Hypercortisolism is a disorder characterized by excessive circulating cortisol from either endogenous or exogenous sources, which can cause detrimental changes to nearly every organ system. Collectively, the ravages of hypercortisolism are best classified as Cushing's syndrome (CS). The term Cushing's syndrome is used for all causes of hypercortisolism, and the term Cushing's disease is reserved specifically for cases of pituitary-dependent CS. The most common cause of CS is exogenous administration of glucocorticoids, which are used for their beneficial antiinflammatory, antineoplastic, and immunosuppressive effects. This chapter focuses solely on endogenous CS and is a summary of our recent review at the Mayo Clinic in Rochester, Minnesota.1
The incidence of CS is approximately two cases per 1 million persons per year.1 Patients who are not cured by surgical intervention or with malignant disease have a poor prognosis, with a standard mortality ratio of 3.8 to 5.0 compared with normal control subjects. Adrenocorticotropic hormone (ACTH)–dependent causes account for 80% of all cases of endogenous CS, with the majority of them (85%) attributed to pituitary-dependent causes; only 15% of cases are caused by ectopic production of ACTH or corticotropin-releasing hormone (CRH). The remaining 20% of cases of endogenous CS are caused by ACTH-independent CS. Specifically, 10% of all cases of endogenous CS are attributed to adrenal adenomas, 5% to 8% are attributed to adrenocortical carcinomas (ACCs), and the remaining 2% to 5% to ACTH-independent macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenal disease (PPNAD) (Figure 14-1).1–3
Classification of endogenous Cushing's syndrome (CS) in adults. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone. (Reproduced with permission from Porterfield JR, Thompson GB, Young WF, et al. Surgery for Cushing's syndrome: a historical review and recent ten-year experience. World J Surg 2008;32(5):659-677.)
Because of the multiplicity of causes, there is no single risk factor or set of risk factors associated with CS. However, a common factor that is present in individuals with CS is a female predilection, with the exception being CS caused by ectopic ACTH production, which is slightly more common in men. In our recent 10-year review of 288 patients who underwent surgery for CS at the Mayo Clinic, women accounted for 79% of all cases of pituitary-dependent CS, 81% of adrenocortical adenomas, and 90% of ACCs. However, among patients with ectopic ACTH syndrome, men are affected slightly more often than women at 54%.1
In 1912, Harvey Cushing described a 23-year-old woman, "Minnie G.," with moon facies, obesity, amenorrhea, and hirsutism.4 It was not until 20 years later that he postulated that this "polyglandular syndrome" was caused by a primary pituitary abnormality that resulted in adrenal hyperplasia. This full-blown clinical picture is not always present, so one must maintain a high index of suspicion when this condition is suspected. In adults, weight gain and centripetal obesity ...