Several pathogenic mechanisms have been proposed to explain the relative hypercortisolemia present in untreated HIV-positive individuals. First, the shift of steroid metabolism from aldosterone, DHEA, and 17-deoxysteroids to cortisol may represent an adaptive response to stress.2,3,5,6 Second, the cortisol-binding globulin of HIV-infected patients shows a higher number of binding sites compared with controls.20 Some authors have also found increased plasma concentrations of cortisol-binding globulin associated with progression of the disease,21 whereas others found normal levels of cortisol-binding globulin in all HIV disease stages.22 Third, the increased cortisol synthesis in the absence of an increase in corticotropin suggests that some nonpituitary factors derived from infected immune cells, such as interleukin (IL)-1β and IL-6,10,23,24 might directly stimulate the adrenal cortex. In patients with hypercortisolemia and increased corticotropin levels, these abnormalities may result from a stimulatory effect of cytokines (eg, interferon-α, IL-1β, IL-2, and IL-6)25 or the HIV envelope protein gp12026 on the hypothalamic corticotropin-releasing hormone release. However, patients with advanced HIV disease often have reduced or blunted pituitary-adrenal responsiveness to corticotropin-releasing hormone infusion,27 and cases of secondary adrenal insufficiency with normal corticotropin stimulation tests have been described.28 Fourth, some patients with AIDS have a syndrome of peripheral cortisol resistance due to acquired abnormalities of the glucocorticoid receptor (GR), characterized by an increase in GR density and a decrease in GR affinity for the substrate.29 These individuals have a high-cortisol, low-corticotropin state with paradoxical Addisonian features, but it is conceivable that a clinical spectrum exists, ranging from subclinical alterations to overt adrenal failure. Finally, the HIV vpr gene product has been reported to act as a GR coactivator in human lymphoid and muscle-derived cell lines,30 which could result in an enhanced effect of glucocorticoids on the target cells.