Metyrapone treatment in Cushing’s syndrome: a real-life study

Ceccato, Filippo; Zilio, Marialuisa; Barbot, Mattia; Albiger, Nora; Antonelli, Giorgia; Watutantrige-Fernando, Sara; Sabbadin, Chiara; Boscaro, Marco; Scaroni, Carla

doi:10.1007/s12020-018-1675-4

Cited by 49 publications

(74 citation statements)

References 40 publications

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“…However, in studies including both exclusively CD and mixed CD and CS populations, a treatment escape was observed in an average of 5.7% of patients, although variably ranging from 0 to 13% among the different studies (4). In CD and CS patients, metyrapone treatment is associated with a general improvement in clinical features, mainly including hypertension, impairment of glucose metabolism, psychiatric disturbances, and muscle weakness (4,60,62,63). In CD patients, no effects on pituitary tumor were reported (62,63).…”

Section: Metyraponementioning

confidence: 99%

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

et al. 2020

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Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

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Section: Metyraponementioning

confidence: 99%

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

et al. 2020

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“…They are generally used when surgery is not indicated or in cases of persistent or recurrent hypercortisolism. Steroidogenesis inhibitors such as ketoconazole or metyrapone effectively lower mean 24-h cortisol values but appear unable to restore the cortisol rhythm (Terzolo et al 1988, Ceccato et al 2018. Conversely, the somatostatin analog pasireotide, alone or in combination therapy with cabergoline or ketoconazole, restored the diurnal cortisol rhythm, albeit, in only half of the patients (van der Pas et al 2013).…”

Section: Treating Cushing's Syndrome and Possible Autonomous Cortisolmentioning

confidence: 99%

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

Minnetti

Hasenmajer

Pofi

et al. 2020

Journal of Endocrinology

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The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing’s syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.

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“…Mitotane is a dichlorodiphenyltrichloroethane (DDT) derivative that acts on the adrenal mitochondria, exhibiting adrenocortical injury, and causing irreversible damage to the adrenal cortex [22]. Furthermore, metyrapone inhibits 11 β hydroxylase and inhibits hormone synthesis in the adrenal cortex [23]. The effects on the adrenal cortex are reversible, and metyrapone is often used as a medication for CS.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model

Yasuda

Seki

Kametani

et al. 2019

International Journal of Endocrinology

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ACTH-independent Cushing’s syndrome (CS) is mainly caused by cortisol-secreting adrenocortical tumours. It is well known that secondary adrenal insufficiency occurs after surgical resection of these tumours. In this regard, impaired adrenocortical function is likely induced by atrophy of the residual adrenal tissue as a result of chronic suppression by the low ACTH levels of the hypercortisolism state. Therefore, we considered the prevention of adrenal atrophy as a method for preventing postoperative adrenal insufficiency. On the basis of these findings, we hypothesized that the use of a glucocorticoid receptor (GR) antagonist before surgery in ACTH-independent CS would rapidly activate the hypothalamic-pituitary-adrenal (HPA) axis and residual adrenal function. We thus examined adrenal function in a dexamethasone- (DEX-) induced CS rat model with or without mifepristone (MIF). In this study, MIF-treated rats had elevated plasma ACTH levels and increased adrenal weights. In addition, we confirmed that there were fewer atrophic changes, as measured by the pathological findings and mRNA expression levels of corticosterone synthase CYP11B1 in the adrenal glands, in MIF-treated rats. These results indicate that MIF treatment prevents the suppression of the HPA axis and the atrophy of the residual adrenal tissue. Therefore, our study suggests that preoperative GR antagonist administration may improve residual adrenal function and prevent postoperative adrenal insufficiency in ACTH-independent CS.

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Metyrapone treatment in Cushing’s syndrome: a real-life study

Abstract: MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects).

Cited by 49 publications

References 40 publications

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model

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