A physiologic approach to diagnosis of the Cushing syndrome.

The relationship among obesity, impaired glucose tolerance or diabetes, hypertension, and gonadal dysfunction was initially recognized in two clinical syndromes described early in the 20th century. In 1932, Harvey Cushing reported these findings as well as other features of endogenous hypercortisolism in patients with small basophilic pituitary adenomas (1). A decade earlier, two French physicians, Drs. Archard and Thiers, described a similar phenotype in the syndrome that is now recognized as the syndrome of insulin resistance (the metabolic syndrome) and the polycystic ovary syndrome (2). Recently, increasing evidence has shown that the Cushing syndrome is a reversible cause of the metabolic syndrome (3) and that it may be more common than previously thought. Some patients with incidentally discovered adrenocortical tumors have subclinical hypercortisolism and experience clinical improvement in diabetes, hypertension, and obesity after adrenalectomy; this illustrates the importance of discovering even mild cases of the Cushing syndrome (4). In addition, two recent studies found that 2% to 3% of patients with poorly controlled type 2 diabetes mellitus may have unrecognized Cushing syndrome (5, 6). The clinical and biochemical discrimination of true Cushing syndrome from the Cushing phenotype and the metabolic syndrome may be very difficult, particularly when hypercortisolism is mild. Since obesity, hypertension, diabetes, and lipid disorders are common in the general population, it is important for internists and other primary care physicians to be able to identify patients with the Cushing syndrome. This review demonstrates that an understanding of the physiologic characteristics of the hypothalamic–pituitary–adrenal axis is essential in formulating strategies to confirm the diagnosis of the Cushing syndrome as well as establish its cause.