1. How do high-dose (i.e., supraphysiologic) steroids work to reduce edema/inflammation? If this is not mediated through classical receptors, maybe RU 486 would not induce the same effect, and RU 486 could be given with high-dose glucocorticoids to prevent iatrogenic Cushing's syndrome while allowing the desired effect.

  2. What are the characteristics of the nonclassical steroid binding sites, membrane, mitochondrial, and cytoplasmic? What is their physiologic significance? Does RU 486 interact with these sites and if not, can it be used in conjunction with steroids to reduce biologic glucocorticoid mediated by classical mechanisms?

  3. What about the use of RU 486 as an antiandrogen—especially topically—in the prevention or treatment of acne, for example, that would exploit both antiglucocorticoid and antiandrogen properties? What about its use to prevent balding?

  4. Would RU 486 be an effective treatment of human glioma tumors in vivo?

  5. Can better glucocorticoid-sensitive end points be developed so as to more efficiently and specifically evaluate the effects of both glucocorticoid agonists and antagonists?

  6. RU 486 deserves further study as a modulator of fuel economy. The well-known importance of cortisol to lipid metabolism and as a counterregulatory hormone for glucose homeostasis suggests that investigation of dose-response and regimen relationships with RU 486 may be fruitful.

In conclusion, RU 486 is a promising compound deserving of further investigation as a physiologic probe and treatment for glucocorticoid-dependent states.

REFERENCES

Bertagna, X., Bertagna, C., Laudat, M.-H., et al. Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing syndrome. Journal of Clinical Endocrinology and Metabolism 63:639–643, 1986.

Bertagna, X., Bertagna, C., Luton, J.-P., et al. The new steroid analog RU 486 inhibits glucocorticoid action in man. Journal of Clinical Endocrinology and Metabolism 59:25–28, 1984.

Bertagna, X., Basin, C., Picard, F., et al. Peripheral antiglucocorticoid action of RU 486 in man. Clinical Endocrinology 28:537–541, 1988.


Chrousos, G.P., and Gold, P.W. The concepts of stress and stress system disorders: Overview of behavioral and physical homeostasis. Journal of the American Medical Association 267:1244–1247, 1992.

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 and Hypertension: From Cloning to Clinic. Mantero, F., Scoggins, B.A., Takeda, R., et al., eds. New York: Raven Press, 1989.



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