https://www.thelancet.com/pdfs/journals/landia/PIIS2213-8587(16)00086-3.pdf

Complications of Cushing's syndrome: state of the art

Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

The Treatment of Cushing's Disease

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2010.04034.x

Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors.

Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

/pdf/metabolic-comorbidities-in-cushing-s-syndrome-1ayplg4f7i.pdf

Metabolic comorbidities in Cushing's syndrome

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

/pdf/the-hypertension-of-cushing-s-syndrome-controversies-in-the-4p6fivgrlc.pdf

The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications

Cushing's syndrome (CS) is associated with high cardiovascular risk. The aim of this study was to analyze intimal media thickness (IMT) in patients with CS and compare them with subjects matched for similar conventional and independent cardiovascular risk factors. Twenty eight patients with CS (mean age: 40.7 +/- 2.5 y) and 28 subjects (mean age: 41.1 +/- 14 y) matched for sex, age, smoking habit, body mass index, blood pressure levels, glucose and lipid metabolism were evaluated. IMT was measured at right and left common carotid (CC), carotid bulb (BC), aorta (Ao) and femoral (F) levels by B-echo-Doppler ultrasonography. Although parameters of cardiovascular risk factors did not differ statistically between patients and controls, IMT was significantly increased (right and left CC-IMT, p < 0.05; right and left BC-IMT, p < 0.01, Ao-IMT p < 0.05) and wall plaques were more common (14.2 % VS. 7.1 %) in patients. In CS patients, CC-IMT and F-IMT correlated positively and significantly with fasting glucose (right CC-IMT: r (2) = 0.37, p = 0.05; left CC-IMT: r (2) = 0.43, p = 0.02; right F-IMT: r (2) = 0.57; p < 0.01; left F-IMT: r (2) = 0.47, p = 0.01) and HOMA index (left CC-IMT: r (2) = 0.64, p < 0.01 and left F-IMT: r (2) = 0.48, p < 0.05). The CS patients' waist-to-hip ratio (WHR) was evaluated and correlated positively and significantly with CC-IMT (right: r (2) = 0.53, p = 0.01 and left: r (2) = 0.44, p = 0.05). No correlation was found between IMT and cortisol levels, however. In conclusion, patients with CS have more severe atherosclerotic damage than a population matched for similar cardiovascular risk factors. Multiple events related to long-term cortisol effects on metabolism and at vascular and endothelial sites may increase the risk of cardiovascular damage in patients with CS.

Patients with Cushing's syndrome have increased intimal media thickness at different vascular levels: comparison with a population matched for similar cardiovascular risk factors.

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Patients with Cushing's syndrome have increased intimal media thickness at different vascular levels: comparison with a population matched for similar cardiovascular risk factors.