and apparent covalent binding was o,p'- > m,p'- > p,p'-DDD. There was also evidence for alpha-hydroxylation at the benzylic carbon with subsequent loss of water to form ethylene derivatives. This was a minor pathway for o,p'-DDD, but was the major pathway for the other two isomers. Thus, while the total yields of metabolites of o,p'- and m,p'-DDD were similar and at least twice that of the p,p'-isomer, their distribution of metabolites differed significantly. The effects of the three isomers on cell growth and cortisol production with the human adrenocortical carcinoma cell line, NCI H-295, followed the same order as their DDA formation and tissue binding. It is proposed that hydroxylation by the adrenal cortex at the beta-carbon leads to an adrenalytic effect, whereas hydroxylation at the alpha-carbon would represent an alternate deactivation pathway.

Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, o,p'-DDD] is an adrenocorticolytic agent of value in the treatment of adrenocortical carcinoma and Cushing's syndrome. In support of a program to develop agents superior to mitotane, it is the purpose of this study to explore the relationship of the metabolism of mitotane to its binding to adrenal cortex tissue from several sources. The objective was to detect the mitotane moiety responsible for its covalent binding in various test systems. Studies were conducted with an 125l-labeled analog of mitotane, 1-(2-chlorophenyl)-1-(4-iodophenyl)-2,2-dichloroethane, prior to a comparison to results with lower specific activity [14C]mitotane. With dog adrenal cortical whole homogenates, the majority of covalent binding was to proteins with an additional one-sixth of the total bound radioactivity associated with a phospholipid fraction. No radioactivity was associated with DNA. The rank order of species in regard to metabolism and protein binding was bovine > dog > rat adrenal homogenates > human normal adrenal or tumor homogenates. The percentage of radioactivity recovered from the hydrolysates of those fractions was uniformly high. In addition, the only metabolite present in the hydrolysates corresponded to 1-(2-chlorophenyl)-1-(4-iodophenyl)acetic acid from the iodo analog of o,p'-DDD and the corresponding o,p'-dichlorodiphenylacetic acid (o,p'-DDA) from o,p'-DDD. Our results are consistent with an acyl chloride being the reactive intermediate formed from the dichloromethyl moiety of mitotane, which leads to both DDA metabolite formation and binding to adrenal cortical bionucleophiles.

Unlabelled: We studied 229 patients with abnormal adrenal anatomy depicted by CT who were without biochemical evidence of endocrine dysfunction using the presence of 131I-6 beta-iodomethyl-nor-cholesterol (NP-59) adrenal gland uptake as an index of differential adrenal function in the evaluation of the clinically "silent" adrenal mass lesion., Methods: NP-59 (1 mCi) was injected intravenously with posterior and lateral abdominal images obtained 5-7 days postinjection., Results: One-hundred and fifty-nine of 185 patients with unilateral adrenal enlargement on CT had scintigraphic evidence that the mass represented a functioning (NP-59 avid) but not hypersecretory, (biochemically normal) adrenal cortical adenoma (concordant imaging pattern). Forty-one of 44 patients with intra-adrenal neoplasms were depicted on scintigraphy as decreased or absent NP-59 accumulation on the side of the adrenal mass (discordant imaging pattern). In this study, sensitivity was 71% (41 of 58 patients; 95% confidence interval (CI), 58% to 88%); specificity was 100% (171 of 171 patients; 95% CI, 95% to 100%) and accuracy was 93% (212 of 229 patients; 95% CI, 88% to 96%)., Conclusions: These data confirm our earlier observations that the functional information depicted by scintigraphy complements the morphological evaluation by CT and in the absence of hormonal dysfunction, the presence of concordant CT and 131I-NP-59 scans are characteristic of functioning, but not hypersecretory, benign adrenocortical adenomas. Conversely, discordant CT and 131I-NP-59 scans are suggestive of nonfunctioning, space-occupying, adrenal lesions.

Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pituitary-ACTH-dependent Cushing's disease (CD) and five with CS from an adrenal tumor. Data were compared to healthy controls of comparable age. Seven patients (32%) demonstrated at least mild sleep apnea (> or = 9.4 events/hour), and four of 22 (18%) had > or = 17.5 events/hour. The apneic CD and CS patients had a trend for a greater complaint of excessive daytime sleepiness. Both apneic and nonapneic groups had considerable snoring and obesity. The electroencephalographic (EEG) sleep of nonapneic patients was compared to that of normal subjects. Nonapneic CD patients differed strikingly from healthy volunteers in sleep continuity and architecture, demonstrating lighter, fragmented sleep. Rapid eye movement (REM) sleep in CD patients bore many similarities to the sleep of patients with major depression, with REM latency being significantly shortened and REM density significantly increased. Continued examination of EEG sleep in CD patients may shed light on similarities in pathophysiology between CD and major depression, disorders which are characterized by both a dysfunction of the hypothalamic-pituitary-adrenal axis and alterations in mood.

Cushing's Disease is often associated with a depressive syndrome, with mood, vegetative, and cognitive abnormalities of variable severity. In 11 patients with (pituitary ACTH-dependent) Cushing's disease (10 women, 1 man), we studied the relationship between severity of the depressive syndrome and concordance of changes in ACTH and beta-lipotropin/beta-endorphin (beta-LPH/beta-E) levels at baseline and in response to metyrapone and dexamethasone. For each condition, blood samples were drawn at 0800h, 1200h, 1600h, and 2200h. Six patients were categorized as mildly depressed (mean [+/- SD] depressed mood score = 0.17 +/- 0.4; modified Hamilton Depression scale score = 7.6 +/- 4.5) and five as severely depressed (mean depressed mood score = 2.4 +/- 0.5; modified Hamilton Depression scale score = 15 +/- 5.6) (p < 0.05). ACTH and beta-LPH/beta-E were measured by radioimmunoassay. For each experimental condition, changes in levels were scored as concordant if the two peptides moved in parallel between sampling points. There was a relationship between greater severity of depression and more frequent discordant changes in ACTH and beta-LPH/beta-E levels: The six patients with mild depression exhibited 23 concordant and 3 discordant change patterns, while the five patients with severe depression showed 8 concordant and 15 discordant patterns. The mean percentage of concordant patterns per patient differed significantly between the two groups (mildly depressed = 90.0 +/- 16.7; severely depressed = 34.6 +/- 8.7 (p < 0.001). When each study condition was examined separately, differences in the frequency of concordance between the groups reached significance during the post-metyrapone phase and with 8.0 mg dexamethasone administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with chronic hypercortisolemia due to Cushing's syndrome (CS) exhibit cognitive dysfunction. Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, we explored the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels in 12 patients with CS. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of dentate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 27% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r = 0.57 to 0.70, p < 0.05). HF volume was negatively correlated with plasma cortisol levels (r = -0.73, p < 0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.

Adrenal scintigraphy with 131I-6 beta-iodomethylnorcholesterol (NP-59) has been widely used to evaluate adrenal cortical tumors during the past 20 years. Unilateral visualization on the side of an adrenal tumor has been considered diagnostic of a benign adrenocortical adenoma in the patient with Cushing's syndrome. Bilateral nonvisualization of the adrenal glands in the presence of Cushing's syndrome is considered diagnostic of adrenocortical carcinoma (ACC). ACCs characteristically are unable to incorporate enough NP-59 to be visualized on NP-59 adrenal scintigraphy. Two patients with well-differentiated cortisol-secreting ACCs, in which the primary tumor or subsequent metastases demonstrated intense uptake (visualization) on NP-59 scans are reported here. As a result of these findings on NP-59 adrenal scintigraphy, the lesions were initially misinterpreted to represent benign disease. In each patient the operative approach selected, based on the interpretation of the NP-59 scan, was inappropriate for the management of the respective adrenal neoplasm or its metastasis. A review of the literature reveals 16 other cases of either ACC or their metastases that were visualized with adrenal scintigraphy. Ninety percent of these cases were associated with adrenocortical hormone hypersecretion. It is concluded that in the presence of Cushing's syndrome or another adrenocortical hormone excess state, unilateral visualization of an adrenal tumor on NP-59 scintigraphy cannot be interpreted to represent uniformly benign disease.

Because patients with Cushing' syndrome (CS) and Major depressive disorder (MDD) share features of hypercortisolism and the depressive syndrome, we compared electro-encephalographic (EEG) sleep in patients with pituitary-ACTH-dependent Cushing's syndrome (Cushing's disease, CD), patients with ACTH-independent Cushing's syndrome (AICS), patients with major depressive disorder (MDD), and normal subjects. There were substantial similarities in the abnormal polysomnography profiles of patients with CD, AICS, and MDD. All three patient groups demonstrated poorer sleep continuity, shortened rapid eye movement (REM) latency, and increased first REM period density compared with normal subjects. In addition, AICS patients and MDD patients had elevated REM activity and density. These findings are discussed in terms of models of pathophysiology that relate abnormalities in sleep, mood, and hypothalamic-pituitary-adrenal function.

Phenylpropanolamine (PPA), an over-the-counter drug, is used for weight reduction but its effectiveness is controversial. One hundred and one ambulatory subjects (85 female; 16 male), 21-61 years old, 15-45% overweight but otherwise healthy, were studied. The study was divided into two phases: (i) a double blind (DB), placebo-controlled (P) phase in which all subjects took placebo for two weeks and subsequently took PPA, 75 mg sustained release or placebo for six weeks and (ii) an extended double blind phase in which subjects chose to continue up to 20 weeks. All subjects were instructed on a 5023 kJ (1200 kcal) diet. Both groups lost weight at weeks 4, 6 and 8, but the weight loss was greater for the PPA treated (2.59 kg) than for the placebo treated (1.07 kg) subjects (P = 0.01). Dropout was 29.4% for PPA and 44% for placebo treated subjects. In the 36 subjects who chose to continue in the extended double blind study, the difference persisted (PPA 5.1; placebo 0.4 kg) (P = 0.02). No difference between the groups was observed in blood pressure, pulse rate or subjective side effects. In spite of greater weight loss on PPA, patients did not report a greater anorexic effect. We conclude that PPA enhances weight loss in subjects treated with a hypocaloric diet and is free of untoward side effects.

A wide spectrum of clinical and biochemical presentations characterize ectopic POMC syndrome. It is presently postulated that ectopic POMC production results from increased expression of the activity of a POMC gene normally occurring in a variety of tissues outside the pituitary gland. The syndrome is rapidly progressive and is characterized by severe clinical manifestations in patients with a more aggressively developing oat cell carcinoma of the lung. However, in patients with slower growing nonpituitary tumors, the presentation may overlap that seen in patients with pituitary ACTH-dependent Cushing's syndrome. In cases in which the biochemical testing results overlap with those seen in pituitary ACTH-dependent disease, a combination of lack of suppression with high-dose dexamethasone and absent response to CRH stimulation greatly increases the diagnostic accuracy. Abnormal alternative processing of POMC in nonpituitary neoplasms may render unusual POMC-derived peptides that could be used as markers in the diagnosis and follow-up of patients with this syndrome. The prognosis of patients afflicted with ectopic POMC syndrome is largely determined by the nature of the underlying tumor. However, the clinical course can be greatly modified by control of the metabolic manifestations of hypercortisolemia. A variety of surgical and pharmacologic options are available, including adrenalectomy and the use of adrenal inhibitors. Cushing's syndrome of long duration, the finding of ectopic pituitary adenomas, and the combined secretion of CRH and POMC by nonpituitary tumors constitute interesting variants of the classic picture.

Exercise training has potential benefits for patients with hyperlipidemia and/or non-insulin dependent diabetes mellitus. In nondiabetic, nonobese subjects with hypertriglyceridemia, exercise training alone increased insulin sensitivity, improved glucose tolerance, and lowered serum triglyceride and cholesterol levels. These improvements did not occur when exercise training alone was given to similar patients with impaired glucose tolerance. In severely obese (X = 125 kg) subjects without diabetes melitus, a 600 calorie diet alone decreased glucose and insulin concentrations and improved glucose tolerance but did not increase insulin sensitivity. The addition of exercise training improved insulin sensitivity. Obese, non-insulin dependent diabetes mellitus subjects on sulfonylurea therapy alone increased insulin levels but failed to improve insulin sensitivity or glucose levels. In contrast, the addition of exercise training to this medication resulted in improved insulin sensitivity and lowered glucose levels. We conclude that exercise training has major effects on lowering triglyceride levels in hyperlipidemic subjects and can potentiate the effect of diet or drug therapy on glucose metabolism in patients with non-insulin dependent diabetes mellitus.

A 49-year old woman with a 5-year history of Cushing's syndrome was evaluated. Biochemical measurements revealed high cortisol and adrenocorticotropic hormone (ACTH) levels consistent with the ACTH-dependent type of Cushing's syndrome. However, the source of ACTH seemed to be autonomous as she demonstrated abnormal feedback control, with lack of response to metyrapone and high coses of dexamethasone. A search for an ectopic ACTH-secreting nonpituitary neoplasm was unsuccessful. Transsphenoidal pituitary exploration revealed a normal pituitary gland, but an ectopic pituitary adenoma was found incidentally in the mucosa of the sphenoid sinus. This adenoma stained strongly positive for ACTH on immunocytochemical studies. Resection of this lesion led to remission of the Cushing's syndrome. This variant of ACTH-dependent Cushing's syndrome can mimic the ectopic ACTH-dependent type and should be looked for in patients who fail to respond to pituitary operation.

The management of the extremely obese patient is best accomplished by a multidisciplinary approach which includes exercise training as an integral component. While diet alone is a potent factor in improving the metabolic complications associated with obesity, the combination of diet and exercise training can further improve these complications and greatly enhance cardiorespiratory function. Although the fitness of extremely obese people is low, individualized exercise programs can be used to safely and progressively train these patients, reduce fatigue, and greatly increase maximum work tolerance. Additional benefits derived from exercise training include improved insulin-mediated glucose utilization, lower serum lipid concentrations, and improved psychological distress scores and anxiety levels. Thus, exercise training can contribute to the success of a weight reducing program by improving metabolic, cardiorespiratory, and psychological factors. Additional important interventions in a multidisciplinary treatment of severe obesity include psychiatric, psychosocial, and vocational counseling.

To correlate iodocholesterol tissue uptake with the ability to visualize adrenal cortical neoplasms, eight female patients with adrenal carcinoma had adrenal scintiscans after the injection of 19-[131I]iodocholesterol. Patients with cortisol-secreting carcinomas failed to image either the tumor or uninvolved adrenal tissue. In contrast, patients with androgen-secreting carcinomas (which do not suppress pituitary ACTH secretion), although still failing to image the tumor, had visible concentration of the radionuclide in the ipsilateral and contralateral adrenal glands. Slices of these tissues obtained at either surgery or postmortem examination were analyzed for iodocholesterol uptake. Results were compared with adrenal tissue obtained from patients with either cortisol- or aldosterone-secreting adenomas and patients on dexamethasone suppression. There was a strong correlation between the adrenal tissue concentration of iodocholesterol and the ability to form an image on scintiscanning. The concentration of iodocholesterol in an adenoma and a carcinoma determined in this manner was compared with their cortisol secretion during in vitro incubation. The concentration of 19-[131I]iodocholesterol and the in vitro secretion of cortisol were greater in the adenoma than in the carcinoma and corresponded with adrenal imaging in the former and lack of imaging in the latter. These data provide a quantitative assessment of the differences in radioactivity concentration required for imaging of adrenal tumors. It also demonstrates that differences in the concentration of radioactivity within adrenal carcinomas and adenomas corresponds to their ability to release cortisol in vitro.

The immunohistochemical characterization of 92 surgically resected abnormal pituitaries showed 24 cases with ACTH immunoreactivity. These included two cases of nodular hyperplasias, 20 functional adenomas, and two silent corticotropic adenomas. Both patients with nodular hyperplasia and 19 patients with functional adenomas had Cushing's disease, while one patient with a functional adenoma had Nelson's syndrome. The two silent corticotropic adenomas were not associated with Cushing's disease, although both patients had slightly elevated serum prolactin levels. The tumors, which were stained for beta-endorphin (12 cases) and alpha and beta-MSH (five cases) were all positive for these peptides. These results show that immunohistochemical staining is indispensable in the diagnosis of nodular hyperplasia and silent corticotropic adenomas and that it is extremely helpful in confirming the diagnosis of ACTH-producing adenomas.

The clinical characteristics and current concepts of pathophysiology of Cushing's syndrome have been reviewed. The specific type of pituitary or ectopic ACTH-dependent and ACTH-independent Cushing's syndrome and the underlying pathology can be determined biochemically and with the aid of anatomic localization procedures. Several approaches are available for treating pituitary ACTH-dependent Cushing's syndrome, but transsphenoidal pituitary microsurgery is the ideal type, with remission of the disease being observed in 80 to 90% of cases. When successful, pituitary microsurgery is followed by preservation of normal pituitary function and restoration of normal hypothalamic-pituitary-adrenal function within 6 to 12 months postoperatively. Medical therapy of Cushing's disease includes drugs that inhibit CRH-ACTH secretion, such as cyproheptadine and bromocriptine, and agents that inhibit cortisol synthesis, such as aminoglutethimide, metyrapone, ketoconazole, and mitotane, or that block the action of cortisol at the glucocorticoid receptor level, such as RU-485. With the exception of mitotane, which has adrenalytic effects, the action of the other pharmacologic agents is promptly reversed when treatment is discontinued. Thus, drug therapy is effective only as temporary treatment for Cushing's syndrome when surgical approaches are contraindicated or when attempts are made to improve the patient's clinical and metabolic status in preparation for surgery. Mitotane is effective in extending survival of patients with adrenal carcinoma, particularly when it is administered early as adjuvant therapy or when it is combined with repeated debulking resection of recurrent tumor. The toxicity associated with mitotane administration limits the use of larger and probably more effective doses in these patients. The synthesis of more specific cytochrome P-450 enzyme inhibitors and of mitotane analogues with more limited toxicity may ultimately provide more effective tools in the pharmacologic management of Cushing's syndrome.

The effect of insulin on motilin release was investigated by use of the euglycemic glucose clamp technique. By use of this technique plasma glucose concentration was maintained constant at 80-90 mg/100 ml, and plasma insulin immunoreactivity (IRI) was increased from 15 +/- 6 microU/ml to 171 +/- 22 microU/ml in 10 min, and remained at this level for 2 hr. Plasma motilin like immunoreactivity (MLI) concentration decreased within 10 min from 199 +/- 36 pg/ml to 120 +/- 28 pg/ml and remained low during the course of study. A significant negative correlation between MLI and IRI concentrations (r = -0.72, p less than 0.01) was observed. The present results indicate that the suppressive effect of insulin on motilin release is a direct action of insulin and is not mediated by glucose.

The endocrinological, radiological, surgical, and pathological experience with 34 consecutive patients operated on for Cushing's disease is presented. Preoperative endocrine evaluation demonstrated that 19 patients had "typical" endocrine patterns for pituitary adrenocorticotropic hormone (ACTH)-dependent hypercortisolism and 11 had "atypical" testing. Pituitary pathology was found in 95% of the patients with typical preoperative endocrine testing but in only 55% of those with atypical testing. Eight of 34 preoperative computerized tomography scans demonstrated tumors, which correlated in all instances with the surgical findings. Microadenomas were removed from 25 patients, 22 of whom achieved postoperative remission of endocrine symptoms. Macroadenomas were found in three patients, only one of whom achieved remission after surgery. One patient had removal of an adenoma in the pharyngeal pituitary, and in another an ectopic lung carcinoid was excised; both of these patients were in postoperative remission. Four patients underwent transsphenoidal exploration but no definitive explanation was found for their hypercortisolism; these patients were not in remission. Immunohistochemical staining was performed on every specimen and all tumors showed excessive ACTH-secreting cells. A new rapid stain of the fibrovascular stroma is described.

To assess the contribution of adrenal-derived androgens in women with hirsutism, adrenal scintigrams under dexamethasone suppression (DS) were performed on 35 women with increasing facial or body hair and irregular or absent menses. Based upon the DS regimen chosen (8 mg/d for 2 days or 4 mg/d for 7 days before the injection of 6 beta-[131I]iodomethylnorcholesterol), three imaging patterns were identified. The first was the absence of uptake before 3 days (8-mg DS) or before 5 days (4-mg DS) after injection. This imaging pattern was seen in 17 of the 35 patients studied and was considered normal. The second pattern was bilateral uptake earlier than 3 days (8-mg DS regimen) or 5 days (4-mg DS) after injection. This was seen in 13 of the 35 patients and was interpreted as bilateral early visualization. Adrenal-vein catheterization performed on six patients with this pattern showed increased adrenal-vein testosterone. The third pattern, observed in five patients, was unilateral early visualization, which in four cases investigated to date was the result of an adrenocortical adenoma. This study confirms the adrenal cortex as a source of androgens in women with hirsutism and hyperandrogenism and demonstrates the DS adrenal scintigraphy can be utilized to identify those women in whom adrenal-derived androgens contribute to their hyperandrogenism.

Twenty-three patients with adrenal carcinoma were treated between 1953 and 1981. Six patients underwent resection of the primary tumor and/or local radiation therapy but received no chemotherapy. Their mean survival (+/- SD) was 10.3 +/- 8.7 months. In contrast, 17 patients who were treated with mitotane had a mean survival of 46.6 +/- 42.7 months. Response to therapy depended on when in the course of the disease chemotherapy was instituted, and on the combination of surgical excision and drug treatment of recurrent disease. Longest survival was observed in patients who received mitotane as adjuvant therapy before clinical evidence of metastases was noted and in those who were treated with mitotane and underwent subsequent surgery for recurrent tumor. Mean survival for this group was significantly longer, 74 +/- 33 months, than for the other patients. Patients treated in this series received low-dose long-term therapy. Adverse effects of mitotane were found to be dose dependent.

Thirty-five consecutive patients with Cushing's syndrome were studied prospectively before treatment. A consistent constellation of neuropsychiatric disturbances was found, including impairments in affect (depressed mood and crying), cognitive functions (decreased libido and insomnia). Thirty-four percent of patients were rated as having a mild, 26% a moderate, 29% a severe, and 11% a very severe psychiatric disability. A statistically significant relationship was found between the overall neuropsychiatric disability rating and cortisol and adrenocorticotropic hormone (ACTH) levels. Patients with adrenal adenomas with high cortisol but low ACTH levels did not have as severe a neuropsychiatric disability.

A 50-yr-old woman presented with a 7-yr history of Cushing's syndrome. She had high urinary free cortisol levels (711 micrograms/day) and a positive response to metyrapone and suppression with 8 mg dexamethasone, suggesting pituitary ACTH-dependent adrenocortical hyperfunction. Plasma cortisol and ACTH levels showed marked temporal variation. Samples obtained at 2-h intervals revealed that plasma ACTH and cortisol levels surged during periods lasting approximately 12 h and fell to levels below normal during the remainder of the 24-h cycle. When urinary free cortisol was measured in urines collected in 12-h aliquots, the corresponding surge in free cortisol excretion was also evident. These cycles were not affected by a 2.5-month course of cyproheptadine. Pituitary irradiation and mitotane therapy resulted in remission of Cushing's syndrome, with disappearance of the peaks of ACTH and cortisol secretion. This case represents an unusual example of the abnormal circadian rhythm of ACTH secretion on Cushing's disease.

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.