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Background: Cushing's syndrome (CS) poses diagnostic challenges, particularly in distinguishing pituitary-dependent Cushing's syndrome, Cushing's disease (CD), from the ectopic ACTH syndrome (EAS). This study evaluated the diagnostic value of the desmopressin stimulation test (DST) in patients with ACTH-dependent CS in helping this discrimination., Methods: Twenty-three ACTH-dependent CS patients underwent sequential DST, bilateral inferior petrosal sinus sampling (BIPSS), and transsphenoidal surgery (TSS). Two definitions of a positive DST results were applied. Diagnostic performance was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios. To avoid bias from predetermined criteria, we generated univariate receiver-operating characteristic (ROC) curves, plotting sensitivity against 1-specificity at various percentage cortisol and ACTH response levels., Results: Against BIPSS, DST demonstrated robust sensitivity (Definition 1: 90.0%, Definition 2: 76.2%) and overall accuracy (Definition 1: 87.0%, Definition 2: 73.9%). PPV was high (Definition 1: 95.0%, Definition 2: 94.1%), but NPV indicated potential false negatives. Compared to TSS, DST showed good sensitivity (Definition 1: 90.9-77.3%) and PPV (100.0%) but limited NPV (16.7%). The likelihood ratios emphasized the diagnostic value of the test. Notably, against TSS, DST showed perfect discriminatory power (AUC 1.000 for percent ACTH, 0.983 for percent cortisol)., Conclusion: The desmopressin test shows promise in accurately identifying the underlying cause of ACTH-dependent CS, potentially reducing the reliance on invasive procedures and providing a practical solution for managing complex cases. Further research with larger cohorts is required to validate the utility of the DST in routine clinical practice.

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)-dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary-dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non-invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH-dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin-releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

In the context of ACTH-dependent Cushing's syndrome, ectopic ACTH secretion from a neuroendocrine tumour is not uncommon, and needs to be carefully differentiated from pituitary-dependent Cushing's syndrome, Cushing's disease, in order to optimise therapy. Some cases may be quite obvious, while in others the diagnosis may be difficult to confirm and the source of ACTH problematic, as many clinical and biochemical tests may overlap with Cushing's disease. Imaging is essential, but needs to be interpreted in the light of both anatomical as well as functional imaging modalities. In this review we summarise some of the main diagnostic problems, and emphasise the multimodal and interdisciplinary nature of the diagnostic pathways., (© 2022 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised., (© 2021. The Author(s).)

Competing Interests: I declare no competing interests.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified., Competing Interests: Declaration of interests MF has received grants to her institution from Novartis, Strongbridge, Novo Nordisk, Crinetics, Millendo, Ascendis, and Pfizer; personal honoraria for consulting and advisory boards from Crinetics, HRA Pharma, Novartis, Recordati, Strongbridge, Sparrow, Ascendis, Novo Nordisk, and Pfizer; and has served on the Board of the Pituitary Society. RA has received grants to his institution from Strongbridge Biopharma, Novartis Pharmaceuticals, and Corcept Therapeutics, and personal honoraria for consulting and advisory boards from Strongbridge Biopharma, Recordati Rare Diseases, Corcept Therapeutics, and Novartis Pharmaceuticals. IB has received grants and fees for consulting, advisory boards, and authorship to her institution from the National Institutes of Health (NIH), Strongbridge, Corcept, HRA Pharma, Sparrow Pharmaceutics, Adrenas Pharmaceutics, and Elsevier, and non-financial support to her institution from HRA Pharma. AB-S has received personal honoraria for advisory boards from Recordati. JB has received grants to his institution from Novartis, HRA Pharma, and Recordati, and personal honoraria for consulting, lectures, and meeting attendance from Novartis, HRA Pharma, Ipsen, and Recordati. NRB has served on the Board or as an advisor for European Neuroendocrine Association and the European Reference Network on Rare Endocrine Conditions. CLB has received grants and personal honoraria for lectures from Novartis and served on the Board or as an advisor for Sociedade Brasileira de Endocrinologia e Metabologia, Endocrine Society, and European Society of Endocrinology. MDB has received grants as principal investigator from Novartis. JDC has received grants to his institution from Novartis, Strongbridge, and Crinetics; personal honoraria for consulting and authorship from Recordati, Novo Nordisk, Corcept, and Merck Manual; and served on the Board or as an advisor for Pituitary Society, Endocrine Society, and American Association of Clinical Endocrinologists. FFC has served on the Board of the Pituitary Society. FC has received personal honoraria for consulting, lectures, and support for meeting attendance from Recordati Rare Diseases, Ipsen, and HRA Pharma. PC has received grants and honoraria to his institution for consulting and lectures from Novartis and Recordati. JF has received grants to his institution from Novartis and personal honoraria for consulting and advisory boards from Corcept, Recordati, and Novartis. MGa has received non-financial support from Novartis and Recordati and served on the Board or as an advisor for Pituitary Society and Brazilian Society of Endocrinology and Metabolism. EBG has received grants and personal honoraria for consulting, lectures, and advisory boards from Novartis, Corcept, Strongbridge, Bristol-Myers Squibb, Recordati, and HRA Pharma; and has served as an advisor for Cushing's Support & Research Foundation. AGi has received grants to his institution from Pfizer and personal honoraria for consulting and advisory boards from Abiogen, Novo Nordisk, and Recordati; and has served on the Board or as an advisor to European Society of Endocrinology and Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group. AGr has served as an advisor to Novartis and as an editor for Neuroendocrinology and Journal of Neuroendocrinology. MGu has received personal honoraria for consulting and lectures from Recordati Rare Diseases UK, HRA Pharma, and Ipsen; and is a Board member or advisor for UK Society for Endocrinology and European Society of Endocrinology. AGI has received grants to her institution from Recordati, Novartis, and Strongbridge; and personal honoraria for consulting from Recordati, HRA Pharma, and Strongbridge. UBK has received grants as co-investigator from Corcept; personal honoraria for consulting, advisory board, and lectures from Acerus Pharmaceuticals and Novo Nordisk; and serves as editor for Journal of Clinical Endocrinology and Metabolism and as Board member for Endocrine Society. NK has received personal honoraria for consulting from Recordati Rare Diseases and HRA Pharma, and has served as Board member or advisor for Pituitary Society, European Neuroendocrine Association, Endocrine Society, and European Society of Endocrinology. LK has received personal honoraria for consulting from Strongbridge and Recordati. DFK has received royalties from Mizuho. AL has received grants from Recordati and Corcept; personal honoraria for lectures, support for meeting attendance, and advisory boards from Pfizer, Ipsen, Corcept, and the European Journal of Endocrinology; royalties from UpToDate Endocrinology; and served as a Board member for International Society of Endocrinology. AM has received grants and personal honoraria for lectures or presentations and support for meeting attendance from Pfizer, Ipsen, Novartis, and Novo Nordisk, and served as a Council member for Endocrine Society of Australia. SM has received grants to his institution from US Food and Drug Administration and non-financial support from Cyclacel. MM has received grants to his institution from Corcept, Novartis, and Strongbridge; fees for expert testimony from Janssen and Corcept; and personal honoraria for advisory boards for Merck, Pfizer, Recordati, and Strongbridge. JN-P has received grants and honoraria to the institution for consulting and advisory boards from Diurnal Ltd and HRA Pharma, Recordati, and Novartis; and served as a Board member or advisor for Pituitary Foundation and Endocrine Society. LN has received royalties from UpToDate and support for meeting attendance from the NIH, and has served as a Board member for Endocrine Society. AMP has received grants to his institution from HRA Pharma and served as advisor for European Reference Network on Rare Endocrine Conditions and European Endocrine Society. SP has received personal honoraria for lectures and advisory boards from HRA Pharma, Recordati Pharma, Novartis Pharma, and Crinetics Pharmaceuticals. RP has received grants to his institution from Novartis, Pfizer, Ipsen, Shire, IBSA Farmaceutici, HRA Pharma, Cortendo AB, Corcept Therapeutics, and Merck Serono, and personal honoraria for consulting, lectures, support for meeting attendance, and advisory boards from Novartis, Shire, HRA Pharma, Cortendo AB, Pfizer, Recordati, IBSA Farmaceutici, and Crinetics Pharmaceuticals. HR has received personal honoraria for consulting from Cerium and non-financial support from Corcept. MR has received personal honoraria for consulting, lectures, and advisory boards from Novartis, Recordati, HRA Pharma, and Ipsen. RS has received grants to his institution from Corcept and Crinetics, and personal honoraria for consulting from Strongbridge, Corcept, HRA Pharma, and Sterotherapeutics. CS has received grants and personal honoraria for lectures from Pfizer, Novartis, Recordati Rare Diseases, and HRA Pharma. IS has received personal honoraria for consulting from Medison Pharma. CAS has received grants from Pfizer; personal honoraria for consulting and support for meeting attendance from Lundbeck Pharma and the NIH; holds patents on the genetics of PRKAR1A, PDE11A, and GPR101; and has served as a Board member or advisor for Society for Pediatric Research, Children's Inn at NIH, and Cushing's Foundation. AT has received grants to his institution from HRA Pharma, and personal honoraria for consulting, lectures, and support for meeting attendance from HRA Pharma, Recordati Rare Diseases, and Ipsen. YT has received personal honoraria for consulting and lectures from Novo Nordisk, Recordati Rare Diseases, Bohringer Ingelheim, and Sumitomo Dainippon Pharma. MT has served as an advisor to European Society of Endocrinology. ST has received grants to his institution from Strongbridge, Crinetics, and Novartis, and personal honoraria for lectures, advisory boards, and support for meeting attendance from Recordati, Pfizer, and Ipsen. EV has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting, lectures, and advisory boards from HRA Pharma, HRA Pharma Spain, and Recordati Rare Diseases. GV has received grants to her institution from Novartis, Recordati, and Corcept; personal honoraria and honoraria to the institution for consulting and lectures from HRA Pharma and Recordati; and served as an advisor for Cushing's Hub. SMW has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting and lectures from HRA Pharma and Recordati Rare Diseases. MCZ has served as a Board member for European Neuroendocrine Association. BMKB has received grants to her institution from Novartis, Opko, Strongbridge, and Millendo; personal honoraria for consulting from Aeterna Zentaris, Ascendis, Crinetics, Merck Serono, Novartis, Novo Nordisk, Recordati, Strongbridge, and Sparrow; and served as an advisor for Endocrine Society. MB, KH, PM, BS, EVV, and JW have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bilateral adrenal macronodular hyperplasia (BMAH) is a rare form of Cushing's syndrome characterised by the presence of bilateral secretory adrenal nodules and hypercortisolism. Familial studies support a genetic basis for BMAH, and the disease has been linked to mutations in ARMC5, a gene shown to have a tumour suppressor-like action in the development of adrenal nodules. This study aimed to investigate whether ARMC5 mutations play a role in the development of incidentally discovered bilateral adrenal nodules. We investigated 39 patients with incidentally discovered bilateral adrenal nodules >0.8 cm in diameter who underwent extensive biochemical testing to look for signs of subclinical hypercortisolism. Genomic DNA was analysed by Sanger sequencing, using primers targeted to ARMC5 transcripts. Of the 39 patients included in our study, three were identified as having variants in ARMC5. Two of these are unlikely to be clinically significant, but there is evidence that the third mutation, Chr16:g.31476122;c.1778G>C (p.Arg593Pro), may be pathogenic. Another variant, affecting the same amino-acid residue c.1777C>T (p.Arg593Trp), has been identified previously in two studies of BMAH patients, where it has been shown to segregate with disease in one BMAH family. This patient had biochemical evidence of hypercortisolism in the absence of overt Cushing's syndrome, and underwent bilateral adrenalectomy separated in time. The presence of a probably clinically significant mutation in ARMC5 in one patient with bilateral adrenal incidentalomas adds to the growing body of evidence in support of ARMC5 as a critical mediator of adrenal nodule development. In addition, the absence of significant ARMC5 mutations in 38 of our patients represents an important negative finding, demonstrating the degree of variability within the pathogenesis of adrenal nodule development.

Severe Cushing's syndrome presents an acute emergency and is defined by massively elevated random serum cortisol [more than 36 μg/dL (1000 nmol/L)] at any time or a 24-h urinary free cortisol more than fourfold the upper limit of normal and/or severe hypokalaemia (<3.0 mmol/L), along with the recent onset of one or more of the following: sepsis, opportunistic infection, intractable hypokalaemia, uncontrolled hypertension, heart failure, gastrointestinal haemorrhage, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism or uncontrolled hyperglycaemia and ketocacidosis. Treatment focuses on the management of the severe metabolic disturbances followed by rapid resolution of the hypercortisolaemia, and subsequent confirmation of the cause. Emergency lowering of the elevated serum cortisol is most rapidly achieved with oral metyrapone and/or ketoconazole; if parenteral therapy is required then intravenous etomidate is rapidly effective in almost all cases, but all measures require careful supervision. The optimal order and combination of drugs to treat severe hypercortisolaemia-mostly in the context of ectopic ACTH-secreting syndrome, adrenocortical carcinoma or an ACTH-secreting pituitary adenoma (mainly macroadenomas)-is not yet established. Combination therapy may be useful not only to rapidly control cortisol excess but also to lower individual drug dosages and consequently the possibility of adverse effects. If medical treatments fail, bilateral adrenalectomy should be performed in the shortest possible time span to prevent the debilitating complications of uncontrolled hypercortisolaemia.

Objective: Paediatric Cushing's syndrome (CS) remains a challenge to diagnose and exclude. We assessed the accuracy of 24-hour urinary free cortisol (UFC) determination in children referred for suspected CS., Design: We conducted a retrospective study of paediatric patients referred to our centre with suspected CS between 1982 and 2014., Patients: Of 66 subjects (mean age 12.9 years; range 4.4-16.9), there were 47 cases of CS (29 males), which included Cushing's disease (CD; 39 patients, 25 males), primary pigmented nodular adrenocortical disease (8 patients, 4 males) and 19 'controls' (6 males) in whom the diagnosis of CS was excluded., Measurements: The subjects had between one and five 24-hour UFC collections analysed by radioimmunoassay, chemiluminescent immunoassay or liquid chromatography-mass spectrometry. The data were normalised, corrected for body surface area (m2) and assessed using receiver operating characteristic analysis and an independent two-tailed t test., Results: The diagnostic accuracy of 24-hour UFC for CS was excellent (area under the curve 0.98, 95% CI 0.946-1.00, sensitivity 89%, specificity 100%)., Conclusions: Twenty-four-hour UFC is a reliable and practical investigation with high diagnostic accuracy for paediatric CS. However, further investigations may be required if the UFC is normal but there is a high diagnostic suspicion of CS., (© 2016 S. Karger AG, Basel.)

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose., Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS., Design: This was designed as a retrospective, multicenter study., Setting: Thirteen University hospitals were studied., Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3)., Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC)., Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible., Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin-antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis., (© 2015 European Society of Endocrinology.)

Context: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing's syndrome. Familial cases have been reported, but at the time we conducted this study, the genetic basis of BMAH was unknown. Recently, germline variants of armadillo repeat containing 5 (ARMC5) in patients with isolated BMAH and somatic, second-hit mutations in tumor nodules, were identified., Objective: Our objective was to identify the genetic basis of familial BMAH., Design: We performed whole exome capture and sequencing of 2 affected individuals from each of 4 BMAH families (BMAH-01, BMAH-02, BMAH-03, and BMAH-05). Based on clinical evaluation, there were 7, 3, 3, and 4 affected individuals in these families, respectively. Sanger sequencing of ARMC5 was performed in 1 other BMAH kindred, BMAH-06., Results: Exome sequencing identified novel variants Chr16:g.31477540, c.2139delT, p.(Thr715Leufs*1) (BMAH-02) and Chr16:g.31473811, c.943C→T, p.(Arg315Trp) (BMAH-03) in ARMC5 (GRch37/hg19), validated by Sanger sequencing. BMAH-01 had a recently reported mutation Chr16:g.31476121, c.1777C→T, p.(Arg593Trp). Sanger sequencing of ARMC5 in BMAH-06 identified a previously reported mutation, Chr16:g. 31473688; c.799C→T, p.(Arg267*). The genetic basis of BMAH in BMAH-05 was not identified., Conclusions: Our studies have detected ARMC5 mutations in 4 of 5 BMAH families tested, confirming that these mutations are a frequent cause of BMAH. Two of the 4 families had novel mutations, indicating allelic heterogeneity. Preclinical evaluation did not predict mutation status. The ARMC5-negative family had unusual prominent hyperaldosteronism. Further studies are needed to determine the penetrance of BMAH in ARMC5 mutation-positive relatives of affected patients, the practical utility of genetic screening and genotype-phenotype correlations.

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.

Glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary bone disorders. Most of our knowledge on its pathogenesis and treatment has been obtained by investigating patients treated with exogenous glucocorticoids. This review will focus on the bone disorder in endogenous Cushing's syndrome, updating recent advances in its pathophysiology, diagnostic aspects and the various predictors which are important in determining bone mineral density (BMD) and fracture risk. We now know strong evidence that beside BMD, bone microarchitecture, one of the most important elements of bone quality, is a key factor in determining fracture risk. Recently, two new methods (spinal deformity index and trabecular bone score) have been shown to be useful markers of bone microarchitecture in GIO. Investigations of GIO in endogenous Cushing's syndrome have also contributed to our understanding on its natural history and reversibility. Relying on recently published guidelines for management of exogenous GIO, a short list of suggestions is provided regarding the optimal diagnostic and therapeutic approach to patients with endogenous GIO., (© 2013 John Wiley & Sons Ltd.)

Objective: To outline the potential role for adrenal venous sampling in the diagnosis and management of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS)., Methods: We present a case description and discuss the management of a 59-year-old woman with an 8-year history of weight gain, centripetal obesity, a round plethoric face, skin thinning, easy bruising, hirsutism, and progressive muscle weakness., Results: The patient reported a prior personal history of asthma, type 2 diabetes mellitus, hypertension, dyslipidemia, and bilateral leg ulcers, but she denied having any personal or family history of endocrinopathy and was not taking any corticosteroid medication. Elevated midnight serum cortisol, failure to suppress cortisol levels with a low-dose dexamethasone suppression test, and undetectable plasma ACTH all indicated ACTH-independent CS. Additional investigations including dynamic tests and adrenal imaging were supported by adrenal venous sampling in order to make a diagnosis and formulate a management plan. She was ultimately noted to have bilateral functioning adrenal nodules (adenoma and adenolipoma) and underwent successful bilateral laparoscopic adrenalectomy, with postoperative glucocorticoid and mineralocorticoid replacement., Conclusion: Adrenal venous sampling may be an important step in the differential diagnosis of CS and localization of the source of cortisol excess. It may distinguish pheochromocytoma or benign nonfunctioning adrenal nodules from cortisol-secreting adenomas and may avoid unnecessary bilateral adrenalectomy. It can also ensure that the correct operation is completed, if required, and thus avoid the increased morbidity and mortality associated with repeated surgical interventions.

The investigation of Cushing syndrome (CS) should start with careful history taking and clinical examination, and exogenous steroid usage must be excluded. It is essential to confirm hypercortisolism before further investigations are undertaken. The recommended first-line tests include midnight salivary cortisol and/or the 1 mg overnight or low-dose dexamethasone suppression tests. The next step is to differentiate adrenocorticotrophin (ACTH)-dependent from ACTH-independent CS by measuring ACTH. With ACTH-dependence, further investigations should differentiate pituitary-dependent from ectopic ACTH-dependent CS. Many dynamic tests may be considered, but we suggest that bilateral inferior petrosal sinus sampling should be performed in almost all patients with ACTH-dependent CS, except for patients with a pituitary macroadenoma. Imaging should include MR scanning of the pituitary, and CT scanning of the chest and abdomen to look for an ectopic source. Confirmation of the diagnosis of CS and accurate localization of its source are vital to optimize therapy for this complex disorder.

This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms 'etomidate', 'Cushing's syndrome', 'adrenocortical hyperfunction', 'drug therapy' and 'hypercortisolaemia' in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.

Purpose of Review: Cushing's syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids. Biochemical tests are always needed to confirm the clinical suspicion: these include measurement of excess total endogenous cortisol secretion assessed by 24-h urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. This review focuses on recent data emerging on the value of UFC as a screening test for Cushing's syndrome., Recent Findings: Considerable evidence has emerged regarding the utility of UFC in the diagnosis of Cushing's syndrome because of its long-term use in clinical practice. Despite the fact that UFC assesses the active (free) component of cortisol, the methodological difficulties in 24-h urine collection and in assay precision have rendered this screening technique increasingly unpopular. Furthermore, the increased prevalence of mild, preclinical or cyclic Cushing's syndrome along with the fact that cortisol is not uniformly secreted during the day do not support its use as a screening test, although strikingly high levels can be useful., Summary: Since the sensitivity and specificity of UFC are less than ideal when compared with other diagnostic modalities, we suggest the use of other more novel tests as first-step diagnostic tests to screen for hypercortisolaemia.

Objective: To present an Iranian patient with a nonclassic form of multiple endocrine neoplasia type 1 (MEN 1) who presented with ectopic Cushing syndrome (CS) secondary to a corticotropin (ACTH)-producing thymic neuroendocrine tumor (NET), recurrent renal stones, and a giant cell granuloma of the jaw due to primary hyperparathyroidism (PHPT) without involvement of the pituitary or pancreas., Methods: Relevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene., Result: Histopathologic evaluation of the thymic tumor removed during the first surgery showed an atypical carcinoid tumor with a Ki-67 labeling index of 5%. Evaluation after the second surgery revealed an invasive carcinoid tumor with a Ki-67 labeling index of 30%. Parathyroid pathology was suggestive of glandular hyperplasia. Menin gene sequencing revealed a novel frameshift mutation c.1642&#95;1648dup in exon 10., Conclusion: This case of MEN 1 is unusual because most thymic NETs in MEN 1 are nonfunctional, and secretion of ACTH or other ectopic hormones rarely occurs. In patients presenting with thymic NETs, the possibility of MEN 1 should be considered, especially in the presence of hyperparathyroidism. This case also demonstrates that the behavior of thymic NETs can change over time from slow-growing tumors to highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN 1.

Background: The term adrenal incidentaloma (AI) indicates an adrenal mass lesion > 1 cm in diameter discovered during testing for conditions unrelated to adrenal disease. The overall prevalence of these lesions ranges between 3% and 10%. Their incidence increases with age, and it is clinically important to identify AI associated with hormonal activity and/or malignant potential., Design: A detailed Medline search of all English language articles related to AI was carried out, and the clinical implications related to their hormonal activity and malignant potential are discussed., Results: The subclinical hypercortisolism observed in a significant percentage of patients with AI is associated with some of the detrimental effects of continuous autonomous cortisol secretion, including a higher prevalence of hypertension, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus and an increased risk for osteoporotic fractures. However, it remains to be proven whether treatment to reverse subtle glucocorticoid excess is beneficial. Clinically silent phaeochromocytomas and primary adrenal cancer are conditions associated with significantly high morbidity and mortality and require urgent treatment, while the prevalence and clinical significance of autonomous mineralocorticoid secretion are less clearly defined. Size and radiological features are the main predictors of malignant potential., Conclusions: Patients harbouring AI should be evaluated for the possibility of malignancy and/or subclinical hypercortisolism which is associated with cardiovascular risk and bone loss. However, in the absence of prospective controlled studies correlating biochemical activity with end-organ complications, the long-term consequences of AI remain uncertain and their management remains largely pragmatic., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Cushing's syndrome (CS) results from sustained pathologic hypercortisolism. Increased identification of cyclical CS and the similarities between the metabolic syndrome and mild CS has resulted in an increased prevalence of CS, necessitating more accurate diagnostic tests to screen and diagnose CS in its earliest stages. Many studies have examined the utility of resistance to steroid feedback by the dexamethasone suppression tests and increases in secretion assessing 24-hour urinary free cortisol; however, the most sensitive indicator is the loss of circadian rhythmicity. Therefore, midnight sleeping cortisol is undoubtedly an extremely sensitive indicator of CS but impractical for screening purposes. In this situation assessment late-night salivary cortisol (NSC) is being increasingly investigated as a simple and convenient outpatient procedure. Salivary cortisol has also been used in stimulation or suppression tests because of the detection of rapid changes in cortisol concentration. This paper discusses the effectiveness of SC as a putative accurate, stress-free, and non-invasive sampling procedure. Some studies have shown no difference between tests while others demonstrated a higher sensitivity of SC, while the combination of tests seems to increase their diagnostic value. However, the different assays used for SC estimation and the variable types of control groups in the published studies render a comparison of studies difficult. In conclusion, NSC measurement is increasingly being used as a first-line test for CS, but we recommend that local centres establish their own normative ranges, and there is still a place for the more traditional tests to confirm the diagnosis., (Copyright © 2010 S. Karger AG, Basel.)

Objective: Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing's syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing's syndrome., Methods: AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing's syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery., Results: The patients with Cushing's syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing's syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol., Conclusions: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing's syndrome.

Purpose of Review: Paediatric Cushing's syndrome presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience in managing children or adolescents with Cushing's syndrome and thus benefit from close consultation with adult colleagues. A protocol for investigation of the child with suspected Cushing's syndrome is presented followed by principles of management., Recent Findings: Cushing's syndrome is rare in childhood, but causes serious morbidity. Investigations have evolved and now include new genetic and imaging techniques as well as classical endocrine studies. In Cushing's disease trans-sphenoidal surgery has transformed management, although only a few surgeons have experience in children. Pituitary radiotherapy is effective second-line therapy., Summary: Early diagnosis and treatment of Cushing's syndrome is vital for long-term outcome. The overall prognosis for Cushing's syndrome is good but challenges remain to ensure normal postcure growth and body composition.

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.

Endogenous Cushing's syndrome (CS) results from chronic exposure to excess glucocorticoids. CS can be ACTH-dependent, caused by ACTH-secreting pituitary or ectopic tumours, or ACTH-independent, caused by cortisol-secreting adrenal tumours. CS can be an extremely difficult diagnosis to make, and assessment will include clinical, biochemical and radiological evaluation. Several screening tests are used for the confirmation of hyper-cortisolaemia and its differentiation from other, more frequent, clinical abnormalities, such as simple obesity, hypertension, depression etc. Other dynamic tests are useful for establishing the aetiology. We have reviewed the current literature on the diagnosis of CS, and based on these data and our own experience, suggest the most useful tests and diagnostic criteria to be used. We conclude that even though laboratory testing is a fundamental part of the investigation of patients with CS, the interpretation of the tests should always be performed with extreme care, as none of the tests has proven fully capable of distinguishing all cases of CS. The biochemical results should be interpreted jointly with the clinical aspects and the radiology findings in a probabilistic matrix, and not as part of a uniform algorithm.

Once the diagnosis of Cushing's syndrome (CS) has been established, the main step is to differentiate between ACTH dependent and independent disease. In adults, 80% of CS is due to ACTH-dependent causes and 20% due to adrenal causes. ACTH-secreting neoplasms cause ACTH-dependent CS. These are usually anterior pituitary microadenomas, which result in the classic Cushing's disease. Non-pituitary ectopic sources of ACTH, such as a small-cell lung carcinoma or carcinoid tumours, are the source of the remainder of ACTH-dependent disease. In the majority of patients presenting with clinical and biochemical evidence of CS, modern non-invasive imaging can accurately and efficiently provide the cause and the nature of the underlying pathology. Imaging is essential for determining the source of ACTH in ectopic ACTH production, locating the pituitary tumours and distinguishing adrenal adenomas, carcinomas and hyperplasias. In our chapter we review the adrenal appearances in ACTH-dependent and ACTH-independent CS. We also include a discussion on the use of MRI and CT for the detection and management of pituitary ACTH secreting adenomas. CT of the chest, abdomen and pelvis with intravenous injection of contrast medium is the most sensitive imaging modality for the identification of the ectopic ACTH source and detecting adrenal pathology. MRI is used for characterising adrenal adenomas, problem solving in difficult cases and for detecting ACTH-secreting pituitary adenomas.

Cushing's syndrome (CS) results from prolonged exposure to supraphysiological levels of circulating glucocorticoids, endogenously or exogenously derived. Although rare in childhood, CS remains a difficult condition to diagnose and treat. A multidisciplinary approach and close collaboration with adult colleagues is adopted at most large centres that manage pediatric CS patients. Although pediatric protocols are derived from adult data, significant differences exist between adult and childhood CS. Furthermore, long term outcome parameters including final height, bone mineral density, reproductive function, body composition and psychological health pose challenges for pediatric care. This article will aim to provide an overall view of pediatric CS highlighting some of the differences between adult and pediatric CS.

The differential diagnosis of Cushing's syndrome requires careful multidisciplinary interaction with a number of specialities, co-ordinated through endocrine centres with good experience of this condition. It is essential that the diagnosis of Cushing's syndrome be fully established before differential diagnosis is attempted. The endocrinologist needs to be aware of the pitfalls and advantages of the tests in use. We discuss the approach to the differential diagnosis of this challenging condition.

Cushing's syndrome (CS), which is caused by excessive circulating glucocorticoid concentrations, is rare in the paediatric age range but presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience of managing children or adolescents with CS and thus benefit from close consultation with colleagues who treat adult patients. A protocol for investigation is required that broadly follows the model for adult patients. Here, the epidemiology and diagnosis of different causes of CS are discussed according to typical age of presentation. Treatment strategies for adrenocorticotrophic hormone (ACTH)-independent and ACTH-dependent CS are described and critically appraised. The management of paediatric CS patients after cure also presents challenges for optimizing growth, bone health, reproduction and body composition from childhood into and during adult life.

Background: A 24-year-old woman presented with a 12.5 kg weight gain over 6 months (mostly abdominal), hirsutism, acne, ankle edema, polydipsia, nocturia, back pain, pigmentation, poor libido and lightened menses to our hospital in May 1986. She had been treated for the previous 2 years with furosemide and spironolactone for peripheral edema, and had stopped the combined oral contraceptive 2 months previously. She did not take tobacco, recreational drugs or alcohol. Upon physical examination she was grossly Cushingoid with florid clinical manifestations., Investigations: Serum potassium and bicarbonate, circadian rhythm of cortisol, low-dose and high-dose dexamethasone suppression tests, plasma adrenocorticotropic hormone (ACTH), corticotropin releasing-hormone stimulation test, CT scan of the pituitary, plain chest radiology, CT scan of the chest and abdomen, trans-sphenoidal pituitary biopsy and histology, CT scan and MRI of the thorax, MRI of the pituitary, octreotide scintigraphy, gastroscopy, colonoscopy, gut peptides, tumor markers, urine 5-hydroxyl-indole-acetic acid, resection, histology, immunocytochemistry and in situ hybridization., Diagnosis: Occult ectopic ACTH syndrome from a presumed appendiceal neuroendocrine tumor. The tumor was only identified some 20 years from initial presentation., Management: Adrenolytic therapy before bilateral adrenalectomy to cure Cushing's syndrome, glucocorticoid and mineralocorticoid replacement therapy, and then repeated surveillance over 20 years to locate the ectopic source of ACTH. This was finally identified by CT scan and excised at laparotomy.

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.

Sex distribution and severity of biochemical indices at the diagnosis of Cushing's disease (CD) were analyzed in 50 patients (21 males and 29 females; aged

Adrenocorticotropic hormone (ACTH)-independent hypercortisolism accounts for 15%-20% of cases of Cushing syndrome and always arises from primary adrenal disease. Computed tomographic (CT) and magnetic resonance (MR) imaging findings in 37 patients with primary adrenal Cushing syndrome were analyzed and correlated with pathologic findings. Hyperfunctioning adenomas (n = 24), together with functioning carcinomas (n = 10), accounted for 92% of cases. Adenomas had a significantly smaller mean size (3.5 vs 14.5 cm) and lower mean unenhanced CT attenuation value (11 vs 28 HU) than did carcinomas. The presence of necrosis, hemorrhage, and calcification favored a diagnosis of carcinoma. Six of 10 carcinoma patients had metastases at presentation. Two adenomas were seen within a myelolipoma, which was recognized at both CT and MR imaging due to its fat content, and two adenomas were of uncertain malignant potential. Bilateral disease--primary pigmented nodular adrenal dysplasia (PPNAD) (n = 2) and ACTH-independent macronodular adrenal hyperplasia (AIMAH) (n = 1)--had characteristic imaging features. In PPNAD, multiple tiny (2-5-mm) nodules were visible bilaterally, with no overall glandular enlargement and normal intervening adrenal tissue. In AIMAH, both glands were grossly enlarged and contained nodules up to 3 cm in diameter. Familiarity with the range of imaging appearances of the adrenal glands in primary adrenal Cushing syndrome may help establish the underlying diagnosis., (Copyright RSNA, 2004)

Cushing's syndrome requires a screening test of high sensitivity, followed by biochemical evaluation of the source of the tumor when the cause is ACTH dependent. The high-dose dexamethasone suppression test is still in common use as an aid in differential diagnosis, although its value has been queried. We have routinely used the low-dose dexamethasone suppression test for many years in the diagnosis of Cushing's syndrome but noticed that patients with pituitary-dependent Cushing's syndrome or Cushing's disease, usually showed some degree of suppression of their serum cortisol, compared to those with the ectopic ACTH syndrome. We therefore analyzed retrospectively the serum cortisol responses during the low-dose dexamethasone suppression test and the high-dose dexamethasone suppression test in 245 patients with ACTH-dependent Cushing's syndrome and compared the diagnostic utility of each test either alone or in combination with a standard test using CRH. Evaluation of the serum cortisol response at 24 and 48 h during the low-dose dexamethasone suppression test correctly identified 98% of patients with ACTH-dependent Cushing's syndrome and distinguished between pituitary and ectopic causes with a sensitivity of 82% and a specificity of 79%. In the same patients, the serum cortisol response to the high-dose dexamethasone suppression test had a slightly higher sensitivity (91%) and specificity (80%). However, the combined criteria of a more than 30% suppression of serum cortisol during the low-dose dexamethasone suppression test and/or a more than 20% increase in the CRH test had a significantly higher sensitivity (97%) and specificity (94%) than either the high-dose dexamethasone or the CRH tests alone in the differential diagnosis of ACTH-dependent Cushing's syndrome. It produced equivalent information to that when high-dose and CRH test results were combined. We therefore conclude that in our patient series, the serum cortisol response during the low-dose dexamethasone suppression test is highly sensitive in diagnosing Cushing's syndrome and, combined with the results of the serum cortisol response to the CRH test, offered a safe and cost-effective test in the differential diagnosis of ACTH-dependent Cushing's syndrome. There does not appear to be any necessity for retaining the high-dose dexamethasone suppression test in this diagnostic work-up.

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.

Cushing's syndrome results from prolonged exposure to excessive circulating glucocorticosteroids, and is associated with significant morbidity and mortality. While the treatment of choice in most patients is surgical, the metabolic consequences of the syndrome, including increased tissue fragility, poor wound healing, hypertension, and diabetes mellitus, increase the risks of such surgery. The hypercortisolemia and its sequelae can be efficiently reversed using medical therapy, either as a temporary measure prior to definitive treatment, or longer term in more difficult cases. Drug treatment has been targeted at the hypothalamic/pituitary level, the adrenal glands, and also at the glucocorticoid receptor level. In this review we discuss the pharmacotherapeutic agents that have been used in Cushing's syndrome, and their efficacy, the monitoring of treatment, and potential therapies that may prove useful in the future in this complex endocrinological disorder.