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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