B10
Uses of RU 486 as an Antiglucocorticoid

LYNNETTE KAYE NIEMAN, M.D.

Senior Investigator,

Developmental Endocrinology Branch,

National Institute of Child Health and Human Development,

National Institutes of Health, Bethesda

Physiologic exposure to glucocorticoid hormones is required for life: both deficiency and excess are lethal. It is surprising, given the importance of these steroids, that much about their action is unclear. The availability of RU 486 (mifepristone), the first potent glucocorticoid antagonist in vivo, 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.

HOW DO GLUCOCORTICOIDS ACT?

Glucocorticoids are steroidal hormones produced and secreted into the bloodstream by the adrenal glands in response to stimulation by the pituitary hormone adrenocorticotropin (ACTH). The synthesis and secretion of ACTH are stimulated, in turn, by corticotropin-releasing hormone (CRH), which is synthesized by the hypothalamus and secreted into portal vessels so as to reach the corticotrope cells of the pituitary gland. CRH secretion is increased by a variety of stimuli, many of which can be considered biologic stressors: states of chronic and acute psychological or physical stress are presumed to increase CRH secretion (Chrousos and Gold, 1992). The system is returned to balance by the negative influence, or feedback, of high levels of glucocorticoids on both CRH and ACTH secretion. Thus, low levels of cortisol, the major glucocorticoid in people, provoke an increase in ACTH that is sustained



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda B10 Uses of RU 486 as an Antiglucocorticoid LYNNETTE KAYE NIEMAN, M.D. Senior Investigator, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda Physiologic exposure to glucocorticoid hormones is required for life: both deficiency and excess are lethal. It is surprising, given the importance of these steroids, that much about their action is unclear. The availability of RU 486 (mifepristone), the first potent glucocorticoid antagonist in vivo, 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. HOW DO GLUCOCORTICOIDS ACT? Glucocorticoids are steroidal hormones produced and secreted into the bloodstream by the adrenal glands in response to stimulation by the pituitary hormone adrenocorticotropin (ACTH). The synthesis and secretion of ACTH are stimulated, in turn, by corticotropin-releasing hormone (CRH), which is synthesized by the hypothalamus and secreted into portal vessels so as to reach the corticotrope cells of the pituitary gland. CRH secretion is increased by a variety of stimuli, many of which can be considered biologic stressors: states of chronic and acute psychological or physical stress are presumed to increase CRH secretion (Chrousos and Gold, 1992). The system is returned to balance by the negative influence, or feedback, of high levels of glucocorticoids on both CRH and ACTH secretion. Thus, low levels of cortisol, the major glucocorticoid in people, provoke an increase in ACTH that is sustained

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda until cortisol levels increase; high levels of cortisol inhibit ACTH secretion. One feature of this hypothalamic-pituitary-adrenal (HPA) axis is the presence of a diurnal rhythm, so that the ACTH nadir occurs in the early morning hours, followed by increasing levels during the night that stimulate cortisol to peak levels in the morning (around 8:00 a.m.). Both ACTH and cortisol values decline to very low levels in the evening between 10:00 p.m. and 2:00 a.m. Glucocorticoids, like other steroid hormones, are thought to exert their biologic effects by binding to an intracellular receptor specific to each class of steroid. The steroid-receptor complex can bind specifically to sites on DNA called response elements and thereby alter rates of transcription of genes. This type of genomic response involves subsequent protein synthesis and is usually detected within hours of exposure to steroids. Importantly, the outcome may be to either increase or decrease an end point. Full expression of the expected effect is deemed a full "agonist" effect. A reduction in the observed effect after the addition of another steroid can be considered "antagonism." When given alone, the second steroid may have a suboptimal agonist effect (partial agonist) or have only antagonist effects. A number of factors influence glucocorticoid effects on a given tissue. These include the type and amount of the glucocorticoid available and the number of intracellular glucocorticoid receptors. About 95 percent of the circulating cortisol in man is bound to corticosteroid-binding protein (CBG). Since only the free, or unbound, cortisol is available for entry into the cells, conditions that alter CBG levels may alter transiently the availability of glucocorticoids to the cells, until a new steady state is achieved by alteration in ACTH, and hence cortisol production and the free cortisol fraction. Studies in man involving agents that compete with cortisol for CBG sites, or agents that do not bind to CBG, and studies in rats, which have no corticosteroid-binding protein, must be interpreted with this in mind. The diurnal rhythm of circulating cortisol already mentioned illustrates the concept that the plasma glucocorticoid concentration may not reflect accurately the physiologic status: circulating levels vary up to 30-fold over a day in normal individuals. 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). Also, the number of glucocorticoid receptors may vary in relation to the cell cycle in in vitro systems. Whether these observations hold in vivo is not known. For these

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda reasons, knowledge of the circulating level of glucocorticoids within the physiologic range does not predict well the biologic response. However, measurement of the production of cortisol, either indirectly by using urine free cortisol excretion or more directly by using radioactive or deuterium-labeled cortisol, is useful clinically to distinguish normal from excessive exposure to cortisol and to predict the presence of the signs of hypercortisolism. The study of glucocorticoids is complicated vastly by the differences in the response of various tissues to any given concentration of steroid. In other words, a concentration or dose of steroid that elicits a maximal response in one tissue may elicit only a very small response in another tissue. 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. This end point responds rapidly to changes in cortisol and is relatively easy to obtain. For these reasons ACTH is often used to assess glucocorticoid action. The classical model of steroid hormone action described above fits many of the known effects of glucocorticoids. Other observations do not conform to this model, however. Some of these have stimulated research that has resulted in important new physiologic insight and modification of the model; other observations remain unexplained. Within the last few years the intracellular receptors for the major classes of steroid hormones have been found to be structurally related, with a high degree of homology. The site conferring specificity is the site that binds to the hormone itself (Evans, 1988). Application of techniques of molecular biology led to the discovery of two receptors that bind with high affinity to glucocorticoids, dubbed the type I and II receptors. Interestingly, the type I receptor also binds aldosterone, the principal circulating mineralocorticoid in man (Funder et al., 1988). This led to the conundrum of how aldosterone can function as the major mineralocorticoid in the presence of much higher circulating levels of cortisol. It appears that the kidney is protected from the mineralocorticoid activity of cortisol by rapid metabolism of cortisol to its 11-keto analogue, cortisone, by the enzyme 11ß-hydroxysteroid dehydrogenase. Since cortisone does not bind to the type I glucocorticoid receptor, this mechanism leaves aldosterone as the specific agonist of the type I receptor in the kidney. This observation elicits questions about the regulation of this enzyme in the kidney and at other sites of glucocorticoid action. There is some indication that the enzyme activity is increased by exposure to glucocorticoids, perhaps even within the physiologic range, but dose-response relationships have not been studied extensively (Hammami and Siiteri, 1991). Similarly, the intracellular

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda metabolism of cortisol to other compounds with glucocorticoid activity has not been studied extensively and may contribute to glucocorticoid activity. One such possibility is the conversion of cortisol to 6ß-OH-cortisol in the liver and kidney. 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 6ß-OH-cortisol 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 (Hua and Chen, 1989; Orchinik et al., 1991). The time course of response, and the inability to block the response with agents that inhibit protein synthesis, suggest strongly that this is a nongenomic response (i.e., not mediated through interaction with DNA). Such plasma membrane-mediated activity has been observed with thyroid hormone (Lawrence et al., 1989) but is not considered a classic effector mechanism of steroid hormones. Second, binding studies of labeled steroids with subcellular fractions have shown specific high-affinity binding to mitochondrial and synaptosomal (cell membrane) fractions (with Kd in the nanomolar range for corticosterone). The signature of binding to a variety of steroids, the pattern of the binding curves, and the ability to isolate membranes and not cytosol, suggest that these are not type I or type II receptors. Third, some effects of glucocorticoids, such as restoration of adrenal phenylethanolamine N-methyltransferase activity after hypophysectomy (Margolis et al., 1966), require glucocorticoid doses that are far in excess of those needed to occupy all classical receptors, thus suggesting that the response is not mediated via this mechanism. Research into these currently heretical areas of steroid action promises to increase our understanding of steroid physiology. Finally, the concept of homeostasis should be considered. When intact, laboratory animals and people tend to maintain themselves in a normal physiologic state, with outcome parameters that fluctuate within a defined "normal" range. This concept is implicit in the consideration of health and disease, since disease is often defined as the extent of variation from the physiologic norm. However, when exploring mechanisms of action or when focusing on a specific end point, experiments often disrupt physiologic mechanisms designed to maintain homeostasis. Thus, pieces of the organism, such as cells or parts of cells, are isolated, or experiments are conducted over very short periods of time so that the compensatory mechanisms are not yet operative. It is especially important to remember the principle of homeostasis when

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda predicting a potential clinical use of a compound based on data from in vitro or subhuman models. Thus, in evaluating glucocorticoid action, the following principles should be kept in mind: Binding of a hormone to a receptor does not predict whether the biologic response will be agonist, antagonist, or mixed. These outcomes must be determined experimentally and may vary between tissues and species. Likewise, dose-response relationships do not generalize from one tissue, outcome measure, or species, to another. The bioavailability, pharmacokinetics, and metabolism of the agent must be determined for each species and physiologic condition (such as gender). The entire animal/person must be studied. Other known actions and unexpected effects should be sought. Initial short-term studies must be extended to evaluate chronic effects that are not initially apparent. PHYSIOLOGIC ROLE OF GLUCOCORTICOIDS What are the physiologic roles of glucocorticoids in people and how could RU 486 be used as an antiglucocorticoid? The importance of glucocorticoids has been inferred largely from states of deficiency and excess. 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. Important among these are effects on fuel disposition and economy, structural catabolism (especially of bone, collagen, and muscle), and the immune system and inflammation. Effects on fuel metabolism seen in sub- and supraphysiologic exposure to glucocorticoids range from hypo- to hyperglycemia (loss of cortisol counter-regulation to insulin resistance), and lipolysis to lipogenesis with muscle catabolism. Excessive glucocorticoids reduce inflammation at the expense of increased susceptibility to infection. Structural integrity of bone, muscle, and skin is reduced by glucocorticoid excess, but does not appear to be increased in adrenal insufficiency. Activation of the hypothalamic-pituitary axis includes increased levels of CRH and pro-opiomelanocorticotropin (POMC) products as well as glucocorticoids and other adrenal products. CRH probably has important actions on the sympathetic nervous system and may participate in apparent "glucocorticoid" modulation of reproductive, immu-

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda nologic, and metabolic function (Chrousos and Gold, 1992). The HPA axis may be activated by stressful conditions with specific behavioral phenotypes (anxiety, major affective disorders); conversely, there is evidence that administration of components of the axis, such as CRH, glucocorticoids, and POMC products, modulates behavior. RU 486 AS AN ANTIGLUCOCORTICOID RU 486 represents the first clinically active glucocorticoid antagonist, and has been used to probe glucocorticoid action and to treat conditions known or suspected to be glucocorticoid sensitive or dependent. The remainder of this paper reviews these studies, and concludes with speculations about other potential uses and further studies to be performed. The antiglucocorticoid activity of RU 486 was first demonstrated in women undergoing induced abortion (Herrmann et al., 1982) and in normal men in acute dose-response studies using ACTH/lipotropin (LPH) and cortisol levels as end points (Bertagna et al., 1984; Gaillard et al., 1984). 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 mg/kg given for one to four days, caused a dose-dependent increase in pituitary or cortisol end points. The effect at 3 mg/kg was transient and was not observed at lower doses. Interestingly, regardless of the time of administration of RU 486 (morning versus evening), the hormonal effect was observed only in morning values, so that the diurnal rhythm was maintained and amplified. The ability of dexamethasone, 1 mg at midnight, to suppress morning cortisol values was completely antagonized by RU 486, 6 mg/kg. Although the apparent "resistance" of the HPA axis to RU 486 effects during the evening hours (8:00 p.m.–2:00 a.m.) remains unexplained, the persistence of a demonstrable effect 24 hours after morning administration of RU 486 may be explained in part by its long plasma half-life of around 20 hours. Patients with Cushing's syndrome, studied in a similar way by using ACTH and cortisol as response measures, had different responses depending on the etiology of Cushing's syndrome. Patients with Cushing's disease, in whom an ACTH-producing pituitary tumor retains many of the normal physiologic regulatory mechanisms, responded to RU 486 with increased cortisol levels. By contrast, patients with other causes of Cushing's syndrome (in whom hypercortisolism presumably suppressed activity of normal ACTH-producing pituitary corticotropes) showed no response to RU 486 (Bertagna et al., 1986). In principle, administration of a glucocorticoid antagonist would

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda represent an ideal treatment of Cushing's syndrome. The short-term studies discussed above demonstrated that the compensatory homeostatic mechanisms of ACTH-producing tumors would probably preclude effective therapy, because the tumor would likely continue to increase ACTH production. In patients with long-standing hypercortisolism not caused by Cushing's disease, however, RU 486-induced antagonism of peripheral glucocorticoid effects presumably would not be overcome. This concept was tested in a few patients with ectopic ACTH secretion and proved correct. At daily doses of 5–22 mg/kg, RU 486 reversed psychosis, hypokalemia, hypertension, weight gain, inhibition of luteinizing hormone, follicle-stimulating hormone, testosterone, thyroid-binding globulin (TBG), corticosteroid-binding protein (CBG), and T4, and restored euglycemia. In most patients there was little effect on cortisol or ACTH levels, although cortisol, but not ACTH levels, fell in an occasional patient, suggesting a potential effect on steroidogenesis (Nieman et al., 1985; Chrousos et al., 1989). The compound worked best in patients with sustained, invariant hypercortisolism. We have given RU 486 to seven such patients for six weeks to a year, with excellent results, either as preoperative preparation or while seeking to localize and remove an ACTH-secreting tumor. Three patients had no adverse side effects. 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), and one had an unmasking of autoimmune thyroid disease (not uncommonly seen after successful reversal of Cushing's syndrome). RU 486 was discontinued in one patient with variable cortisol levels, for whom it was not possible to find an optimal daily dose. The agent was discontinued within three weeks, and dexamethasone was instituted, in three others in whom hypotension and clinical deterioration suggested either sepsis or RU 486-induced adrenal insufficiency. Of these, one developed Pneumocystis carinii pneumonia. Thus, while RU 486 can be an effective agent for the treatment of hypercortisolism, it is difficult to monitor therapy and adjust dose because of the temporal pattern of response, and the risk of adrenal crisis alternating with undertreatment is great in patients with variable hormonogenesis. RU 486 has potential activity as a tumoricidal agent in tumors with glucocorticoid or progesterone receptors, and has been tested in breast cancer, leiomyomas (reviewed elsewhere in this report) and meningiomas. The effects of RU 486, 200 mg/day, given for up to a year, have been reported in 38 patients with meningioma (Lamberts et al., 1991; 1992; Grunberg, 1993). Regression of tumor size was documented by objective measures in about 30 percent of patients; in the remainder, responses were evenly divided between tumor stabilization and growth.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Pain decreased and subjective well-being improved in a majority. Signs of adrenal insufficiency developed within three weeks of initiation of therapy in about half of the patients in one study, prompting concomitant prednisone therapy (Lamberts et al., 1992). Activation of the adrenal axis was apparent, with increased urine cortisol values, and gradual increase in adrenal androgens, leading to follicular phase estrogen values, presumably via peripheral conversion. Although all women were amenorrheic during the study, one developed bleeding shortly after discontinuation of RU 486 and had endometrial hyperplasia. In the other study, 11 of 14 patients complained of mild to moderate fatigue; 5 had hot flushes (including 3 of 6 men); 3 of 6 men developed gynecomastia; 2 of 6 postmenopausal women had transient alopecia; and both premenopausal women were amenorrheic. 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. RU 486 has also been tested in a rat model of fibrosarcoma, where it retarded tumor growth even in intact, nonadrenalectomized animals (Laue et al., 1988b), and in human glioma cells in vitro, where it inhibited dexamethasone-induced stimulation of growth (Langeveld et al., 1992). Notably, the glucocorticoid effects correlated with the level of expression of the glucocorticoid receptor, suggesting that gliomas with high expression of glucocorticoid receptors might respond to RU 486 treatment in vivo. This concept has not been tested, however. Other potential clinical uses for RU 486 have been suggested by disease states or by use of the agent as a probe of glucocorticoid function. Glucocorticoid-induced animal or tissue culture models of hypertension, wound healing, cataracts, inflammation, and arthritis have suggested a potential role for RU 486 in these states. Whether these results will pertain in people is largely unexplored. Apart from local/topical administration, systemic administration is likely to result in a compensatory increase in cortisol that may blunt the desired effect of RU 486. Dexamethasone induces hypertension in rats that is effectively prevented or reduced by the addition of RU 486 but not mineralocorticoid antagonists (Kalimi, 1989). Hypertension in Cushing's syndrome can be reversed by RU 486 treatment also (Nieman et al., 1985). Taken together, these observations suggest that glucocorticoid hypertension is mediated through the type II glucocorticoid receptor. It is possible, however, that in states of marked cortisol excess, the ability of 11ß-hydroxysteroid dehydrogenase to metabolize cortisol is decreased, so that some cortisol

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda accesses the type I receptor. A conflicting observation was made by Watlington and colleagues, who showed that cortisol-induced sodium retention and hypertension could not be reversed by RU 486 (type II receptor antagonist) or the potent type I receptor antagonists spironolactone or 9a-fluorohydrocortisone (Clore et al., 1992). This group has proposed that other intracellular metabolites of cortisol, such as 6ß-cortisol, acting through another receptor, may have sodium-retaining and hypertensive effects. This concept was derived from studies using A6 cells derived from kidney of Xenopus laevis. 6ß-OH-Corticosterone, the major metabolite of corticosterone in these cells, binds to a third type of receptor (dubbed the type IV receptor) with half-maximal occupancy at an extracellular corticosterone concentration one order of magnitude higher than the physiologic level (3 × 10-7 versus 10-8 M). Occupancy of type IV receptors is postulated to be important in the presence of high circulating glucocorticoid levels or if activity of the 6ß-OH enzyme is altered. Although data regarding the presence of a type IV receptor in man are not available, other evidence for this hypothesis is the increased urinary 6ß-OH-cortisol excretion in some hypertensive patients, including those with Cushing's syndrome, toxemia of pregnancy, and hypothyroidism. The concept of local renal alteration in cortisol metabolism as a cause of some forms of hypertension is an intriguing hypothesis deserving further investigation. The activity of renal 6ß-hydroxylation appears to be increased by glucocorticoids, but its regulation is not well understood. In particular, the effect of RU 486 on the fractional excretion of 6ß-OH-cortisol is not known. 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). A similar preliminary study evaluating fuel metabolism after acute administration of RU 486 to men showed no effect on metabolic rate, however (Garrel, 1993), and chronic administration of RU 486, 200 mg/day, to patients with meningioma, did not alter weight (Grunberg et al., 1993). Thus, any potential lipolytic or anorexic effect of RU 486 in people remains to be elucidated. The effects of RU 486 on inflammation and the immune system have been studied largely in animal or in vitro models involving dexamethasone-induced alterations (Emilie et al., 1984; Laue et al., 1988a; Van Voorhis et al., 1989). In these systems, RU 486 antagonizes dexamethasone effects. It is important, however, to study the effects of RU 486 in individuals not receiving exogenous glucocorticoids. One such study showed no effect of chronic (14-day) administration of RU 486, 10 mg/kg per day, on the total and differential white cell counts, or of T, B, and NK cell phenotypes in normal men. The cytotoxic and proliferative

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda responses of lymphocytes, the erythrocyte sedimentation rate, C reactive protein concentration and quantitative immunoglobulin G levels were unaltered (Laue et al., 1990). A similar lack of effect on blood leukocyte counts was shown in another acute study (RU 486, 400 mg; Bertagna et al., 1988). It is likely that the compensatory increase in cortisol after RU 486 administration at these doses may cancel out or mask any effects of RU 486 in an intact person. Bimodal effects on inflammation have been noted in some rat models, in which an inflammation-promoting action was abolished at higher doses. 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. It may be of interest also to examine effects on the immune system that might be discerned in the evening after a morning dose of RU 486, while bearing in mind the finding that cortisol levels increase after RU 486 only at certain times of day. This feature may allow enhancement of the immune system at times when cortisol levels remain ''normal." Such a possibility deserves examination. Topical glucocorticoid eyedrops cause increased intraocular pressure in the majority of patients treated for open-angle glaucoma. In the rabbit model, topical administration of RU 486 reduced intraocular pressure (Phillips et al., 1989). These observations may provide a foundation for similar work in humans, if a satisfactory vehicle can be found for the non-water-soluble RU 486. The concept is especially appealing because topical administration may limit systemic effects. Although RU 486 may be a good probe of the physiology of the affective disorders, few data are available in this regard. The agent has been given to patients with major depression and produced mild activation of the HPA axis reminiscent of the effects seen in normal individuals (Kling et al., 1989; Krishnan et al., 1992). Few adverse effects have been noted in studies of RU 486 using single doses or doses of up to 10 mg/kg daily for as long as seven days. RU 486, at daily doses of 200 mg, given for more than seven days has been associated with fatigue, anorexia, and nausea, in decreasing frequency. It is important to note, however, that these effects have not been uniformly reported. Although they are consistent with relative adrenal insufficiency and improve with the administration of dexamethasone or other glucocorticoids, it is not clear that they represent adrenal insufficiency. Here, too, the paucity of glucocorticoid-sensitive end points makes discrimination of this diagnosis difficult. Additionally, there are insufficient data to evaluate these events in terms of RU 486 levels, other medications, or other predisposing factors. RU 486 induced a maculopapular erythematous cutaneous eruption in 8 of 11 normal men receiving the agent at a dose of 10 mg/kg for 9 to 14 days and in 5 of 28

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda patients receiving treatment for meningioma, 200 mg/day (Laue et al., 1990; Grunberg et al., 1993). The cause of this spontaneously resolving rash is unknown. At higher doses, up to 22 mg/kg per day given for months to patients with Cushing's syndrome, no exanthema was seen. Nausea was common in these patients. Four of eleven patients begun on RU 486 had a deterioration in clinical condition that prompted discontinuation of the agent. Again, the diagnosis of adrenal crisis was difficult to ascertain in this setting. The antiandrogenic properties of RU 486 probably underlie reports of gynecomastia and impotence in men receiving chronic therapy with RU 486: gynecomastia occurred in two of three men with Cushing's syndrome and in four of nine men with meningioma, whereas impotence was reported at a slightly lower rate (one of three and three of nine men respectively, in the two studies). RESEARCH DIRECTIONS FOR ANTIGLUCOCORTICOIDS The "state of the science" regarding RU 486 invokes many questions germane to glucocorticoid action, and provokes others relating to its potential therapeutic efficacy, as follows: RU 486 may be useful in better understanding renal physiology and in the treatment of some forms of hypertension. Questions in this area follow. What is the role of renal 6ß-hydroxylation in the development of hypertension and the maintenance of electrolyte balance? Does RU 486 undergo 6ß-hydroxylation in the kidney? Does RU 486 alter 11ß-hydroxysteroid dehydrogenase activity? Can RU 486 affect absolute or diurnal rhythm in blood pressure in normal individuals or in patients with essential hypertension? What is the role of 6ß-OH-cortisol in hypertensive states? Although RU 486 did not reverse hypertension caused by exogenous cortisol, could it possibly modulate 6ß-hydroxylation in a subset of patients with increased activity? Can RU 486 alter glucocorticoid-receptor number? (For example, if up-regulation occurs, could tumors be sensitized to glucocorticoids by previous RU 486 administration?) Can RU 486 modulate immune function or inflammation when given systemically to people? 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. What about local forms of administration—topical or intracavitary—for eye disease, wound healing, keloid reduction, joint abnormalities?

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 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. 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? 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? Would RU 486 be an effective treatment of human glioma tumors in vivo? Can better glucocorticoid-sensitive end points be developed so as to more efficiently and specifically evaluate the effects of both glucocorticoid agonists and antagonists? 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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