Available online 14 November 2022, 101718

Abstract

The first-line treatment of Cushing’s disease is transsphenoidal surgery. Medical treatment of Cushing’s disease can be considered in several situations: as a presurgical treatment in patients with severe comorbidities, when surgery fails, or while waiting for the maximal efficacy of radiation techniques. Several modalities of medical treatment are possible, from adrenal-targeting drugs (steroidogenesis inhibitors) to pituitary-targeting drugs (somatostatin receptor ligand pasireotide or the dopamine agonist cabergoline), or even drugs that antagonize the glucocorticoid receptor (mifepristone). Given the morbidities associated with hypercortisolism, and the fact that medical treatment can be delivered on a long-term basis, it is important to obtain eucortisolism and to monitor the drug effectively. The efficacy of these drugs will not be detailed in this review, nor their roles in the therapeutic algorithm of Cushing’s disease. This review will rather focus specifically on adverse events associated with these drugs (ketoconazole, levoketoconazole, metyrapone, osilodrostat, pasireotide, cabergoline and mifepristone), and the way in which to monitor and treat them, based on retrospective studies and the most recently published prospective studies.

Introduction

The first-line treatment of Cushing’s disease is transsphenoidal surgery. It usually leads to remission in 30-80% of cases when taking into account the mid to long-term risk of recurrence. The medical treatment of Cushing’s disease can be considered in several situations: as a presurgical treatment in patients with severe comorbidities, when surgery fails, or while waiting for the maximal efficacy of radiation techniques to be obtained. Several modalities are possible from drugs that target the adrenals (steroidogenesis inhibitors such as ketoconazole, levoketoconazole, metyrapone or osilodrostat; mitotane will not be discussed in this review as its first-line use is mainly adrenal carcinoma, nor etomidate which is usually delivered in life-threatening hypercortisolism), to drugs that target the pituitary (the somatostatin receptor ligand pasireotide or the dopamine agonist cabergoline), or even a drug aimed antagonizing the glucocorticoid receptor (mifepristone). The aim of this review is not to detail the efficacy of these drugs, or the reasons why some drugs would be preferred over others in specific situations, as this has been the subject of several reviews and guidelines over the last 5 years (1, 2, 3, 4) Here, we will focus only on the tolerance profile of all these drugs when delivered as a treatment for hypercortisolism. It is important to consider that some of these drugs have been used for decades, and reported only in retrospective studies, while others have only been reported in prospective randomized studies, thus leading to a more exhaustive recording of side effects. A strict comparison of the tolerance of all of these drugs is thus not possible. Hence, we will rather detail the side effects, and the way in which to control them, or even, to anticipate them. The tolerance of the association of drugs, which is usually used in severe hypercortisolism, will not be covered in this review.

Section snippetsSteroidogenesis Inhibitors

The use of all of these drugs can theoretically lead to adrenal insufficiency. The prevalence of adrenal insufficiency will be given for each drug, but this specific point will be addressed through the prism of a titration approach. Any patient on steroidogenesis inhibitor should be educated on the clinical signs of adrenal insufficiency, have a prescription of hydrocortisone, and be warned to call the treating endocrine department (or go to the emergency department) in case of suspicion of

a. Pasireotide

Pasireotide is a somatostatin receptor ligand (SRL) with high affinity to all somatostatin receptor subtypes, with the exception of subtype 4. It is thus of theoretical interest in Cushing’s disease due to its high affinity for somatostatin receptor subtype 5, the most abundantly expressed somatostatin receptor in corticotroph tumors. An extensive safety profile of pasireotide in pituitary diseases has been recently published (32). We will thus only describe here some points of interest,

The Glucocorticoid Receptor Antagonist Mifepristone

Mifepristone is the only available glucocorticoid receptor antagonist, and has an affinity for the glucocorticoid receptor which is 10-fold higher than that of cortisol (39). The mechanism of action leads to side effects mainly via 2 mechanisms: first, the blockade of pituitary glucocorticoid receptors leads to increased ACTH levels, and hence, increased cortisol levels, which can activate the mineralocorticoid receptor; second, mifepristone also has an antiprogestin activity, leading to a

Conclusions

Cushing’s disease is generally difficult to manage since transsphenoidal surgery does not cure all patients, and medical treatment is frequently required on a long-term basis. This implies the need for obtaining eucortisolism, which is sometimes difficult to determine with the currently available biochemical tools (assays of urinary free cortisol, salivary cortisol…) (26). It is thus important to know the safety profile of each of these drugs and the period after commencing treatment at which

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