Cushing's syndrome: from patients to proteins.

In 1932, Harvey Cushing reviewed the medical history of Minnie G and 11 other patients with a rapid weight gain confined to the face, neck, and trunk, but sparing the extremities (1). This adiposity was associated with kyphosis, amenorrhea or impotence, hirsutism, purplish lineae atrophicae, hypertension, and extreme weakness. Cushing concluded ‘that the peculiar polyglandular syndrome may accompany basophil adenoma in the absence of any apparent alteration in the adrenal cortex other than a possible secondary hyperplasia.’ Cushing’s reasoning was correct. The majority of patients with the syndrome that now bears his name suffer from adrenal hypersecretion of cortisol due to excess of corticotropin (ACTH). The basophilic cells in Cushing’s series were most likely expansions of the population of pituitary corticotropes. But what is the pathogenesis of ACTH hypersecretion? Why do some ‘silent’ pituitary tumors show histochemical evidence for ACTH production but do not hypersecrete it? And why are not all ACTH-secreting tumors associated with atrophy of the neighboring normal corticotropes which should be suppressed? Current research has begun to elucidate the answers to some of these questions. The anterior pituitary corticotropes produce ACTH by processing products of the pro-opiomelanocortin (POMC) gene (see Fig. 1). Up to 10% of normal subjects may harbor small, POMC-containing pituitary adenoma (2). These adenoma are endocrinologically silent, presumably due to production of inactive POMC peptides or peptides that are not secreted. In patients with Cushing’s Disease, the frequency of identifiable pituitary tumors is much greater. However, the pathological findings are sometimes classified as corticotrope hyperplasia rather than adenoma. This has led to two major outlooks on the pathogenesis of Cushing’s disease, i.e. the hypothalamic theory and the pituitary theory (3). Evidence favoring the hypothalamic theory is that many histopathological specimens are classified as hyperplasia rather than adenoma. Of course, this may be due to difficulty in interpreting pathology of small tumor fragments. However, excess corticotropin-releasing hormone (CRH) has been shown to produce Cushing’s disease in patients with ectopic CRH production and in transgenic mice that overexpress the CRH gene (4). Evidence favoring the pituitary theory, which proposes that mutated corticotropes give rise to neoplastic clones that produce excess ACTH, is that permanent cure results from successful resection of pituitary tumors in the majority of patients. Successfully treated patients regain normal circadian rhythms for ACTH and other pituitary hormones. The factors that may lead to the development of corticotrope neoplasms, whether entirely of pituitary or perhaps of hypothalamic origin, are yet to be identified. Although most corticotrope neoplasms are believed to arise from the anterior pituitary, there have been patients with ACTH-secreting tumors whose origins seem to have been from the intermediate lobe (2). In humans, the intermediate lobe is a rudimentary structure; however, in other species it is well developed and functions to regulate skin pigmentation. Intermediate lobe melanotropes produce a-melanocyte-stimulating hormone (a-MSH), an alternative splice product of POMC, which is generated by tissue-specific enzyme cleavage. The enzyme prohormone convertase 2 (PC2), a member