THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel, Eleni; Newell‐Price, John

doi:10.1530/eje-14-1014

Cited by 81 publications

(121 citation statements)

References 167 publications

(206 reference statements)

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“…A review of clinical studies reporting the efficacy of ketoconazole in patients with Cushing's disease revealed a mean response rate of 64.3 % [3]. Ketoconazole, however, also inhibits androgen synthesis and may cause liver damage [61]. The approved agent ketoconazole is a racemic mixture of two enantiomers.…”

Section: Medical Therapymentioning

confidence: 99%

Cushing’s disease: the burden of illness

et al. 2016

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Cushing's syndrome is caused by prolonged exposure to elevated cortisol levels. The most common form of endogenous Cushing's syndrome is Cushing's disease, which results from an adrenocorticotropic hormone-secreting pituitary tumour. Cushing's disease is associated with increased mortality, mostly attributable to cardiovascular complications, and a host of comorbidities such as metabolic and skeletal disorders, infections and neuropsychiatric disturbances. As a consequence, Cushing's disease substantially impairs health-related quality of life. It is crucial that the condition is diagnosed as early as possible, and that rapid and effective treatment is initiated in order to limit long-term morbidity and mortality. The initial treatment of choice for Cushing's disease is selective transsphenoidal pituitary surgery; however, the risk of recurrence after initial surgery is high and remains so for many decades after surgery. A particular concern is the growing body of evidence indicating that the negative physical and psychosocial sequelae of chronic hypercortisolism may persist in patients with Cushing's disease even after long-term surgical 'cure'. Current treatment options for post-surgical patients with persistent or recurrent Cushing's disease include second surgery, radiotherapy, bilateral adrenalectomy and medical therapy; however, each approach has its limitations and there is an unmet need for more efficacious treatments. The current review provides an overview of the burden of illness of Cushing's disease, underscoring the need for prompt diagnosis and effective treatment, as well as highlighting the need for better therapies.

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Section: Medical Therapymentioning

confidence: 99%

Cushing’s disease: the burden of illness

et al. 2016

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“…Pituitarydirected approaches include the dopamine agonist cabergoline (18) and the multi-receptor somatostatin-analogue pasireotide (19). Inhibitors of steroidogenesis that inhibit cytochrome P450 enzymes include metyrapone, ketoconazole and LCI699 (20,21). Hypercortisolism can also be controlled by the adrenolytic agent mitotane (22,23,24) and by the glucocorticoid receptor antagonist mifepristone (25).…”

Section: Introductionmentioning

confidence: 99%

A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome

Reincke

Ritzel

Oßwald

et al. 2015

European Journal of Endocrinology

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Objective: Our aim was to review short-and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome. Methods: We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution. Results: BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour. Conclusion: BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.European Journal of Endocrinology (2015) 173, M23-M32 Invited Author's profile Prof. Martin Heinrich Reincke is Director of the Medizinische Klinik and Poliklinik IV, Ludwig-MaximiliansUniversität München, and Chair of the Department of Endocrinology and Diabetology. His research specialities include adrenal physiology and pathophysiology, endocrine hypertension, pituitary disease, mineralocorticoid and glucocorticoid action and stress research. Professor Reincke heads a research team that specifically explores the prevalence and relevance of Cushing's syndrome at the epidemiological, clinical, genetic and molecular levels. The research teams of his clinic have particular expertise in assay development and validation for endocrine disease and in the development of genetically manipulated animals as models for human adrenal disease.

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“…Ketoconazole inhibits key cytochrome P450 (CYP) enzymes involved in multiple steps of steroidogenesis in the adrenal cortex, including CYP17A1, CYP11A1, CYP11B1, and CYP11B2 [10, 14, 15]. Ketoconazole is a 50/50 racemic mixture of 2S,4R and 2R,4S enantiomers [16], and these enantiomers exhibit differences in inhibitory potency for the enzymes involved in steroidogenesis [17–19].…”

Section: Adrenal Steroidogenesis Inhibitors Currently In Clinical Usementioning

confidence: 99%

“…Metyrapone is FDA approved for the diagnosis of AI in the US [27] and is used clinically, off label, for the treatment of CS [10]. In the European Union, metyrapone is approved for the treatment of CS [13].…”

Section: Adrenal Steroidogenesis Inhibitors Currently In Clinical Usementioning

confidence: 99%

“…1). Adrenal steroidogenesis inhibitors, which act by blocking various steps in the steroid biosynthesis pathway resulting in reduced production of cortisol and other steroids, are a cornerstone of medical treatment of CS [10]. This review summarizes the key features of different adrenal steroidogenesis inhibitors for the treatment of CS, with particular emphasis on steroidogenesis inhibitors currently in clinical development.…”

Section: Introductionmentioning

confidence: 99%

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

Fleseriu

Castinetti

2016

Pituitary

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PurposeEndogenous 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.MethodsWe performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs.ResultsCurrently 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).ConclusionsThe 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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THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Cited by 81 publications

References 167 publications

Cushing’s disease: the burden of illness

Cushing’s disease: the burden of illness

A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome

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

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