Abstract
Cushing’s disease (CD) in a stricter sense derives from pathologic adrenocorticotropic hormone (ACTH) secretion usually triggered by micro- or macroadenoma of the pituitary gland. It is, thus, a form of secondary hypercortisolism. In contrast, Cushing’s syndrome (CS) describes the complexity of clinical consequences triggered by excessive cortisol blood levels over extended periods of time irrespective of their origin. CS is a rare disease according to the European orphan regulation affecting not more than 5/10,000 persons in Europe. CD most commonly affects adults aged 20–50 years with a marked female preponderance (1:5 ratio of male vs. female). Patient presentation and clinical symptoms substantially vary depending on duration and plasma levels of cortisol. In 80% of cases CS is ACTH-dependent and in 20% of cases it is ACTH-independent, respectively. Endogenous CS usually is a result of a pituitary tumor. Clinical manifestation of CS, apart from corticotropin-releasing hormone (CRH-), ACTH-, and cortisol-producing (malign and benign) tumors may also be by exogenous glucocorticoid intake. Diagnosis of hypercortisolism (irrespective of its origin) comprises the following: Complete blood count including serum electrolytes, blood sugar etc., urinary free cortisol (UFC) from 24 h-urine sampling and circadian profile of plasma cortisol, plasma ACTH, dehydroepiandrosterone, testosterone itself, and urine steroid profile, Low-Dose-Dexamethasone-Test, High-Dose-Dexamethasone-Test, after endocrine diagnostic tests: magnetic resonance imaging (MRI), ultra-sound, computer tomography (CT) and other localization diagnostics. First-line therapy is trans-sphenoidal surgery (TSS) of the pituitary adenoma (in case of ACTH-producing tumors). In patients not amenable for surgery radiotherapy remains an option. Pharmacological therapy applies when these two options are not amenable or refused. In cases when pharmacological therapy becomes necessary, Pasireotide should be used in first-line in CD. CS patients are at an overall 4-fold higher mortality rate than age- and gender-matched subjects in the general population. The following article describes the most prominent substances used for clinical management of CS and gives a systematic overview of safety profiles, pharmacokinetic (PK)-parameters, and regulatory framework.
Highlights
Both, Cushing’s disease (CD) and Cushing’s syndrome (CS), are rare diseases characterized by high cortisol blood levels and impairment of circadian oscillation [1]
CD derives from pathologic adrenocorticotropic hormone (ACTH) secretion usually triggered by micro- or macroadenoma of the pituitary gland [2]
Due to its hepatotoxic properties, oral formulations of Ketoconazole are no longer marketed as anti-fungal medicines as recommended by the European Medicines Agency (EMA) after the Committee for Medicinal Products for Human Use (CHMP) concluded that the risk of liver injury is greater than the benefits in treating fungal infections [60]
Summary
Both, Cushing’s disease (CD) and Cushing’s syndrome (CS), are rare diseases characterized by high cortisol blood levels and impairment of circadian oscillation [1]. Due to its hepatotoxic properties, oral formulations of Ketoconazole are no longer marketed as anti-fungal medicines as recommended by the European Medicines Agency (EMA) after the Committee for Medicinal Products for Human Use (CHMP) concluded that the risk of liver injury is greater than the benefits in treating fungal infections [60] In fungi it mechanistically acts as an ergosterole synthesis inhibitor by blocking various CYP-dependent enzymes, thereby explaining both, its hepatotoxic side-effects and its efficacy in Cushing’s treatment: Steroidogenesis in the zona fasciculata of the adrenal cortex mainly depends on CYP enzymes [61]. Therapy of Cushing’s syndrome in children First of all, in the pediatric population no final conclusion can be drawn on any of the medicines under investigation due to lack of pivotal evidence This is best reflected by the fact that the EMA accepted a waiver for clinical data from pediatric patients for centrally approved Pasireotide (a so-called “PIP-Waiver”; PIP, pediatric investigation plan). ➢ Depressive disorder [83] - evidence level S3 ➢ Arterial hypertension [84] - evidence level S2
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