Evaluation and treatment of Cushing's syndrome
ABSTRACT Cushing's syndrome results from sustained pathologic hypercortisolism caused by excessive corticotropin (ACTH) secretion by tumors in the pituitary gland (Cushing's disease, 70%) or elsewhere (15%), or by ACTH-independent cortisol secretion from adrenal tumors (15%). The clinical features are variable, and no single pattern is seen in all patients. Those features most specific for Cushing's syndrome include abnormal fat distribution, particularly in the supraclavicular and temporal fossae, proximal muscle weakness, wide purple striae, and decreased linear growth with continued weight gain in a child. Patients with characteristics of glucocorticoid excess should be screened with measurements of saliva or urine cortisol or dexamethasone suppression testing. The diagnosis of Cushing's syndrome should be followed by the measurement of plasma ACTH concentration to determine whether the hypercortisolism is ACTH-independent. In ACTH-dependent patients, bilateral inferior petrosal sinus sampling with measurement of ACTH before and after administration of ACTH-releasing hormone most accurately distinguishes pituitary from ectopic ACTH secretion. Surgical resection of tumor is the optimal treatment for all forms of Cushing's syndrome; bilateral adrenalectomy, medical treatment, or radiotherapy are sought in inoperable or recurrent cases. The medical treatment of choice is ketoconazole. The prognosis is better for Cushing's disease and benign adrenal causes of Cushing's syndrome than adrenocortical cancer and malignant ACTH-producing tumors.
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ABSTRACT: OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27(Kip1), CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.Neurosurgical FOCUS 02/2015; 38(2):E17. DOI:10.3171/2014.10.FOCUS14683 · 2.14 Impact Factor
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ABSTRACT: Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone-secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.Neurosurgical FOCUS 02/2015; 38(2):E4. DOI:10.3171/2014.11.FOCUS14704 · 2.14 Impact Factor
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ABSTRACT: Cushing's syndrome (CS) results from sustained exposure to excessive levels of free glucocorticoids. One of the main causes of CS is excessive adrenocorticotropic hormone (ACTH) secretion by tumors in the pituitary gland (Cushing's disease [CD]). Cushing's disease and its associated hypercortisolism have a breadth of debilitating symptoms associated with an increased mortality rate, warranting urgent treatment. Currently, the first line of treatment for CD is transsphenoidal surgery (TSS), with excellent long-term results. Transsphenoidal resections performed by experienced surgeons have shown remission rates ranging from 70% to 90%. However, some patients do not achieve normalization of their hypercortisolemic state after TSS and continue to have persistent or recurrent CD. For these patients, various therapeutic options after failed TSS include repeat TSS, radiotherapy, medical therapy, and bilateral adrenalectomy (BLA). Bilateral adrenalectomy has been shown to be a safe and effective treatment modality for persistent or recurrent CD with an immediate and definitive cure of the hypercortisolemic state. BLA was traditionally performed through an open approach, but since the advent of laparoscopic adrenalectomy, the laparoscopic approach has become the surgical method of choice. Advances in technology, refinement in surgical skills, competency in adrenopathology, and emphasis on multidisciplinary collaborations have greatly reduced morbidity and mortality associated with adrenalectomy surgery in a high-risk patient population. In this article, the authors review the role of BLA in the treatment of refractory CD. The clinical indications, current surgical and endocrinological results reported in the literature, surgical technique (open vs laparoscopic), drawbacks, and complications of BLA are discussed.Neurosurgical FOCUS 02/2015; 38(2):E9. DOI:10.3171/2014.10.FOCUS14684 · 2.14 Impact Factor