pubmed.ncbi.nlm.nih.gov

Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies - PubMed

Review

Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies

Maria Fleseriu et al. Pituitary. 2016 Dec.

Abstract

Purpose: Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development.

Methods: We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs.

Results: Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing).

Conclusions: The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.

Keywords: Adrenal steroidogenesis inhibitor; Cushing’s disease; Cushing’s syndrome; Ketoconazole; LCI699; Levoketoconazole; Metyrapone; Osilodrostat.

PubMed Disclaimer

Conflict of interest statement

MF has received research grant support from and has consulted for Chiasma, Novartis, Ipsen, Strongbridge Biopharma, and Pfizer. FC has received research grant support from Novartis, Ipsen, Pfizer, and HRA Pharma and has consulted for Novartis, Strongbridge Biopharma, and HRA Pharma.

Figures

Fig. 1
Fig. 1

Effects of adrenal steroidogenesis inhibitors on the cortisol synthesis pathway [9]. The enzymatic pathways in cortisol synthesis are represented schematically. Inhibitors are depicted in purple boxes and may inhibit multiple steps in the pathway. aAt high doses. CYP, cytochrome P450

Similar articles

Cited by

References

    1. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–293. - PMC - PubMed
    1. Dekkers OM, Horvath-Puho E, Jorgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sorensen HT. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98:2277–2284. doi: 10.1210/jc.2012-3582. - DOI - PubMed
    1. Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines. Clin Endocrinol (Oxf.) 2004;61:768–777. doi: 10.1111/j.1365-2265.2004.02168.x. - DOI - PubMed
    1. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173:M33–M38. doi: 10.1530/EJE-15-0464. - DOI - PMC - PubMed
    1. Sharma ST, Nieman LK. Cushing’s syndrome: all variants, detection, and treatment. Endocrinol Metab Clin North Am. 2011;40(2):379–391. doi: 10.1016/j.ecl.2011.01.006. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances