Diagnostic work-up of ACTH-dependent Cushing's syndrome in the context of CRH shortage: recommendation of a task force from the European Society of Endocrinology

The company that has been the main worldwide supplier of corticotropin-releasing hormone (CRH) provided recently the statement that CRH is not being manufactured anymore due to the breakdown of essential production equipment.1 The unavailability of stock duration is currently unknown, and there is no clear indication on future timelines. This imposes a threat on the availability of CRH. While other suppliers of CRH may emerge, alternative diagnostic approaches are required, particularly for the work-up of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), where CRH is most useful. Therefore, the European Society of Endocrinology (ESE) has established a task force to provide recommendations on how to deal with this issue. Here, we present the key recommendations of our group; a more extended version is available at the ESE website.2 CRH has been extensively used as a testing agent for differential diagnosis of ACTH-dependent CS.3–5 CRH stimulation test aims to distinguish between pituitary and extra-pituitary ACTH source, and its usefulness is clearly stated in current guidelines on CS.6–8 In contrast to non-pituitary ACTH-dependent CS, CRH administration leads to a rise in plasma ACTH and serum cortisol in most patients with pituitary ACTH-dependent CS.5,9–12 Consequently, ACTH and cortisol responses to CRH can be useful in the diagnosis of ACTH-dependent CS, although it should be used with other biochemical and imaging procedures.6,7 However, in the absence of CRH, alternative tests (discussed below) can be used for the differential diagnosis of ACTH-dependent CS. Combining the various biochemical and imaging diagnostic tests may increase the sensitivity and specificity of investigations in ACTH-dependent CS.13–15