The Cushing Syndrome: Quest for the Holy Grail

The endogenous Cushing syndrome results from excessive cortisol secretion that is usually secondary to excessive adrenocorticotropin (ACTH) secretion. About 85% of patients with the ACTH-dependent Cushing syndrome have ACTH-secreting pituitary microadenomas (Cushing disease). Most of the remaining patients have ACTH-secreting nonpituitary tumors (the ectopic ACTH syndrome), usually small-cell lung carcinomas, and follow an acute clinical course different from that of patients with Cushing disease [1]. However, about one fifth of patients with the ectopic ACTH syndrome have indolent tumors (usually bronchial carcinoids) and may present with a clinical picture indistinguishable from that of Cushing disease. Further, the classic test for distinguishing between the two, the high-dose dexamethasone suppression test [2], is unreliable in at least half of patients with bronchial carcinoids [3-5].

Investigators at the National Institutes of Health (NIH) began to recruit patients with the Cushing syndrome in the early 1980s to explore the diagnostic usefulness of newly available corticotropin-releasing hormone. They have now studied more than 500 patients for several weeks each, have subjected them to multiple diagnostic test procedures with contemporary adrenal steroid and ACTH assays, and have amassed an enormous and unique database on this uncommon endocrine disorder. Having popularized petrosal sinus sampling [6], they now seek noninvasive, alternative differential diagnostic procedures. In this issue, Avgerinos and colleagues [7] compare the metyrapone stimulation [8] and high-dose dexamethasone suppression [2] tests for the differential diagnosis of the ACTH-dependent Cushing syndrome. They confirm that each test is useful and that both are better than either alone. Although this is reassuring, I have concerns about this latest in the series of articles resulting from this clinical investigation project, as I have had about some others [9, 10].

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