RESUMEN
BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.
Asunto(s)
Encéfalo/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Emociones/fisiología , Expresión Facial , Lóbulo Frontal/fisiopatología , Lateralidad Funcional , Reconocimiento Visual de Modelos/fisiología , Adulto , Amígdala del Cerebelo/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Corteza Cerebral/fisiopatología , Femenino , Neuroimagen Funcional , Giro del Cíngulo/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/terapia , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Humanos , Estadificación de NeoplasiasRESUMEN
OBJECTIVE: The objective of this study was to use Cushing's disease as a unique human model to elucidate the cognitive deficits resulting from exposure to chronic stress-level elevations of endogenous cortisol. METHODS: Forty-eight patients with a first episode of acute, untreated Cushing's disease and 38 healthy control subjects were studied. RESULTS: Scores for four of five verbal IQ subtests were significantly lower in patients with Cushing's disease; their scores were significantly lower for only one nonverbal performance IQ subtest (block design). Verbal, but not visual, learning and delayed recall at 30 minutes were significantly decreased among patients with Cushing's disease. Although verbal delayed recall was significantly lower in these patients, the retention index (percentage), which compares the amount of initially learned material to that recalled after the delay, was not significantly decreased. There was no significant association between depression scores and cognitive performance. A higher degree of cortisol elevation was associated with poorer performance on several subtests of learning, delayed recall, and visual-spatial ability. CONCLUSIONS: Chronically elevated levels of glucocorticoids have deleterious effects on particular domains of cognition. Verbal learning and other verbal functions seem more vulnerable than nonverbal functions. The results suggest that both the neocortex and hippocampus are affected.
Asunto(s)
Trastornos del Conocimiento/etiología , Síndrome de Cushing/complicaciones , Síndrome de Cushing/metabolismo , Hidrocortisona/metabolismo , Adulto , Enfermedad Crónica , Trastornos del Conocimiento/diagnóstico , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/inmunología , Quimiocinas CXC/genética , Interleucina-8/genética , 17-Hidroxicorticoesteroides/orina , 17-Cetosteroides/orina , Adenoma/genética , Adenoma/inmunología , Adenoma/patología , Adenoma/cirugía , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/cirugía , Hormona Adrenocorticotrópica , Anciano , Quimiocina CXCL5 , Quimiocinas CXC/análisis , Ritmo Circadiano , Fiebre , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Inmunohistoquímica , Interleucina-8/análogos & derivados , Interleucina-8/análisis , Leucocitosis , Masculino , Activación Neutrófila , Neutrófilos/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Carcinoma/tratamiento farmacológico , Mitotano/uso terapéutico , Antineoplásicos Hormonales/metabolismo , Humanos , Mitotano/análogos & derivados , Mitotano/metabolismoRESUMEN
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.
Asunto(s)
Adenoma/terapia , Neoplasias de la Corteza Suprarrenal/terapia , Adenoma/diagnóstico , Adenoma/metabolismo , Corticoesteroides/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Síndrome de Cushing/sangre , Hipocampo/patología , Hidrocortisona/sangre , Hipofisectomía , Adulto , Factores de Edad , Atrofia , Núcleo Caudado/patología , Síndrome de Cushing/etiología , Síndrome de Cushing/cirugía , Síndrome de Cushing/orina , Femenino , Humanos , Hidrocortisona/orina , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
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.
Asunto(s)
Corteza Suprarrenal/metabolismo , Antineoplásicos Hormonales/metabolismo , Mitotano/metabolismo , Proteínas/metabolismo , Corteza Suprarrenal/enzimología , Animales , Autorradiografía , Western Blotting , Bovinos , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Perros , Humanos , Unión ProteicaRESUMEN
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.
Asunto(s)
Hormona Adrenocorticotrópica/fisiología , Síndrome de Cushing/inmunología , Hidrocortisona/fisiología , Sistema Hipotálamo-Hipofisario/fisiopatología , Células Asesinas Naturales/inmunología , Sistema Hipófiso-Suprarrenal/fisiopatología , Subgrupos de Linfocitos T/inmunología , betaendorfina/fisiología , Adulto , Relación CD4-CD8 , Femenino , Humanos , Tolerancia Inmunológica/inmunología , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Psiconeuroinmunología , Valores de ReferenciaRESUMEN
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.
Asunto(s)
Síndrome de Cushing/sangre , Depresión/sangre , Epinefrina/sangre , Hidrocortisona/sangre , Norepinefrina/sangre , Adulto , Anciano , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/fisiopatología , Valores de ReferenciaRESUMEN
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.
Asunto(s)
Corteza Suprarrenal/metabolismo , Mitotano/metabolismo , Animales , Biotransformación , Bovinos , División Celular/efectos de los fármacos , Línea Celular/efectos de los fármacos , Hidrocortisona/análisis , Técnicas In Vitro , Isomerismo , Mitotano/análogos & derivados , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Corteza Suprarrenal/metabolismo , Mitotano/metabolismo , Animales , Biotransformación/fisiología , Bovinos , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Perros , Humanos , Hidrólisis , Técnicas In Vitro , Radioisótopos de Yodo , Ratas , Especificidad de la Especie , Fracciones Subcelulares/metabolismo , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Adosterol , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Adenoma/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cintigrafía , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
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.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Corteza Suprarrenal/efectos de los fármacos , Mitotano/análogos & derivados , Mitotano/farmacología , Corteza Suprarrenal/citología , Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Animales , Carcinoma/tratamiento farmacológico , División Celular/efectos de los fármacos , Perros , Femenino , Cobayas , Humanos , Hidrocortisona/biosíntesis , Mitotano/uso terapéutico , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Síndrome de Cushing/fisiopatología , Polisomnografía , Síndromes de la Apnea del Sueño/fisiopatología , Fases del Sueño/fisiología , Síndrome de ACTH Ectópico/fisiopatología , Adenoma/fisiopatología , Adolescente , Hormona Adrenocorticotrópica/sangre , Adulto , Anciano , Corteza Cerebral/fisiopatología , Dexametasona , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Obesidad/fisiopatología , Neoplasias Hipofisarias/fisiopatología , Tiempo de Reacción/fisiología , Factores de Riesgo , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
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.
Asunto(s)
Síndrome de Cushing/fisiopatología , Hipocampo/patología , Hidrocortisona/sangre , Imagen por Resonancia Magnética , Recuerdo Mental/fisiología , Trastornos Neurocognitivos/fisiopatología , Pruebas Neuropsicológicas , Adolescente , Adulto , Anciano , Mapeo Encefálico , Síndrome de Cushing/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Neurocognitivos/psicología , Retención en Psicología/fisiología , Aprendizaje Verbal/fisiología , Percepción Visual/fisiología , Escalas de WechslerRESUMEN
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.