Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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B10. Uses of RU 486 as an Antiglucocoticoid
B10. Uses of RU 486 as an Antiglucocoticoid
Pages 229-242
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From page 229... ...
, the first potent glucocorticoid antagonist in viva, was hailed as a potential breakthrough both to expand knowledge about glucocorticoid action and to treat glucocorticoid-dependent disease states. This paper first reviews current concepts of the physiology of glucocorticoids and conundrums arising from this knowledge; second, it summarizes studies using RU 486; and third, it suggests promising areas of research.
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From page 230... ...
For this reason, daily urine free cortisol excretion is a better index of the integrated exposure of the body to cortisol, because it derives from unbound plasma cortisol. Finally, the number of glucocorticoid receptors in a given cell population may be regulated, usually inversely, by glucocorticoid exposure, so that exposure to glucocorticoids may induce a decrease of up to 50 percent in receptor number (Hoeck et al., 1989~.
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Additionally, as reviewed below, although a number of measures are known to be glucocorticoid sensitive or dependent, few end points of steroid action are easy to measure in the intact animal or person, especially acutely. One exception to this is the change in plasma ACTH levels.
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Although at normal circulating concentrations, only a small portion of cortisol is metabolized in this way, in states of glucocorticoid excess, both urine and plasma levels of 6,13-OHcortisol increase (Clore, 1992~. One controversial area of glucocorticoid physiology is the possibility that glucocorticoids act through nonclassical receptor mechanisms, either through intracellular receptors that are not type I or II, or through binding to membrane "receptors." The evidence for this activity derives from three sources: First, in certain animal models, glucocorticoids and progestins induce changes within minutes (Hue and Chen, 1989; Orchinik et al., 1991~.
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Adrenal insufficiency and Cushing's syndrome represent experiments of nature that illustrate the effects of too little and too much glucocorticoid. Although concomitant mineralocorticoid excess and deficiency may cloud consideration of pure glucocorticoid effects, the leitmotif of glucocorticoid action derived from observation of these diseases reveals the involvement of nearly all tissues and many physiologic processes.
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From page 234... ...
The rationale of this experimental design is that interruption of glucocorticoid negative feedback should increase CRH, ACTH, and eventually cortisol secretion to overcome RU 486 inhibition. A consistent dose-response relationship emerged: RU 486, at daily doses of 3-6 mold given for one to four days, caused a dose-dependent increase in pituitary or cortisol end points.
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Although no hepatic, hematologic, renal, or dermatologic toxicity was observed, three patients had nausea, one with prostration reminiscent of adrenal insufficiency. Two of three men developed gynecomastia (presumably because of antiandrogenic properties)
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Shortcomings of these studies include the failure to characterize tumor receptors and inclusion of a clinically diverse patient population, so that outcome could not be clearly correlated with clinical features. However, the observation that tumor size remained stable or decreased in two-thirds of individuals with previous progression indicates that RU 486 may be a promising treatment of their disease.
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Acute injection of RU 486 in rats increases oxygen consumption and brown adipose tissue activity, effects mediated by sympathetic activation and increased CRH levels. In lean animals, RU 486 inhibited weight gain without altering food intake (Hardwick et al., 1989~.
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This might be explained by activation of the HPA axis. These findings suggest that studies directed to elucidating RU 486 effects on the immune system should include doses of the agent that do not increase ACTH and cortisol levels.
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Specific indicators of immune function need to be developed that can be examined over a broad dose range, including doses below the threshold of activation of the HPA axis. The responses to a variety of schedules of administration, including alternate day, once weekly, and night versus morning, should be examined for time-of-day and time-course characteristics.
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8. Would RU 486 be an effective treatment of human glioma tumors in viva?
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Down-regulation and phosphorylation of glucocorticoid receptors in cultured cells. Investigations with a monospecific antiserum against a bacterially expressed receptor fragment.
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Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man: Toxicity, immunological, and hormonal aspects. Journal of Clinical Endocrinology and Metabolism 71:1474-1480, 1990.
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