Cushing Syndrome

ObjectiveWe aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS).MethodsThe protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies.ResultsSMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

PurposeLiterature regarding endogenous Cushing syndrome (CS) largely focuses on the challenges of diagnosis, subtyping, and treatment. The enigmatic phenomenon of glucocorticoid withdrawal syndrome (GWS), due to rapid reduction in cortisol exposure following treatment of CS, is less commonly discussed but also difficult to manage. We highlight the clinical approach to navigating patients from GWS and adrenal insufficiency to full hypothalamic-pituitary-adrenal (HPA) axis recovery.MethodsWe review the literature on the pathogenesis of GWS and its clinical presentation. We provide strategies for glucocorticoid dosing and tapering, HPA axis testing, as well as pharmacotherapy and ancillary treatments for GWS symptom management.ResultsGWS can be difficult to differentiate from adrenal insufficiency and CS recurrence, which complicates glucocorticoid dosing and tapering regimens. Monitoring for HPA axis recovery requires both clinical and biochemical assessments. The most important intervention is reassurance to patients that GWS symptoms portend a favorable prognosis of sustained remission from CS, and GWS typically resolves as the HPA axis recovers. GWS also occurs during medical management of CS, and gradual dose titration based primarily on symptoms is essential to maintain adherence and to eventually achieve disease control. Myopathy and neurocognitive dysfunction can be chronic complications of CS that do not completely recover.ConclusionsDue to limited data, no guidelines have been developed for management of GWS. Nevertheless, this article provides overarching themes derived from published literature plus expert opinion and experience. Future studies are needed to better understand the pathophysiology of GWS to guide more targeted and optimal treatments.

PurposeThe efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization.MethodsLOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases.Results79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).ConclusionsLevoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

Medical treatment of hypercortisolism may be necessary for a high proportion of patients with Cushing syndrome (CS), including those who are not candidates for curative surgery. It may also be used in the presurgical period when hypercortisolism is severe, as long-term treatment following surgical failure or recurrence after surgery, or while waiting for the effects of pituitary radiation in Cushing disease. Currently available medical treatments include adrenal steroidogenesis inhibitors that block cortisol secretion (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate), drugs that modulate pituitary ACTH secretion (pasireotide and cabergoline), and drugs that block peripheral glucocorticoid receptors (mifepristone). In addition, there are other medical treatments in development that target pituitary signaling pathways, ACTH or its adrenal receptor, or the conversion of cortisol from cortisone by 11ßHSD1. Steroidogenesis inhibitors can be administered using either a titration or a block-and-replace approach. Titration requires adjusting the daily drug dose with the aim of normalizing circulating cortisol levels, whereas the block-and-replace strategy uses higher drug doses to fully suppress endogenous cortisol production, followed by glucocorticoid supplementation. In this review, we summarize the main indications for medical treatment in CS, the mechanism of drug action, efficacy, recommended doses, and safety of the currently available drugs, as well as potential future treatments. We also discuss titration and block-and-replace approaches for control of hypercortisolism and provide recommendations for the use and monitoring of medical treatment in CS, including patients with endogenous hypercortisolism in special situations such as pregnancy, cyclic CS, and mild autonomous cortisol secretion.