Cushing's syndrome and pituitary tumors: Pathophysiology and ocular manifestations of ACTH-secreting pituitary adenomas

Abstract

The “dyspituitarism” which Harvey Cushing originally ascribed to pituitary basophilic adenomas is now known to be the result of increased levels of adrenal cortical hormones, and the naturally occurring forms of Cushing's syndrome are most commonly associated with bilateral adrenal hyperplasia (50 to 70 per cent of cases). Clinically demonstrable pituitary tumors are found in only about 10 per cent of patients with Cushing's syndrome. Present evidence suggests that Cushing's syndrome with bilateral adrenal hyperplasia, with or without an overt pituitary tumor, is the consequence of inappropriate control and excessive secretion of corticotrophin-releasing factor (CRF). This derangement in neuroendocrinologic function occurs at least at the level of the hypothalamus, and possibly even higher in the limbic system of the brain. Excessive hypothalamic stimulation causes elevated levels of CRF, resulting in increased secretion of ACTH by the pituitary gland, which then induces bilateral adrenal hyperplasia with increased serum cortisol levels and the resultant metabolic and clinical stigmata of Cushing's syndrome. Although only about 10 per cent of patients with Cushing's syndrome have clinically recognizable pituitary tumors, when present these tumors are apt to be unusually aggressive, undergoing rapid expansion and compression, and even invasion of supra- and parasellar structures; rarely, extracranial metastases are seen. When pituitary tumors are associated with Cushing's syndrome, they are usually composed of agranular ACTH-secreting chromophobe cells, rather than the classically described basophilic adenomas. Adrenalectomy, especially total adrenalectomy performed in patients with bilateral adrenal hyperplasia for alleviation of the endocrinopathy, may serve as the “triggering mechanism” responsible for the clinical appearance and rapid growth of the pituitary tumors. The ophthalmologic signs and symptoms of the pituitary tumors which occur with Cushing's syndrome are outlined in this review and compared with the less severe visual disorders which have been well described in association with the more common nonsecretory chromophobe adenomas.