PMC:3724972 / 25904-29508 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3724972","sourcedb":"PMC","sourceid":"3724972","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3724972","text":"Other medical treatment modalities in Cushing’s disease\n\nMifepristone: glucocorticoid receptor blockade\nMifepristone is a glucocorticoid receptor (GR2) antagonist, recently FDA-approved to treat hyperglycemia in adult patients with Cushing’s syndrome who have failed surgery or are not surgical candidates. Regulatory approval was based on a 24-week open-label trial studying 50 Cushing’s patients (43 with CD) and associated type 2 diabetes mellitus/impaired glucose tolerance (DM/IGT), or hypertension [74]. At the end of the treatment period, 15/25 patients (60 %) in the DM/IGT group achieved ≥25 % reductions in glucose AUC0–120 min. Patients also exhibited reductions in HbA1c and fasting plasma glucose levels, as well as reduced body weight and waist circumference, improvements in clinical status and quality of life.\nWith GR2 receptor blockade, ACTH and cortisol will likely increase, potentially resulting in hypokalemia, increased blood pressure, edema, or alkalosis through activation of mineralocorticoid receptors [75]. Other potential adverse reactions include adrenal insufficiency (AI) and endometrial thickening with vaginal bleeding—both requiring close monitoring and treatment [76, 77]. As there is no biochemical marker to follow (cortisol values are not reliable), treatment efficacy and potential adrenal insufficiency must be gauged through changes in clinical signs and symptoms [77]. Mifepristone is also a potent antagonist of progesterone, thus premenopausal women must be tested for pregnancy before administration. Caution is also warranted in combination with drugs metabolized by CYP3A or CYP2C (e.g., simvastatin, cyclosporine, fentanyl, ciprofloxacin, NSAIDs, warfarin).\n\nAdrenal-targeted drugs\nDrugs inhibiting adrenocortical steroidogenesis include ketoconazole, mitotane, etomidate and metyrapone. In general, use of these drugs requires careful clinical monitoring for adverse effects, including AI [77]. Ketoconazole has been widely used to treat CD because it inhibits several steps in adrenal steroid synthesis and reduces UFC in the majority of patients with CD [78]. However, it also inhibits androgen synthesis and is associated with liver toxicity in some patients [79]. There is little prospective information on the long-term use of adrenal-targeted agents [11, 80]; however, 1 small retrospective study showed promising results [81, 82]. Mitotane also inhibits several steps in steroidogenesis, and can be adrenolytic during long-term therapy at doses \u003e4 g/day [77]. Because mitotane is sequestered in adipose tissue and eliminated slowly, pregnancy must be avoided for 5 years after discontinuation [77].\nLCI699 is a novel inhibitor of 11β-hydroxylase (the final enzyme in the cortisol synthesis pathway) under development for several indications, including CD. In a recent proof-of-concept study in patients with CD (UFC \u003e1.5× ULN), all participants (N = 12) achieved either UFC normalization or ≥50 % reduction from baseline after 70 days of treatment. While all patients experienced ≥1 AE, most were mild or moderate. Some AEs consistent with AI were reported, and resolved after dose reduction. Four patients experienced hypokalemia; all cases were managed without dose reduction, and 3 patients received oral potassium supplementation [83]. A larger-scale, 22-week expansion trial is currently underway [84]. A summary of potential therapeutic targets in CD is shown in Fig. 4 [85].\nFig. 4 Potential targets and medical therapies in Cushing’s disease. From Fleseriu, M (2012) Neurosurg Clin N Am volume 23, page 657 [85]. 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