RU 486 is a synthetic steroid hormone antagonist which acts at the receptor level. It has both intrinsic antiprogesterone and antiglucocorticosteroid properties in animals. We investigated the antiglucocorticosteroid activity in humans by evaluating the pituitary-adrenal response to RU 486 in men and in pregnant and nonpregnant women. In nonpregnant women, RU 486 (-1 mg/kg of body weight per day) produced an interruption of the luteal phase without affecting the pituitary-adrenal axis, thereby indicating a more potent antiprogesterone than antiglucorticosteroid effect. In the course of pregnancy interruption by RU 486 (-4 mg/kg per day), there was a significant increase in plasma corticotropin, f-lipotropin, and cortisol concentrations. In normal men, RU 486 administration led to a dose-dependent stimulation of plasma corticotropin, -endorphin, and cortisol. This disinhibition of the pituitary-adrenal axis was only observed during the morning hours of the circadian rhythm. When administered concomitantly with 1 mg of dexamethasone at midnight, 6 mg of RU 486 per kg completely suppressed the dexamethasone inhibitory effect on the pituitary-adrenal axis. These results indicate that RU 486 is an antiglucocorticosteroid that disrupts the negative pituitary feedback of both the morning cortisol rise and administered dexamethasone. Furthermore, they demonstrate the possibility of optimizing the antiprogestational effect of the compound and its potential use for human fertility control by modifying the dose and the time of administration of the drug and thereby minimizing the antiglucocorticosteroid effect.RU 486 [17p8-hydroxy-11,-(4-dimethylaminophenyl)-17a-(prop-1-ynyl)-estra-4,9-dien-3-one] is a synthetic 19-nor-steroid with high binding affinity for progesterone and glucocorticosteroid receptors (1-4). In vitro and in vivo experiments in animals have established that RU 486 displays no agonist activity but is an antagonist to both progesterone and endogenous (cortisol) or synthetic (dexamethasone) glucocorticosteroids. In vitro, it antagonizes the inhibitory effect of dexamethasone on uridine incorporation in rat thymocytes and the dexamethasone induction of tyrosine aminotransferase by rat hepatoma cells (D. Philibert and R. Deraedt, personal communication); it also suppresses the inhibition of corticotropin (ACTH) secretion induced by corticosteroids in rat pituitary cells (5) and the dexamethasone action on cultured L-929 mouse fibroblasts (2). In rats in vivo, it antagonizes the effects of corticosteroids on liver glycogen and tryptophan pyrrolase, thymolysis, and diuresis (1) and the inhibition of ACTH secretion induced by dexamethasone (5).RU 486 was first used in humans to interrupt the luteal phase of the menstrual cycle and early pregnancy (6). In women who received RU 486 to induce abortion during weeks 6-8 of pregnancy, an increase in blood cortisol was observed. The present work was undertaken to investigate the possible antiglucocorticosteroid effect of RU 486 on the pituitary-adrenal axis in h...

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a synthetic steroid receptor antagonist. To evaluate the peripheral antiglucocorticoid action of this compound, we investigated its ability to antagonize cutaneous steroid-induced vasoconstriction. This phenomenon, produced by three different topical steroids in six normal men, was consistently and significantly attenuated or abolished by oral administration of 6 mg/kg RU 486. This demonstration of a peripheral action of RU 486 is important in relation to the potential therapeutic use of this well tolerated drug in states of hypercortisolism. It also indicates that the cutaneous vasoconstrictor effects of topical steroids are mediated by occupancy of glucocorticoid receptors.

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1. The influence of four diuretics on renal prostaglandins was investigated in a study designed in two parts (A and B): A, 24 normal subjects on a constant sodium intake received frusemide (80 mg daily), or hydrochlorothiazide (100 mg), or triamterene (200 mg) or spironolactone (300 mg); B, the same subjects were pretreated for 3 days with indomethacin (150 mg daily), which was continued during the 3 day administration of the respective diuretics and during a 2 day post-diuretic period. 2. In study A, only triamterene provoked a rise in urinary prostaglandins E2 and F2 alpha (+ 474 +/- SEM 92%, P less than 0.01, and + 192 +/- 7%, P less than 0.01). In study B, prostaglandins were significantly inhibited in all subjects. After indomethacin, the natriuretic effect of frusemide and spironolactone was reduced by 80 +/- 12% (P less than 0.01) and 54 +/- 11% (P less than 0.001), whereas the natriuresis induced by hydrochlorothiazide and triamterene was unchanged. No correlation was found between urinary PGE2 and F2 alpha and natriuresis. 3. When triamterene was associated with indomethacin, two subjects developed reversible acute renal failure. 4. Plasma renin activity and urinary aldosterone were stimulated by the four diuretics in study A, but their response was blunted in study B. Urinary antidiuretic hormone was not modified by diuretics but was suppressed by indomethacin. 5. Diflunisal, a structurally unrelated nonsteroidal anti-inflammatory drug, given to 12 of the subjects provoked similar interactions with frusemide, hydrochlorothiazide and spironolactone. 6. The results suggest that prostaglandins contribute to the natriuretic effects of frusemide and spironolactone, but not to those of hydrochlorothiazide and triamterene.

It is well established that the liver is a major site of metabolic inactivation of aldosterone. In 1962 Coppage, Island, Cooner, and Liddle (2) reported that the human liver was capable of converting aldosterone both to its acid-hydrolyzable conjugate (AHC) 1 and to tetrahydroaldosterone. The same study also demonstrated that aldosterone was almost completely inactivated during a single passage through the normal liver. More recent studies by Luetscher and associates (4) have indicated that the normal liver extracts about 97%o of the aldosterone delivered to it by the arterial circulation, and the studies of Bougas and co-workers (5, 6) have indicated that in subjects with minimal cardiac dysfunction the rate of splanchnic clearance of aldosterone amounts to about 89%o of the hepatic blood flow.The fact that the liver metabolizes almost all of the aldosterone presented to it does not imply that the liver is the only site of metabolism of aldosterone. Sandor and Lanthier (7) observed that kidney slices could convert aldosterone to AHC. From their analyses of hepatic and peripheral venous plasma after the continuous infusion of tritiated aldosterone into human subjects, Bougas and co-workers (5,6)

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