RESUMO
PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.
Assuntos
Síndrome de Cushing/epidemiologia , Terremotos , Hidrocortisona/metabolismo , Hipotálamo/patologia , Sistema Hipófise-Suprarrenal/patologia , Glândula Tireoide/patologia , Hormônios Tireóideos/metabolismo , Adulto , Big Data , Síndrome de Cushing/metabolismo , Síndrome de Cushing/patologia , Análise de Dados , Feminino , Seguimentos , Humanos , Hipotálamo/metabolismo , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Retrospectivos , Glândula Tireoide/metabolismoRESUMO
STUDY QUESTION: What is the impact of glucocorticoid (GC) on female reproduction? SUMMARY ANSWER: Corticosterone (CORT) exposure causes little damage to oocyte quality or developmental competence but has an adverse effect on the uterus, which causes decreased implantation, embryo death and subsequent infertility. WHAT IS KNOWN ALREADY: Chronic treatment with high GC doses is effective in controlling most allergic diseases but may lead to metabolic disorders such as obesity that are closely related with reproductive function. STUDY DESIGN, SIZE, DURATION: Hypercortisolism was induced in a female mouse model by supplementing the drinking water with 100 µg/ml of CORT. Controls received vehicle (1% v/v ethanol) only. After 4 weeks treatment mice were either mated or killed in estrus for hormone and organ measurements. In the first experiment, treatment with CORT or control continued during pregnancy but in the second CORT treatment was stopped after mating. To identify the effects of GC exposure on the uterus, blastocysts were generated by IVF of oocytes from CORT and control mice and replaced into recipients receiving the opposite treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effects of hypercortisolism on female mice were first characterized by living body fat content, body weight, food intake, hormone and biochemical measurements, a glucose tolerance test and an insulin resistance test. Fertility was determined with or without CORT-treatment during pregnancy. Oocyte quality was assessed by oocyte maturation, mitochondrial distribution, reactive oxygen species production, mitochondrial DNA mutations and morphology of blastocysts produced in vivo or in vitro. Blastocyst cross-transfer was done to evaluate the causes of embryonic development failure. Fetus development and uterus morphology evaluation as well as culture of oocytes in vitro with gradient concentrations of CORT were also carried out. MAIN RESULTS AND THE ROLE OF CHANCE: In the hypercortisolism female mouse model, body weight and food intake were much higher than in the control, and corticosterone, estradiol, cholesterol (CHO) and triglycerides (TG) in the plasma of CORT-treated mice was significantly increased. The hypercortisolism female mice were infertile when CORT-treatment was sustained during pregnancy but fertile if CORT-treatment was stopped after mating. The rate of successful implantation in hypercortisolism mice with sustained CORT-treatment during pregnancy was significantly lower than in the control, and the implanted embryos could not develop beyond 13.5 dpc. Blastocyst cross-transfer showed that blastocysts from CORT-treated mice could develop to term in the uterus of control mice, but blastocysts from control mice failed to develop to term when they were transferred into CORT-treated mice, providing evidence that the infertility was mainly caused by an altered uterine environment. CORT administration did not affect oocyte maturation, mitochondrial distribution, ROS production and blastocyst morphology, but increased mitochondrial DNA mutations. Culture of oocytes in vitro with gradient concentrations of CORT showed that only very high concentrations of CORT caused damage to oocyte developmental competence. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: The mouse model has the advantages of a consistent genetic and physiological background and openness to experimental manipulation over clinical studies but may not represent the human situation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that special care should be taken when administering CORT during pregnancy, and provide important information concerning female reproduction when treating patients by subjecting them to chronic GC exposure. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key R&D Program of China (Nos. 2016YFA0100400 and 2017YFC1000600) and the National Natural Science Foundation of China (31472055). The authors have no conflicts of interest.
Assuntos
Corticosterona/farmacologia , Síndrome de Cushing/metabolismo , Glucocorticoides/farmacologia , Infertilidade Feminina/metabolismo , Oócitos/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Síndrome de Cushing/induzido quimicamente , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Infertilidade Feminina/induzido quimicamente , Camundongos , Oócitos/metabolismo , Triglicerídeos/sangue , Útero/metabolismoRESUMO
AMP-activated protein kinase (AMPK), a regulator of cellular and systemic energy homeostasis, can be influenced by several hormones. Tissue-specific alteration of AMPK activity by glucocorticoids may explain the increase in appetite, the accumulation of lipids in adipose tissues, and the detrimental cardiac effects of Cushing's syndrome. Endocannabinoids are known to mediate the effects of various hormones and to influence AMPK activity. Cannabinoids have central orexigenic and direct peripheral metabolic effects via the cannabinoid receptor type 1 (CB1). In our preliminary experiments, WT mice received implants of a corticosterone-containing pellet to establish a mouse model of Cushing's syndrome. Subsequently, WT and Cb1 (Cnr1)-knockout (CB1-KO) littermates were treated with corticosterone and AMPK activity in the hypothalamus, various adipose tissues, liver and cardiac tissue was measured. Corticosterone-treated CB1-KO mice showed a lack of weight gain and of increase in hypothalamic and hepatic AMPK activity. In adipose tissues, baseline AMPK activity was higher in CB1-KO mice, but a glucocorticoid-induced drop was observed, similar to that observed in WT mice. Cardiac AMPK levels were reduced in CB1-KO mice, but while WT mice showed significantly reduced AMPK activity following glucocorticoid treatment, CB1-KO mice showed a paradoxical increase. Our findings indicate the importance of the CB1 receptor in the central orexigenic effect of glucocorticoid-induced activation of hypothalamic AMPK activity. In the periphery adipose tissues, changes may occur independently of the CB1 receptor, but the receptor appears to alter the responsiveness of the liver and myocardial tissues to glucocorticoids. In conclusion, our data suggest that an intact cannabinoid pathway is required for the full metabolic effects of chronic glucocorticoid excess.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Síndrome de Cushing/metabolismo , Glucocorticoides/farmacologia , Hipotálamo/metabolismo , Receptor CB1 de Canabinoide/deficiência , Tecido Adiposo/metabolismo , Animais , Corticosterona/sangue , Corticosterona/farmacologia , Modelos Animais de Doenças , Hipotálamo/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Miocárdio/enzimologia , Receptor CB1 de Canabinoide/fisiologiaRESUMO
IMPORTANCE OF THE FIELD: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors. AREAS COVERED IN THIS REVIEW: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR(5), the receptor most prevalent in corticotroph tumors. WHAT THE READER WILL GAIN: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease. TAKE HOME MESSAGE: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.
Assuntos
Síndrome de Cushing/tratamento farmacológico , Receptores de Somatostatina/agonistas , Somatostatina/análogos & derivados , Hormônio Adrenocorticotrópico/metabolismo , Animais , Ensaios Clínicos Fase III como Assunto , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação Proteica , Somatostatina/efeitos adversos , Somatostatina/farmacocinética , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To report a rare cause of ectopic adrenocorticotropic hormone (ACTH) secretion leading to severe Cushing syndrome. METHODS: We describe the clinical presentation and management of a case of Cushing syndrome attributable to ectopic ACTH secretion from small cell cancer of the prostate. RESULTS: In a 70-year-old man with hypertension and diabetes, congestive heart failure developed. He was found to have severe hypokalemia (serum potassium, 1.7 mEq/L) and a huge pelvic mass on a computed tomographic scan performed because of a complaint of urinary retention. Transurethral biopsy of the prostate showed features of small cell prostate cancer. Hormonal evaluation revealed a high urine free cortisol excretion of 6,214.5 microg/d (reference range, 36 to 137), confirming the diagnosis of Cushing syndrome. A serum ACTH level was elevated at 316 ng/dL (reference range, 10 to 52). An overnight high-dose (8 mg orally) dexamethasone suppression test was positive (serum cortisol levels were 43.2 and 41 microg/dL before and after suppression, respectively), and magnetic resonance imaging of the pituitary gland disclosed no abnormalities. A prostate biopsy specimen showed small cell prostate cancer with positive staining for ACTH. The tumor was found to be unresectable, and the poor condition of the patient did not allow for bilateral adrenalectomy. He was treated with ketoconazole and metyrapone, which yielded good temporary control of his Cushing syndrome (24-hour urine free cortisol decreased to 55.2 microg/d). He received 1 cycle of chemotherapy (etoposide and cisplatin), but he died 6 months later as a result of sepsis. CONCLUSION: Small cell prostate cancer is a rare subtype that can be associated with ectopic secretion of ACTH and severe Cushing syndrome. With this subtype of prostate cancer, Cushing syndrome should be considered and appropriately managed.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Carcinoma de Células Pequenas/complicações , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Neoplasias da Próstata/complicações , Idoso , Síndrome de Cushing/diagnóstico , Humanos , MasculinoRESUMO
The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.
Assuntos
Sistema Endócrino/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Adipocinas/metabolismo , Glândulas Suprarrenais/metabolismo , Adulto , Androgênios/metabolismo , Síndrome de Cushing/complicações , Síndrome de Cushing/metabolismo , Diabetes Mellitus Tipo 2/complicações , Estrogênios/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/etiologia , Hipotálamo/metabolismo , Hipotireoidismo/complicações , Hipotireoidismo/metabolismo , Insulina/metabolismo , Resistência à Insulina , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Obesidade/complicações , Obesidade/etiologia , Pâncreas/metabolismo , Hipófise/metabolismo , Síndrome do Ovário Policístico/complicações , Pós-Menopausa , Glândula Tireoide/metabolismoRESUMO
Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing's syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid-excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.
Assuntos
Síndrome de Cushing/metabolismo , Glucocorticoides/farmacologia , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP , Tecido Adiposo/enzimologia , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Síndrome de Cushing/enzimologia , Dexametasona/farmacologia , Humanos , Hipotálamo/enzimologia , Hipotálamo/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Metabolismo/efeitos dos fármacos , Metformina/farmacologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Especificidade de Órgãos , RatosAssuntos
Antitireóideos/uso terapêutico , Reabsorção Óssea/metabolismo , Síndrome de Cushing/complicações , Glucocorticoides/efeitos adversos , Hipertireoidismo/complicações , Osteoporose/etiologia , Fosfatase Alcalina/metabolismo , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Cálcio/sangue , Síndrome de Cushing/metabolismo , Citocinas/metabolismo , Feminino , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Humanos , Hipertireoidismo/metabolismo , Hipertireoidismo/terapia , Masculino , Osteoporose/metabolismo , Fósforo/sangueRESUMO
Pituitary adenomas are very common in humans. They are of monoclonal origin, very heterogeneous, and produce frequently paradoxical secretion. The normal anterior pituitary (AP) contains some unorthodox multifunctional cells able to store more than one AP hormone (polyhormonal) and/or to express multiple hypothalamic-releasing hormone receptors (multiresponsive). Multifunctional AP cells seem to be involved in plasticity processes such as transdifferentiation or paradoxical secretion. Here, we have characterized the single-cell phenotypes of 15 human pituitary tumors, including prolactinomas, nonfunctioning adenomas, and adenomas from multiple endocrine neoplasia type I (MEN-I) and pituitary Cushing's disease patients. Individual tumor cells were typed according to expression of AP hormones and hypothalamic-releasing hormone receptors by combination of calcium imaging and multiple sequential immunocytochemistry in the same cells. We found a large heterogeneity among the different tumors. In eight of the 15 tumors studied, more than 80% of the cells presented a multifunctional phenotype. This may explain the occurrence of paradoxical secretion. In addition, our results suggest that human pituitary adenomas might derive from multifunctional cells. This is consistent with the existence of a link between pituitary plasticity and tumorigenesis.
Assuntos
Adenoma/patologia , Hormônios Adeno-Hipofisários/metabolismo , Neoplasias Hipofisárias/patologia , Receptores de Hormônios Reguladores de Hormônio Hipofisário/análise , Adenoma/etiologia , Adenoma/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Síndrome de Cushing/metabolismo , Síndrome de Cushing/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/patologia , Fenótipo , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Prolactinoma/patologiaRESUMO
Two key players in adrenal steroid hormone biosynthesis are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2 that catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. Overproduction of both hormones contributes to a number of severe diseases, as illustrated by the association of elevated aldosterone levels with hypertension and higher mortality in congestive heart failure, and by Cushing's syndrome as the clinical correlate of chronic hypercortisolism. Thus, CYP11B1 and CYP11B2 comprise new targets for drug treatment and selective inhibitors of both enzymes are of high pharmacological interest. To facilitate the search for such compounds, we have established novel test procedures using recombinant fission yeast strains that stably express these enzymes. The aim of this study was to compare the inhibition profiles displayed by these enzymes in established mammalian cell culture test systems to those obtained with the new fission yeast assays, and to evaluate the usefulness of the Schizosaccharomyces pombe strains as screening systems for the identification of novel lead compounds. Using these test systems, we were able to identify a new and very selective CYP11B2 inhibitor (SIAS-1) that displayed no detectable interference with CYP11B1 activity.
Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Chumbo/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Fibrose Endomiocárdica/tratamento farmacológico , Fibrose Endomiocárdica/metabolismo , Inibidores Enzimáticos/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Chumbo/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Schizosaccharomyces , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Especificidade por Substrato/efeitos dos fármacosRESUMO
Proopiomelanocortin gene (POMC) is recognised as playing an important role in the regulation of the hypothalamo-pituitary-adrenal axis, adrenal development and obesity. POMC is activated in ACTH-dependent Cushing's syndrome. The syndrome may occur when the highly tIssue-specific 5' promoter of human POMC is activated in pituitary and non-pituitary sites. Whilst the factors involved in transcription in the corticotrophs of the anterior pituitary gland are becoming well delineated, the mechanism of activation in non-pituitary sites is not fully understood. This promoter is embedded within a defined CpG island, and, in contrast to somatically expressed CpG island promoters reported to date, is methylated in normal non-expressing tIssues, but is specifically unmethylated in expressing tIssues, tumours and the POMC-expressing DMS-79 small-cell lung cancer cell line. Methylation in vitro is sufficient for silencing of expression. In particular, methylation near the response element for the tIssue-specific POMC activator PTX1, diminishes POMC expression. Sites outside the PTX1 response element may be important for binding, and this may have implications for pituitary development. DMS-79 cells lack POMC-demethylating activity, implying that the methylation and expression patterns are likely to be set early or prior to neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy. It is conceivable that in POMC neurons of the hypothalamus the POMC promoter is subject to a variable density of methylation with clear implications for the signalling of satiety and obesity.
Assuntos
Síndrome de Cushing/metabolismo , Metilação de DNA , Regulação da Expressão Gênica/fisiologia , Hipófise/metabolismo , Pró-Opiomelanocortina/genética , Regiões Promotoras Genéticas , Síndrome de ACTH Ectópico/metabolismo , Animais , Ilhas de CpG , Humanos , Hipotálamo/metabolismo , Neoplasias/metabolismo , Obesidade/metabolismo , Elementos de RespostaRESUMO
OBJECTIVE: The aim of this study was to compare bone turnover and mass in women with either Cushing's syndrome (CS) or adrenal incidentaloma (AI), which is a possible model for minimal hypersecretion of cortisol. DESIGN AND PATIENTS: We studied 15 patients with CS (seven premenopausal and eight postmenopausal women); 23 patients with AI (five premenopausal and 18 postmenopausal women) and 20 matched controls (seven premenopausal and 13 postmenopausal women). Alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), osteocalcin (BGP), 24-h urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) and serum and 24-h urinary calcium and phosphorus were determined in all subjects. Bone mineral density (BMD) at lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry (DEXA). RESULTS: We found a significant reduction of BGP and serum phosphorus in CS and AI (P < 0.05) vs. controls and significantly lower levels of Pyr only in CS (P < 0.05) vs. AI and controls. Spinal and femoral BMD z-values were significantly lower (P < 0.05) in patients with CS (z-score: lumbar spine -1.44 +/- 1.5 and femoral neck -1.07 +/- 1; mean +/- SD) compared to AI and controls. CONCLUSIONS: Our data show that hypercortisolism reduces osteoblastic function and bone resorption and that osteocalcin can contribute to the precocious diagnosis of silent glucocorticoid excess. Patients with active CS were found to have lower BMD, particularly at vertebral level.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Osso e Ossos/metabolismo , Síndrome de Cushing/metabolismo , Achados Incidentais , Neoplasias do Córtex Suprarrenal/fisiopatologia , Idoso , Aminoácidos/urina , Densidade Óssea , Osso e Ossos/fisiopatologia , Cálcio/sangue , Cálcio/urina , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Síndrome de Cushing/fisiopatologia , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteocalcina/sangue , Fósforo/sangue , Fósforo/urinaRESUMO
The clinical features, pathogenesis and management of bone involvement in Cushing's syndrome are briefly reviewed. Personal data on bone mineral density and markers of bone turnover in Cushing's syndrome and adrenal incidentalomas are also reported. As long ago as 1932, Harvey Cushing recognized osteoporosis as a serious consequence of endogenous hypercortisolism. The introduction of cortisone in the therapy of autoimmune, rheumatic, allergic or dermatologic disorders was followed by several reports of detrimental effects on bone of patients who had undergone prolonged glucocorticoid treatment. Due to the rarity of Cushing's syndrome, most of the studies in the literature on glucocorticoid-induced osteoporosis refer to exogenous over-exposure to cortisone and its synthetic derivatives. Only a small number of works concern endogenous hypercortisolism, even if the characteristics of bone damage seem qualitatively the same. Finally, very few data are reported on the hypothetical detrimental effect on bone in the condition of the silent hypercortisolism of adrenal incidentalomas. Glucocorticoid-induced osteoporosis in Cushing's syndrome often results in vertebral fractures, and bone loss is more evident in trabecular than in cortical bone. Notwithstanding some distinctive features in osteoporosis induced by endogenous and exogenous glucocorticoid excess, the common eventual picture is notable bone damage that involves mainly the trabecular bone. Prompt and effective therapy is mandatory to reduce the risk of fractures. The present options include calcium and vitamin D supplementation, estrogen replacement therapy, bisphosphonates, either oral or parenteral. A novel approach to the clinical problem of glucocorticoid-induced osteoporosis might, in the future, be based on studies on selective glucocorticoid receptor modulators, a new class of synthetic glucocorticoids that exhibit significant anti-inflammatory and immunosuppressive activities, with reduced side effects on bone.
Assuntos
Glucocorticoides/efeitos adversos , Osteoporose/induzido quimicamente , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/metabolismo , Hiperfunção Adrenocortical/complicações , Hiperfunção Adrenocortical/metabolismo , Densidade Óssea/efeitos dos fármacos , Síndrome de Cushing/complicações , Síndrome de Cushing/metabolismo , Feminino , Humanos , Osteoporose/metabolismoRESUMO
In a previous study from our group [A. Khiat, C. Bard, A. Lacroix, J. Rousseau, Y. Boulanger, Brain metabolic alterations in Cushing's syndrome as monitored by proton magnetic resonance spectroscopy, NMR Biomed. 12 (1999) 357-363], proton magnetic resonance spectroscopy (1H MRS) was used to evaluate changes in cerebral metabolites in patients with Cushing's syndrome as compared to normal subjects. Data recorded in the frontal, thalamic and temporal areas demonstrated statistically significant decreases of the Cho/Cr ratios in the frontal and thalamic areas but not in the temporal area for Cushing's syndrome patients. No statistically significant changes in the NAA/Cr ratios were measured in any of the areas studied. In this follow-up study, MRS data are reported for ten patients after correction of hypercortisolism which demonstrate a statistically significant recovery of the choline levels in the frontal and thalamic areas. No variation in the NAA, Cr and mI metabolite ratios relative to H(2)O could be measured. Results are interpreted as an inhibition of the phosphatidylcholine degrading phospholipases by glucocorticoids which disappears after correction of hypercortisolism.
Assuntos
Colina/metabolismo , Síndrome de Cushing/metabolismo , Lobo Frontal/metabolismo , Glucocorticoides/metabolismo , Tálamo/metabolismo , Adulto , Síndrome de Cushing/diagnóstico , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prótons , Lobo Temporal/metabolismoRESUMO
Dopamine negatively regulates POMC gene expression in melanotrophs of the intermediate lobe of the pituitary gland. The dopaminergic receptor involved in this control is the dopamine D2 receptor (D2R). The principal products of the POMC gene in melanotrophs are beta-endorphin and alpha-MSH. POMC is differently processed in the corticotrophs, where it is not regulated by dopamine and it is principally processed into ACTH. Here we show that D2R-deficient mice have increased POMC expression and intermediate lobe hypertrophy. Strikingly, D2R-deficient mice have unexpected elevated ACTH levels with a corresponding increase of corticosteroids and consequent hypertrophy of the adrenal gland. This phenotype is reminiscent of Cushing's syndrome in humans. Interestingly, we show that the elevation in ACTH levels is due to an aberrant processing of POMC in melanotrophs. Indeed, we demonstrate that in addition to controlling POMC gene expression in these cells, dopamine, by modulating the expression of the convertases involved in the cleavage of the POMC prohormone, strictly regulates its processing. These results reveal a key role for dopamine in the control of POMC-derived peptides and furthermore indicate an implication of the dopaminergic system in the genesis of Cushing's syndrome.
Assuntos
Síndrome de Cushing/metabolismo , Hipófise/citologia , Pró-Opiomelanocortina/genética , Receptores de Dopamina D2/genética , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/sangue , Animais , Ácido Aspártico Endopeptidases/metabolismo , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Cushing/genética , Hiperplasia , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Mutantes , Hipófise/patologia , Pró-Opiomelanocortina/metabolismo , Pró-Proteína Convertase 2 , Pró-Proteína Convertases , Receptores de Dopamina D2/deficiência , Subtilisinas/metabolismoRESUMO
Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Neoplasias das Glândulas Suprarrenais/fisiopatologia , Glândulas Suprarrenais/fisiopatologia , 17-alfa-Hidroxiprogesterona , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Adrenalectomia , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Androstenodiona/sangue , Osso e Ossos/metabolismo , Colágeno/metabolismo , Hormônio Liberador da Corticotropina , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/metabolismo , Síndrome de Cushing/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Hidroxiprogesteronas/sangue , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/sangue , Pró-Colágeno/metabolismo , Radioimunoensaio , Tomografia Computadorizada por Raios XRESUMO
We experienced 41 cases of Cushing's syndrome (12 males and 29 females, 15 years old - 65 years old) during the last 20 years. These included 20 patients with unilateral adrenal adenoma (Cushing's syndrome), 19 patients with bilateral adrenal hyperplasia (Cushing's disease), one patient with adrenal carcinoma and one patient with primary adrenocortical nodular dysplasia (PAND). Moreover, these cases included some special ones, i.e. 5 cases with destructive thyroiditis after treatment, 2 cases with aggravation of arthritis after treatment, a case of Carney's complex with PAND, one case with paradoxical response to dexamethasone, and one case combined with empty sella syndrome. The most specific clinical signs were moon face (95% occurrence), hypertension (95%) and subcutaneous bruising (80%). Other significant signs were eye edema (66%), buffalo hump (68%), subcutaneous purpura (63%) and osteoporosis (49%). Skin striae was not a common sign in our cases (41%). Renal stone was observed in only 20% of our patients but was a significant sign in this syndrome. There was no difference in the occurrence of each clinical sign between Cushing's syndrome and Cushing's disease. The elevation of white blood cell count (WBC) and serum sodium, a decrease of serum potassium, and a decrease of reabsorption of phosphate (%TRP) were observed. Thyroid-stimulating hormone (TSH) and human growth hormone (HGH) were suppressed in patients with Cushing's syndrome and patients with Cushing's disease. These results were consistent with those of previous reports. However, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were high in those patients with Cushing's syndrome and those with Cushing's disease. Oral glucose tolerance test was carried out in 34 patients before and after treatment. Thirty-one percent of those had diabetes mellitus and 26% had impaired glucose tolerance (IGT). The response of IRI in this test was high in patients with Cushing's syndrome and patients with Cushing's disease, and decreased 4 weeks after treatment in those with Cushing's syndrome but remained high in those with Cushing's disease. Plasma ACTH level and urinary 17-OHCS excretion were significantly higher in Cushing's disease than in Cushing's syndrome. During an 8mg-high-dose dexamethasone suppression test, urinary 17-OHCS excretion in 13 of 14 patients with Cushing's disease (93%) was suppressed by more than 50% of baseline on the second day of testing. However, all of 18 patients with Cushing's syndrome, who had an 8mg-dexamethasone suppression test, failed to suppress urinary 17-OHCS by 50% of baseline.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Adenoma/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Síndrome de Cushing/metabolismo , Adenoma/diagnóstico , Adolescente , Corticosteroides/metabolismo , Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Adulto , Idoso , Síndrome de Cushing/diagnóstico , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperplasia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hormônios Adeno-Hipofisários/metabolismo , Tomografia Computadorizada por Raios XRESUMO
The potential role of paraneoplastic Cushing's syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complications and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features of CS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognostic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eighty-two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initiation of chemotherapy was 12 days for the 11 patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11), death was attributed to opportunistic fungal or protozoal infection compared with 8% of control patients (six of 77). Paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemotherapy, leading to clinical deterioration and death before antineoplastic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis.
Assuntos
Carcinoma de Células Pequenas/mortalidade , Síndrome de Cushing/mortalidade , Neoplasias Pulmonares/mortalidade , Síndromes Endócrinas Paraneoplásicas/mortalidade , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/tratamento farmacológico , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Metirapona/uso terapêutico , Pessoa de Meia-Idade , Síndromes Endócrinas Paraneoplásicas/tratamento farmacológico , Síndromes Endócrinas Paraneoplásicas/metabolismo , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Nontumorous primary adrenal causes of Cushing's syndrome are exceedingly rare. Herein we review our results with seven patients in whom there is biochemical evidence of a primary (adrenocorticotropin independent) bilateral adrenal cause of endogenous hypercortisolism. Each patient had low plasma adrenocorticotropin levels. All patients had elevated 24-hour urinary free cortisol levels and 17-hydroxycorticosteroids that were not suppressed by high-dose dexamethasone. Plasma levels of adrenocorticotropin and cortisol were not elevated by ovine corticotropin-releasing factor. No patient had a gradient between petrosal and peripheral adrenocorticotropin levels. No pituitary tumors were detected by magnetic resonance imaging or computed tomography. Five of six patients who underwent iodocholesterol scanning showed bilateral adrenal activity. Computed tomographic and magnetic resonance imaging of the abdomen demonstrated bilateral small adrenal glands in three patients, an adrenal mass in one patient with Carney's complex, and massively enlarged glands in three patients. Each patient underwent bilateral adrenalectomy and was given glucocorticoid and mineralocorticoid replacement. Pathologic examination of four of these bilateral adrenal specimens revealed primary pigmented micronodular adrenocortical disease, with adrenal gland weights between 2.5 and 13.4 gm (mean 5.2 gm). However, the remaining three patients had primary adrenocorticotropin-independent bilateral macronodular adrenocortical disease with adrenal gland weights between 32 and 81 gm (mean 52 gm). Although each of the patients with primary pigmented micronodular adrenocortical disease was cured by bilateral adrenalectomy through a posterior approach, two of the three patients required an anterior approach. We conclude that Cushing's syndrome can arise through two distinct forms of primary bilateral adrenal cortical disease. Computed tomography is important in evaluation of these patients because the size of the adrenal glands influences the surgical approach.