5
Antiglucocorticoid Effects of Antiprogestins

All antiprogestins studied to date have been found to have some antiglucocorticoid effects as well as antiprogestational effects (Baulieu, Appendix B1; Nieman, Appendix B10; Spitz and Bardin, in press). Although antiprogestins can be used as probes to study glucocorticoid function, their antiglucocorticoid effects are undesirable, and it would be preferable to have classes of pure antiprogestins and of pure antiglucocorticoids that would not display any other endocrine effects. Present knowledge is insufficient to set a rational strategy that would assure the synthesis of such pharmaceutical agents; therefore, the search now proceeds using empirical tactics and the outcome of this research is, as always in research, unpredictable.

GLUCOCORTICOID FUNCTION

Glucocorticoids are steroid hormones produced by the adrenal glands in response to stimulation by the pituitary hormone adrenocorticotropin (ACTH), which is in turn regulated by a hypothalamic hormone, corticotropin-releasing hormone. The control of glucocorticoid secretion is summarized by Nieman (Appendix B10). Briefly, production of cortisol, the main glucocorticoid, is stimulated by ACTH. ACTH secretion, in turn, is inhibited by increasing levels of cortisol. This process is termed negative feedback regulation. The system is fine-tuned, therefore, through a feedback control mechanism that is similar to those of many other hormone systems, including estrogen and gonadotropins in the reproductive system.

Glucocorticoids, like other steroid hormones, exert their biologic effects by binding to specific intracellular receptors. There are two



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 5 Antiglucocorticoid Effects of Antiprogestins All antiprogestins studied to date have been found to have some antiglucocorticoid effects as well as antiprogestational effects (Baulieu, Appendix B1; Nieman, Appendix B10; Spitz and Bardin, in press). Although antiprogestins can be used as probes to study glucocorticoid function, their antiglucocorticoid effects are undesirable, and it would be preferable to have classes of pure antiprogestins and of pure antiglucocorticoids that would not display any other endocrine effects. Present knowledge is insufficient to set a rational strategy that would assure the synthesis of such pharmaceutical agents; therefore, the search now proceeds using empirical tactics and the outcome of this research is, as always in research, unpredictable. GLUCOCORTICOID FUNCTION Glucocorticoids are steroid hormones produced by the adrenal glands in response to stimulation by the pituitary hormone adrenocorticotropin (ACTH), which is in turn regulated by a hypothalamic hormone, corticotropin-releasing hormone. The control of glucocorticoid secretion is summarized by Nieman (Appendix B10). Briefly, production of cortisol, the main glucocorticoid, is stimulated by ACTH. ACTH secretion, in turn, is inhibited by increasing levels of cortisol. This process is termed negative feedback regulation. The system is fine-tuned, therefore, through a feedback control mechanism that is similar to those of many other hormone systems, including estrogen and gonadotropins in the reproductive system. Glucocorticoids, like other steroid hormones, exert their biologic effects by binding to specific intracellular receptors. There are two

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 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). THERAPEUTIC USE OF MIFEPRISTONE (RU 486) AS AN ANTIGLUCOCORTICOID1 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, 1   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.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda ACTH secretion in the subset of patients with a defective feedback mechanism (Cushing's disease) will respond to changing concentrations of glucocorticoids. In patients with an ectopic ACTH-secreting tumor, it was possible to alleviate the deleterious effects of the high levels of cortisol in 7 of 11 subjects by using mifepristone at doses of 5 to 22 mg/kg per day for periods ranging from four weeks to one year (Chrousos et al., 1989). This study showed that mifepristone may have a role to play in the preoperative preparation for surgery of a patient with Cushing's syndrome caused by fixed cortisol secretion. By contrast, in Cushing's disease where cortisol secretion is not fixed but the system set point is altered, mifepristone was not effective in alleviating symptoms. In this case, the antiglucocorticoid activity of mifepristone actually enhances ACTH and cortisol secretion (Spitz and Bardin, in press). There are also potential therapeutic applications of mifepristone as a local antiglucocorticoid. Studies in rabbits have demonstrated that local application of eye drops containing mifepristone can lower intraocular pressure (Philips et al., 1984). Moreover, it is unlikely that enough mifepristone would be administered by this route to increase adrenal cortisol secretion. There have been no studies to date to evaluate the applicability of these data to humans. In addition to its use in the treatment of Cushing's syndrome, Spitz and Bardin (in press) discuss the use of mifepristone to counteract (antagonize) large doses of exogenous glucocorticoid given for therapeutic purposes. For example, Konagaya et al. (1986) used mifepristone to block dexamethasone-induced loss of muscle and body weight in rats. Mifepristone may have potential use in humans in the treatment of steroid-induced myopathy, such as that produced by dexamethasone when it is given as an anti-inflammatory agent; however, Spitz and Bardin (in press) point out that use of antiglucocorticoids for therapy would require selective antagonistic effects on muscle without reducing the beneficial effects for which the glucocorticoid was given. In other words, selective inhibition of the catabolic, but not the antiinflammatory, properties of glucocorticoids has, to date, eluded chemists trying to synthesize antiglucocorticoid agents. Use of mifepristone to antagonize endogenous cortisol might also be of benefit in a wide variety of disorders. Spitz and Bardin (in press) reviewed some of these potential uses such as attenuation of muscle atrophy associated with androgen withdrawal, denervation, and muscular dystrophy. In addition, Regelson et al. (1990; reviewed in Spitz and Bardin, in press) suggest that antagonism of the action of endogenous cortisol could prevent progression of certain viral diseases. However, systematic administration of antiglucocorticoids is likely to cause a compensatory increase in cortisol, which might blunt the desired effect.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Whether dose amounts and schedules can be developed that allow selective beneficial actions of glucocorticoid antagonists in the above settings will have to be established by clinical trials for each specific condition (Spitz and Bardin, in press). Glucocorticoid-induced animal or tissue culture models of hypertension, wound healing, cataracts, inflammation, and arthritis have suggested a potential role for antiglucocorticoids in these states. Whether these results will pertain in humans is largely unexplored (Nieman, Appendix B10). ADVERSE ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS Mifepristone has been used at doses of up to 10 mg/kg per day for as long as seven days with few adverse effects, including adverse antiglucocorticoid effects. Daily doses of more than 3 mg/kg given for more than seven days have been associated with fatigue in the majority of subjects (Grunberg et al., 1991); anorexia and nausea may also occur (Klijn et al., 1989; Bakker et al., 1990; Grunberg et al., 1991; Lamberts et al., 1991). These effects are consistent with relative adrenal insufficiency, and improve with administration of dexamethasone or other glucocorticoids; however, it is not completely clear that they represent adrenal insufficiency (Nieman, Appendix B10; Spitz and Bardin, in press). Clearly, for long-term antiprogestin therapy applied to conditions other than Cushing's syndrome, the antiglucocorticoid actions of these compounds are an undesirable side effect. For obvious medical reasons, it would be preferable to have separate classes of pure antiprogestins and of pure antiglucocorticoids that do not display any other endocrine effects. Recommendation No. 20. Antiglucocorticoid effects are an unwanted property of existing antiprogestins. Therefore, the committee recommends expanded efforts to produce pure antiprogestins that would not display any other endocrine effects at therapeutic doses. REFERENCES Bakker, G.H., Setyono-Han, B., Portengen, H., et al. Treatment of breast cancer with different antiprogestins: Preclinical and clinical studies. Journal of Steroid Biochemistry and Molecular Biology 37:789–794, 1990. Chrousos, G.P., Laue, L., Nieman, L.K., et al. Clinical applications of RU 486, a prototype glucocorticoid and progestin antagonist. Pp. 273–284 in The Adrenal Hypertension: From Cloning to Clinic. Mantero, F., Scoggins, B.A., Takeda, R., et al., eds. New York: Raven Press, 1989. Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Treatment of unresectable meningiomas

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda with the antiprogesterone agent mifepristone. Journal of Neurosurgery 74:861-866, 1991. Klijn, J.G.M., de Jong, F.H., Bakker, G.H., et al. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Research 49:2851–2856, 1989. Konagaya, M., Bernard, P.A., and Max, S.R. Blockage of glucocorticoid receptor binding and inhibition of dexamethasone-induced muscle atrophy in the rat by RU 38486, a potent glucocorticoid antagonist. Endocrinology 119:375–380, 1986. Lamberts, S.W., Koper, J.W., and de Jong, F.H. The endocrine effects of long-term treatment with mifepristone (RU 486). Journal of Clinical Endocrinology and Metabolism 73:187–191, 1991. Nieman, L.K., Chrousos, G.P., Kellner, C., et al. Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. Journal of Clinical Endocrinology and Metabolism 61:536–540, 1985. Regelson, W., Loria, R., and Kalimi, M. Beyond "abortion": RU 486 and the needs of the crisis constituency. Journal of the American Medical Association 264:1026–1027, 1990. Spitz, I.M., and Bardin, C.W. Clinical pharmacology of RU 486—An antiprogestin and antiglucocorticoid. Contraception, in press (also see: RU 486—A modulator of progestin and glucocorticoid action. New England Journal of Medicine, in press).