GLUCOCORTICOID RESISTANCE IN MAN AND NEW WORLD PRIMATES (RECEPTOR, INSENSITIVITY, PROGESTERONE, ESTROGEN, MINERALOCORTICOID)

Target organ resistance to glucocorticoids occurs as a rare familial syndrome in man and in many New World primates. In man, the disorder is characterized by increased plasma and urinary free cortisol, resistance to adrenal suppression by dexamethasone and absence of stigmata of Cushing's syndrome. Hypertension and hypokalemic alkalosis may be present due to increased biosynthesis of sodium-retaining corticoids. New World primates have increased plasma and urinary free cortisol concentrations, and exhibit marked resistance to adrenal suppression by dexamethasone with no physiologic evidence of glucocorticoid or mineralocorticoid excess. Characteristics of the glucocorticoid receptor (GR) were studied in patients with the syndrome and in New World primates for alteration(s) that might explain their insensitivity to glucocorticoids. In several whole cell assays mononuclear leukocytes (MNL), cultured skin fibroblasts (SF), and Epstein-Barr virus transformed lymphocytes (TL) , the GR from a severely affected patient had low affinity for dexamethasone. Concentrations of GR were normal in MNL and SF. Induction of GR, which normally occurs during Epstein-Barr viral transformation, was diminished in B-lymphocytes from patients. Activation in vivo and nuclear content of GR were decreased in TL from the severely affected patient. Several properties of the GR (thermolability, mero-receptor formation and molecular mass) from TL of these patients, however, were normal. The GR of New World primates had low affinity for dexamethasone explaining the absence of pathophysiologic effects associated with glucocorticoid excess. The kidney aldosterone receptor, on the other hand, cross-reacted poorly with cortisol, explaining the lack of excess mineralocorticoid effect. Target tissues (MNL and SF) of the squirrel monkey had normal concentrations of GR when compared to Old World primates. Studies of TL from the marmoset, another New World primate, showed that GR induction, activation in vitro and nuclear content were all decreased. Since New World primates also have elevated concentrations of progesterone, estrogen, androgen and aldosterone without any pathophysiologic consequences, generalized steroid hormone resistance is implied. In these species, compensatory decreases in receptor concentrations for these steroids occur.