Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies
Open accessAbstract
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.
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Ketoconazole affects multiple steps of adrenal steroidogenesis.
“Effects of the well-known inhibitor of steroidogenic enzymes, ketoconazole which affects multiple steps of adrenal steroidogenesis was also examined in the HFA ex vivo model.”
From Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis (2021) · cites this paper as [58]
Ketoconazole has different IC50 values for each steroidogenic enzyme.
“Ketoconazole has different IC50 values for each steroidogenic enzyme (58)”
From Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis (2021) · cites this paper as [58]
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- Authors
- Fleseriu, M., & Castinetti, F.
- Affiliations
- Oregon Health & Science University (US)
- Corresponding author
- Fleseriu, Maria
- ORCID
- Fleseriu, Maria
- Venue
- Pituitary
- Published
- 2016-09-06
- Volume
- 19
- Issue
- 6
- Pages
- 643-653
- ISSN
- 1386-341X (ISSN-L)
- 1573-7403
- PMC
- PMC5080363
- OpenAlex
- W2508025007
- Cited by
- 87
- References
- 63
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 11 · 2020: 6 · 2019: 14 · 2018: 10 · 2017: 11
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Pituitary (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Strongbridge Biopharma
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- Cushing's syndrome, Cushing's disease, ketoconazole, metyrapone, etomidate, mitotane, osilodrostat, hypercortisolism, drug safety and efficacy, new drugs
- MeSH terms
- Cushing Syndrome, Humans, Steroid Synthesis Inhibitors
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