Endocrine Abstracts

Cushing’s disease (CD) is often severe and debilitating and is caused by a POMC-expressing corticotrope tumour autonomously secreting ACTH to cause chronic hypercortisolism. Untreated CD is associated with excess mortality. The mainstay of management remains transsphenoidal surgery, but the overall long-term remission rate is a disappointing 55–60%. Compared to surgery for other states of pituitary hormone hypersecretion, there is an excess of new hypopituitarism, itself associated with excess mortality. Bilateral adrenalectomy may be needed to control disease but is associated with the risk of corticotrope tumour progression and Nelson’s syndrome. Pituitary radiotherapy delivered by any means is associated with hypopituitarism. Thus, overall management of hypercortisolism is not optimal, and improvements are needed to specifically control ACTH secretion.

What is surprising is the fact that some of the adverse effects of hypercortisolism persist even if remission is achieved. Even after a microadenomectomy the HPA axis is often suppressed for months to years (and occasionally permanently) with risk of adrenal insufficiency and need for glucocorticoid replacement. Recent molecular data suggest that part of the on-going HPA axis suppression is mediated by continued inhibition of POMC expression and its transcription factors by histone deacetylation. Excess mortality of CD appears to return to normal after remission, but several data show that cardiovascular risk remains, with a persisting metabolic syndrome characterized by insulin resistance. Osteoporosis appears to improve, but the effects of vertebral fracture remain. The improvement in hypercortisolaemia can also herald an increase in autoimmune disease. Whilst psychological impairment tends to improve in many, for some the most debilitating features are the persistence of cognitive and psychiatric disturbance and significantly impaired Quality of Life.