Familial glucocorticoid resistance: an overview.

Abstract

Familial glucocorticoid resistance is an inherited form of generalized end-organ insensitivity to glucocorticoids, associated with qualitative and/or quantitative abnormalities of the glucocorticoid receptor. The glucocorticoid resistance syndrome is characterized by elevated plasma corticotropin (ACTH) and cortisol concentrations, set at higher levels but maintaining a circadian rhythm, and no clinical evidence of hypoor hypercortisolism. The clinical spectrum of this syndrome is broad, ranging from completely asymptomatic to mildly or severely symptomatic, characterized by manifestations of mineralocorticoid and/or androgen excess (Chrousos et al., 1982; Lamberts et al., 1986). The secretion of glucocorticoids is strictly regulated by an elaborate feedback system, the suprahypothalamic-hypothalamic-pituitary-adrenal-axis (SHPA) (Kellerwood and Dallman, 1984; Dallman et al., 1987; Jakobsen and Sapolsky, 1991): Corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), secreted by the hypothalamus, stimulate the release of ACTH by the pituitary gland. ACTH then stimulates secretion of glucocorticoids by the adrenal cortex. Glucocorticoids exert negative feedback effects on the hippocampus, the hypothalamus and the pituitary, presumably via the classic (Type II) glucocorticoid receptor and/or the mineralocorticoid receptor (glucocorticoid receptor type I) (De Kloet, 1991). By Experimental and