Pituitary and Adrenal Responses to the Anti-Progesterone and Anti-Glucocorticoid Steroid Ru 486 in Primates1

Healy, David; Chrousos, G. P.; Schulte, H.M.; Williams, Robert F.; Gold, P. W.; Baulieu, Étienne-Émile; Hodgen, Gary D.

doi:10.1210/jcem-57-4-863

Cited by 77 publications

(13 citation statements)

References 15 publications

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“…It is well known that RU 38486 also binds to glucocorticoid receptors and has potent antiglucocorticoid activity for a number of biological responses (35)(36)(37). In agreement with such observations, we found that several natural adrenal corticoids and the synthetic glucocorticoid triamcinolone were able to displace [ 3 H]RU 38486 from binding sites in HPOA cytosols.…”

Section: Discussionsupporting

confidence: 89%

Antagonism of Female Sexual Behavior with Intracerebral Implants of Antiprogestin RU 38486: Correlation with Binding to Neural Progestin Receptors*

Etgen

Barfield

1986

Endocrinology

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The steroidal antiprogestin 17 beta-hydroxyl-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynl)estra-4,9-dien-3-one (RU 38486) was administered systemically or was implanted into the ventromedial hypothalamus and other brain regions (habenula, preoptic area, interpeduncular region, in order to determine whether the compound could antagonize progesterone (P) activation of estrous responsiveness and whether the compound would exert its behavioral effects at the presumed site of P action and/or at other neural sites implicated in the regulation of female sexual behavior. RU 38486 (5 mg) administered sc 1 h before 200 micrograms P inhibited P facilitation of lordosis behavior in estrogen-primed rats. Intracerebral application of RU 38486 to the ventromedial hypothalamus reduced lordosis responses in 14 of the 25 animals tested. Similar implants in the habenula also inhibited lordosis in 5 of the 14 animals tested. Antiprogestin implants in the interpeduncular region and preoptic area were virtually without effect (1 of 7 inhibited in each group). Interactions of RU 38486 with steroid binding sites in the hypothalamus-preoptic area (HPOA) were also assessed. RU 38486 appeared to be a competitive inhibitor of progestin ([3H] R5020) binding in HPOA cytosols. Scatchard analysis of [3H]RU 38486 binding showed that when unlabeled P was used as the competitor to assess nonspecific binding, the antiprogestin bound with high affinity [dissociation constant Kd = 8.4 nm] to brain cytosols. In addition, the number of [3H]RU 38486 binding sites in HPOA cytosol increased by approximately 50% in estrogen-primed female rats. Competition studies indicated that unlabeled RU 38486 was the most effective competitor for [3H]RU 38486 binding but that P and R5020 were nearly as effective. Corticosterone, hydrocortisone, deoxycorticosterone, and triamcinolone also competed for [3H]RU 38486 binding but were somewhat less effective than the progestins. Testosterone and estradiol did not displace [3H]RU 38486 except at very high molar excesses. Thus RU 38486 appears to bind with highest affinity to HPOA progestin receptors, but it also binds to glucocorticoid receptors. These data are consistent with the interpretation that inhibition of estrous responsiveness by RU 38486 is associated with the antagonist's interference with brain progestin binding.

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Section: Discussionsupporting

confidence: 89%

Antagonism of Female Sexual Behavior with Intracerebral Implants of Antiprogestin RU 38486: Correlation with Binding to Neural Progestin Receptors*

Etgen

Barfield

1986

Endocrinology

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“…In animals and humans with an intact hypothalamic-pituitary-adrenal (HPA) axis, RU 486 antagonizes the negative feedback of cortisol by blocking central GRs (2,18). The increase in plasma ACTH and cortisol levels induced by RU 486 is particularly evident in the early morning hours, when ACTH and cortisol concentrations are physiologically peaking (19).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Mifepristone (RU 486) in Cushing's syndrome

Johanssen¹,

Allolio²

2007

European Journal of Endocrinology

112

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Context: Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome. Evidence acquisition: Original articles and reviews were identified using a PubMed search strategy covering the time period until February 2007. Evidence synthesis: Treatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.

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“…MIF, also designated RU486 (Roussel Uclaf, Population Council), was the first antiprogestational agent synthesized and tested (14,15) and is considered to be the prototype antiprogestin. MIF is a steroid [17ß-hydroxy-11ß-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)estra-4,9-dien-3-one] that has high affinity for PR, mediating its significant antiprogestational effects (15)(16)(17)(18)(19). When MIF binds to PR, progesterone is blocked from binding the PR and progesteronemediated transcription is inhibited (20,21).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer

Schoenlein¹,

Hou²,

Samaddar³

et al. 2007

Int J Oncol

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Abstract. In this study, human MCF-7 breast cancer cells, which express functional estrogen and progesterone receptors, were used to compare the efficacy of combined antiestrogen plus antiprogestin therapy to antiestrogen monotherapy. Cells were treated with the antiestrogen 4-hydroxytamoxifen (4-OHT) and/or the antiprogestin mifepristone (MIF) and effects on cell proliferation (cytostatic action), cell cycle phase, the phosphorylation state of the tumor suppressor retinoblastoma protein (Rb), and induction of active cell death (cytotoxic action) were determined. Combination hormonal therapy showed both increased cytostatic and cytotoxic activity as compared to either monotherapy. The increased cytostatic action was mediated by Rb activation; whereas, the cytotoxic (pro-apoptotic) action of combined hormonal therapy correlated to a significant reduction in Rb protein levels. To test the apparent role of Rb protein loss in the pro-apoptotic action of combined hormonal therapy, Rb was downregulated in MCF-7 cells using siRNA-targeting. The siRNA-mediated knockdown of Rb combined with 4-OHT therapy resulted in a pro-apoptotic action similar to that resulting from 4-OHT and MIF combination treatment, which included increased cell detachment from the monolayer, high-molecular-weight genomic DNA fragmentation, and cleavage of poly ADP-ribose polymerase (PARP) and lamin A. From these studies, we conclude that Rb protein downregulation is required for 4-OHT-treated, estrogen receptor positive (ER + ) breast cancer cells to undergo active cell death. We discuss the potential of using an antiprogestin such as MIF plus antiestrogen treatment to more effectively downregulate Rb in ER + breast cancer cells to increase the overall cytotoxic action of hormonal therapy.

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Pituitary and Adrenal Responses to the Anti-Progesterone and Anti-Glucocorticoid Steroid Ru 486 in Primates1

Cited by 77 publications

References 15 publications

Antagonism of Female Sexual Behavior with Intracerebral Implants of Antiprogestin RU 38486: Correlation with Binding to Neural Progestin Receptors*

Antagonism of Female Sexual Behavior with Intracerebral Implants of Antiprogestin RU 38486: Correlation with Binding to Neural Progestin Receptors*

Mifepristone (RU 486) in Cushing's syndrome

Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer

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