Cortisol resistance in acquired immunodeficiency syndrome.

Abstract

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.

Cortisol Response Mediates HIV-1-Related Cognitive Deficits Among Injecting Drug Abusers

“…GC resistance is reported to exist in about 17% of HIV-1+ subjects and may result in a decoupling of circulating cortisol levels and corticosteroid receptor activity [31] . GC resistance can result from: a) a defect in translocation of GR receptors from the cytoplasm to the nucleus [32,33] b) an increased and prolonged CRH concentration presumably due to defective glucocorticoid negative feedback; and c) inflammatory cytokine induced hypercortisolemia. In addition, a novel complication has been introduced in this area by studies showing that an HIV auxiliary protein, vpr (viral protein R), interacts with glucocorticoid type II receptors [34,35] .…”

The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone.

“…Pituitary resistance to glucocortieoids in ICU patients could be caused by abnormalities in the transduction of the effects of glucocorticoids. Recently, a subgroup of acquired immunodeficiency syndrome patients was identified who had cortisol resistance characterized by elevated ACTH and cortisol concentrations and a diminished glucocortieoid receptor affinity in circulating mononuclear cells (30). Similar alterations in glucocorticoid receptor function may be partially responsible for changes in the HPA axis of ICU patients and could result in an augmented ACTH response to CRH.…”

Dysfunction of the Hypothalamic-Pituitary-Adrenal axis in HIV infection and disease

“…26 In these patients, glucocorticoid affinity to its ligand was reduced and the glucocorticoid receptor (GR) number was increased, suggesting a partial glucocorticoid resistance state. As mentioned above, this phenomenon might be due to altered cytokine action.…”