Mild Adrenal Cortisol Excess

Turcu, Adina F.; Auchus, Richard J.

doi:10.1007/978-3-319-45950-9_10

The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease 2016

DOI: 10.1007/978-3-319-45950-9_10

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Mild Adrenal Cortisol Excess

Adina F. Turcu

Richard J. Auchus

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2021

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Cited by 2 publications

References 94 publications

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Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Fleseriu

Auchus

Pivonello

et al. 2021

Expert Review of Endocrinology & Metabolism

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Introduction: Endogenous Cushing's syndrome (CS) is a rare, life-threatening endocrine disorder that is caused by chronic exposure to cortisol overproduction. Levoketoconazole (Recorlev), a 2S, 4R stereoisomer of ketoconazole, is a steroidogenesis inhibitor under investigation for the treatment of CS. Areas covered: This review covers the pharmacology, efficacy, and safety of levoketoconazole for the treatment of patients with endogenous CS. Expert opinion: Based on the preclinical and clinical pharmacology findings, levoketoconazole appears to be the relevant enantiomer of ketoconazole for inhibition of steroidogenesis, with more potent inhibition of both cortisol and androgen synthesis relative to ketoconazole racemate and the 2R, 4S stereoisomer dextroketoconazole. Results from the phase III SONICS study showed that levoketoconazole was effective in normalizing cortisol levels and improving biomarkers of cardiovascular risk in a significant percentage of patients. In addition, treatment with levoketoconazole showed improvements in subjective clinical assessments of clinician-rated CS clinical signs and symptoms, patientreported quality of life, and depression symptom severity. Testosterone levels decreased significantly in women. Levoketoconazole had an acceptable safety profile with no unexpected safety signals. The favorable pharmacology, efficacy, and safety profile of levoketoconazole supports its use as medical therapy for CS, if approved.

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Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Fleseriu

Auchus

Pivonello

et al. 2021

Expert Review of Endocrinology & Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

Targeted Mutational Analysis of Cortisol-Producing Adenomas

Rege

Hoxie

Liu

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Background Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPA). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1. Objective To expand our understanding of the prevalence of somatic mutations in CPA from patients with overt Cushing syndrome (OCS) and “subclinical” mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue. Method We analyzed FFPE adrenal tissue from 77 patients (n=12 men, 65 women) with either OCS (n=32) or MACE (n=45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPA (32 OCS-CPA and 46 MACE-CPA). Genomic DNA was isolated from the FFPE CPA and subjected to targeted amplicon sequencing for identification of somatic mutations. Results Somatic mutations were identified in 71.8% (56/78) of the CPA. While PRKACA was the most frequently mutated gene in OCS-CPA (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE-CPA. Most GNAS mutations were observed in MACE-CPA (5/7,71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored two adjacent tumors within the same adrenal gland: one patient had two CPA, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase). Conclusion Comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPA. OCS-CPA demonstrated a distinct mutation profile compared to MACE-CPA.

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Mild Adrenal Cortisol Excess

Cited by 2 publications

References 94 publications

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Targeted Mutational Analysis of Cortisol-Producing Adenomas

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