Resumen de New Molecular Targets for Treatment of Cushing’s Disease

Elizabeth Foulkes, John Newell-Price

• *NORMAL PHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS In considering potential new molecular targets for the treatment of Cushing’s disease, it is useful to consider first the normal physiologic regulation of ACTH synthesis and release. The normal hypothalamic-pituitary-adrenal axis relies on regulatory negative feedback from circulating cortisol levels.

  1Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are released from the paraventricular nucleus of the hypo- thalamus and act on pituitary corticotroph cells, in the anterior pituitary, to ultimately stimulate the release of adrenocorticotropic hormone (ACTH) into the circulation.

  2CRH acts by binding to the CRH-R1 receptor on the surface of the corticotroph cells, activating a stimulatory G-protein alpha subunit, and causing a downstream signaling cascade.

  The outcome of this signaling cascade is the promotion of proopiomela- nocortin (POMC) gene transcription, resulting in the synthesis of POMC and ACTH