receptors that bind with high affinity to glucocorticoids; these have been dubbed the type I and type II receptors. The receptors and their involvement in glucocorticoid action are described in detail by Nieman (Appendix B10).
Several factors influence glucocorticoid actions on a given tissue. These include the type and amount of steroid available, and the number of glucocorticoid receptors. The number of glucocorticoid receptors in a cell is usually inversely regulated by glucocorticoid exposure, and glucocorticoid administration may decrease the number of receptors by as much as 50 percent (down-regulation). Moreover, the response to a specific dose of glucocorticoid may vary widely across tissues, so that a dose of steroid that elicits a maximal response in one tissue may elicit only a small response in another (Nieman, Appendix B10).
The importance and function of glucocorticoids are made clear by examining information from states of deficiency and excess. Cushing's syndrome and adrenal insufficiency are diseases of too much and too little glucocorticoid, respectively. These diseases involve nearly all tissues and many physiologic processes, including fuel consumption and economy, structural catabolism (especially of bone, collagen, and muscle), the immune system, and inflammation (Nieman, Appendix B10).
Nieman et al. (1985) were the first to use the antiglucocorticoid properties of mifepristone to treat Cushing's syndrome, a condition caused by excess glucocorticoid levels and characterized by depression, hypertension, carbohydrate intolerance, and gonadal and thyroid hormone suppression. Cushing's syndrome is a generic term describing chronic excess glucocorticoid production that may be secondary to ACTH secretion by a tissue other than the pituitary (ectopic secretion), or elevated ACTH due to a defective feedback mechanism in which the homeostatic regulatory mechanism does not function correctly (changed ''set point"). Ectopic secretion of ACTH is not responsive to the normally operative negative feedback by glucocorticoids. In contrast,
During the committee's work, Irving Spitz and C. Wayne Bardin of the Population Council shared with the committee an exhaustive review, "Clinical Pharmacology of RU 486: An Antiprogestin and Antiglucocorticoid," which the authors have submitted to Contraception. A shorter version of the manuscript is in press, in the New England Journal of Medicine . The following discussion borrows extensively from their manuscript.