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Cushing's Syndrome Learning Zone

Management

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Disease Management

Patients with Cushing’s Syndrome have increased morbidity and mortality rates compared with the general population. Providing effective and timely management is therefore essential. Access the latest information on treatment, including guideline recommendations and managing comorbidities. Details of the ultimate expectations and goals are from treatment, the different comorbidities, current guidelines, transsphenoidal surgery, radiotherapy, bilateral adrenalectomy, pharmacological interventions and future treatments are all discussed. 

Clinical treatment guidelines

In 2015, the Endocrine Society produced a comprehensive set of guidelines for the treatment of CS (Nieman et al., 2015). 

The guidelines were co-sponsored by the European Society of Endocrinology and participants included an Endocrine Society-appointed Task Force of experts from France, the UK and the US. The Task Force assessed the quality of the available evidence, resulting in consensus on best practice for the treatment of CS.

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Managing comorbiditites

In 1952, before effective treatment was available, patients with CS had a median survival of 4.6 years. Despite treatments for comorbidities becoming available, patients with active CS continue to have an increased standardised mortality rate that is 1.7–4.8-fold greater than the general population.

In contrast, when CS and its associated comorbidities are successfully treated, the standardised mortality rate improves, although it is unclear whether this is similar or not to mortality rates in the general population (Niemann et al., 2015). Recent data suggest that curative therapy with initial surgery is most likely to provide a normalised standardised mortality ratio (Clayton et al., 2016).

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Treatment

The aim of Cushing’s Syndrome treatment is a rapid normalisation of the metabolic and biochemical abnormalities associated with the disorder. 

Current guidelines provide advice on the surgical, radiological and medical management of CS with clear recommendations on lines of therapy and patient suitability (Nieman et al., 2015).

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Second-line treatment

Second-line therapies include repeat TSS, radiation therapy/radiosurgery, bilateral adrenalectomy and medical therapy (Niemann et al., 2015). 

Patients with adrenal carcinomas may require chemotherapy, radiotherapy or mitotane therapy post-surgery, and should be managed by an adrenal cancer-specific multidisciplinary team (Nieman et al., 2015).

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Adrenal steroidogenesis inhibitors

These therapies control cortisol production by decreasing steroid hormone production in the adrenal gland by inhibiting one or more enzymes involved in steroid synthesis (Morgan and Laufgraben, 2013).

Etomidate

Etomidate, an intravenous medication used for anaesthesia induction, inhibits cholesterol side chain cleavage and 11-beta-hydroxylase. Etomidate was initially developed as a nonopioid anaesthetic, but an association with increased mortality in critically ill patients led to the discovery of an inhibitory effect on adrenal steroid synthesis (Morgan and Laufgraben, 2013). Guidelines indicate that etomidate can be used to manage hypercortisolaemia in severely ill patients of any age who cannot receive surgery immediately or take oral medications. It has a quick onset of action but requires monitoring in a high-dependency unit (Nieman et al., 2015). Initial bolus dose is 0.03 mg/kg/h followed by an infusion of 0.1 mg/kg/h with a maximum dose of 0.3 mg/kg/h. Sedation scoring should be performed every 2 hours for the first 24 hours, and then every 12 hours until the infusion is stable (goal serum cortisol level of 500–800 nmol/L in a physiologically stressed patient and 150–300 nmol/L in a nonphysiologically stressed patient) (Preda et al., 2012; Morgan and Laufgraben, 2013).

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Neuromodulators of ACTH release

These therapies directly target the corticotroph pituitary adenomas to reduce ACTH hypersecretion. Two currently available classes of medications that act centrally are dopamine type 2 receptor agonists (DAs), and somatostatin receptor ligands (SRLs) (Morgan and Laufgraben, 2013).

 

Cabergoline

Cabergoline is a DA indicated for the inhibition of lactation and treatment of hyperprolactinaemia disorders. It acts by direct stimulation of the D2-dopamine receptors on pituitary lactotrophs, thus inhibiting prolactin secretion. Cabergoline for CS is typically initiated at 0.5 mg per week, with titration to a maximal dose of 7 mg/week (Morgan and Laufgraben, 2013; Nieman et al., 2015). In a study of 30 CS patients, long-term treatment resulted in complete remission in 30% of patients. However, some patients subsequently relapse (Godbout et al., 2010). Adverse effects include gastrointestinal upset, asthenia and dizziness (Nieman et al., 2015).

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Glucocorticoid receptor blockers

Glucocorticoid receptor antagonists bind with higher affinity than cortisol resulting in inhibition of the glucocorticoid receptor causing rapid control of the systemic effects of cortisol excess in patients with CS (Morgan and Laufgraben, 2013).

 

Mifepristone

Mifepristone is an anti-glucocorticoid approved by the FDA (but not approved in Europe) for use in CS. It binds the glucocorticoid receptor with a four-fold higher affinity than dexamethasone and 18-fold higher affinity than cortisol (Morgan and Laufgraben, 2013). Initial dosing is 300 mg/d and dose adjustments (to a maximum of 1200 or 2000 mg/d) on clinical parameters, primarily glucose and weight reduction (Morgan and Laufgraben, 2013; Nieman et al., 2015). A large open-label 24-week multicentre study showed a reduction in glucose and improvement in a number of other parameters in 50 CS patients (Fleseriu et al., 2012). Mifepristone is abortifacient and other adverse effects include those associated with cortisol insufficiency (fatigue, nausea, vomiting, arthralgias and headache), hypertension, hypokalaemia, oedema and endometrial thickening (Nieman et al., 2015). However, the absence of a biochemical marker for the control means mifepristone is not easy to monitor and surrogate measures such as improvements in CS clinical and metabolic features should be used (Cuevas-Ramos et al., 2016).

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Future treatments

As no single drug has demonstrated complete efficacy and current treatments have numerous adverse effects, drug combinations offer the potential of reduced doses and fewer side effects (Cuevas-Ramos et al., 2016).

Combinations tested in small studies include up to three different steroidogenesis inhibitors, cabergoline and ketoconazole, and pasireotide, cabergoline and ketoconazole (Cuevas-Ramos et al., 2016).

There are also a number of novel treatments currently under investigation (Cuevas-Ramos et al., 2016):

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Management references

Arnaldi G, Angeli AB, Atkinson X, Bertagna F, Cavagnini F, Chrousos GP et al. Diagnosis and complications of Cushing’s Syndrome: A consensus statement. J Clin Endocrinol Metab 2003; 88:5593–602.

Baudry C, Coste J, Bou Khalil R, et al. Efficiency and tolerance of mitotane in Cushing’s Disease in 76 patients from a single center. Eur J Endocrinol 2012; 167:473–81.

Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, et al, on behalf of the ESMO Guidelines Working Group. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 31–138.

Berruti A, Grisanti , Pulzer A, Claps M, Daffara F, Loli P, et al. Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 2017; 102:1358–65.

Castinetti F, Morange I, Jaquet P, Conte-Devoix B, Brue T. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing’s Disease. Eur J Endocrinol. 2008; 158:91–9.

Clayton RN, Jones PW, Reulen RC, Stewart PM, Hassan-Smith ZK, Ntali G et al. Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 2016; 4:569–76.

Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing’s Disease. N Engl J Med 2012; 366:914–24.

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Dekkers OM, Biermasz NR, Pereira AM, Roelfsema F, van Aken MO, Voormolen JH, et al. Mortality in patients treated for Cushing’s Disease is increased compared to patients treated for nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab 2007; 92:976–81.

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Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross CÍž et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s Syndrome. J Clin Endocrinol Metab 2012; 97:2039–49.

Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Carbergoline monotherapy in the long-term treatment of Cushing’s Disease. Eur J Endocrinol 2010; 163:709–16.

Hassan-Smith ZK, Sherlock M, Reulen RC, Arlt W, Ayuk J, Toogood AA, et al. Outcome of Cushing’s Disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 2012; 97:1194–201.

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Newell-Price J, Petersenn S, Biller BMK, Roughton M, Ravichandran S, Lacroix A. Once-monthly injection of pasireotide LAR reduces urinary free cortisol (UFC) levels in patients with Cushing’s Disease: Results from a randomised, multicentre, phase III trial. Endocrine Abstracts 2016; 41:GP153.

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