Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing’s disease: comparison with GH‐releasing peptide‐6 (GHRP‐6)

Correa‐Silva, Silvia R.; Nascif, SÃ©rgio O.; Molica, PatrÃ­cia; Sã, Larissa B. P. C.; Vieira, José Gilberto H.; Lengyel, Ana‐Maria J.

doi:10.1111/j.1365-2265.2009.03618.x

Cited by 8 publications

(3 citation statements)

References 33 publications

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“…The modest rise in ACTH in patients with CD receiving levoketoconazole [57], and the preclinical findings of inhibitory effects on ACTH secretion and corticotroph cell growth [36], suggest the possibility of direct antisecretory effects on ACTH and/or a direct effect of tumor inhibition in the pituitary gland, similar to what has been reported with ketoconazole [42,62]. In addition, there is no evidence that short-or long-term treatment with ketoconazole has adverse effects on pituitary function in patients with CD or in healthy individuals or patients with other endocrine disorders [88][89][90][91][92][93][94][95].…”

Section: Place Of Levoketoconazole In the Treatment Algorithm For Cushing's Syndromementioning

confidence: 68%

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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Section: Place Of Levoketoconazole In the Treatment Algorithm For Cushing's Syndromementioning

confidence: 68%

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Fleseriu

Auchus

Pivonello

et al. 2021

Expert Review of Endocrinology & Metabolism

View full text Add to dashboard Cite

show abstract

“…Ketoconazole exerts its effect through interference with enzymes involved in the conversion of cholesterol to cortisol [ 6 ]. A further effect at hypothalamo–pituitary level had been reported [ 7 , 8 ] but not confirmed in later studies. To date, there are no prospective clinical studies on ketoconazole in CS and available data is drawn from retrospective analyses.…”

Section: Adrenal Blocking Agentsmentioning

confidence: 77%

Role of “old” pharmacological agents in the treatment of Cushing’s syndrome

Ambrogio

Cavagnini

2016

J Endocrinol Invest

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Despite recent advances in the management of endogenous Cushing’s syndrome (CS), its treatment remains a challenge. When surgery has been unsuccessful or unfeasible as well in case of recurrence, the “old” pharmacological agents represent an important alternative for both ACTH-dependent and independent hypercortisolism. Especially in the latter, the advent of novel molecules directly targeting ACTH secretion has not outweighed the “old” drugs, which continue to be largely employed and have recently undergone a reappraisal. This review provides a survey of the “old” pharmacological agents in the treatment of CS.

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“…These data suggest uncoupling of ACTH and cortisol after achieving maximal cortisol values similar to that observed in states of psychological or physical stress [27] or during pharmacological stimulation [28]. Correa-Silva et al [29] have tested ACTH and cortisol responses to growth hormone-releasing peptide 6 and ghrelin in patients with CD before and after 6 months of treatment with the cortisol-lowering drug ketoconazole. According to the authors, significant decrease in cortisol levels, after ketoconazole treatment, was accompanied by further increase in ACTH responses to hormone-releasing peptide 6 and ghrelin, indicating recovery of healthy, previously suppressed corticotroph cells.…”

Section: Discussionmentioning

confidence: 99%

Combined Administration of Ghrelin and Corticotropin-Releasing Hormone in the Diagnosis of Cushing's Disease

Miljić¹,

Polovina²,

Doknic³

et al. 2016

Neuroendocrinology

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Background/Aims: Exaggerated adrenocorticotropic hormone (ACTH) and cortisol responses to ghrelin in Cushing's disease (CD) have previously been reported, similarly to responses to corticotropin-releasing hormone (CRH). We assessed the ability of ghrelin to enhance ACTH and cortisol responses when added to CRH stimulation in CD patients. Methods: In 21 CD patients (18 females, 3 males; age 49.8 ± 10.2 years; BMI 29.8 ± 0.8) and 8 healthy subjects (7 females, 1 male; age 40.6 ± 5.3 years; BMI 29.9 ± 1.2), we administered (1) ghrelin 100 µg i.v. bolus, (2) CRH 100 µg i.v. bolus, and (3) ghrelin + CRH combination. ACTH and cortisol were analyzed by commercially available kits from samples taken at 0, 15, 30, 45, 60, 90 and 120 min. ACTH and cortisol responses were calculated as peak and area under the curve (AUC_{0-120 min}). Results: ACTH and cortisol at baseline and stimulated with ghrelin and/or CRH (peak and AUC_{0-120 min}) were significantly higher in CD patients compared to controls (p < 0.01). ACTH and cortisol responses to ghrelin or CRH were similar in CD patients. Combined ghrelin + CRH administration in CD patients produced the highest ACTH response (peak and AUC_{0-120 min}) compared to ghrelin or CRH alone (p < 0.01). Cortisol responses after ghrelin + CRH were uncoupled with ACTH responses and similar to the response to ghrelin or CRH alone in both groups. ACTH and cortisol responses, during all three tests, were similar in CD patients with micro- or macroadenomas. Conclusion: Ghrelin administration causes exaggerated ACTH and cortisol responses in CD patients compared to healthy controls. In combination with CRH, it additionally enhances ACTH secretion without further additive effect on cortisol output.

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Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing’s disease: comparison with GH‐releasing peptide‐6 (GHRP‐6)

Cited by 8 publications

References 33 publications

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Role of “old” pharmacological agents in the treatment of Cushing’s syndrome

Combined Administration of Ghrelin and Corticotropin-Releasing Hormone in the Diagnosis of Cushing's Disease

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