The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

Heikinheimo, Oskari; Kekkonen, Raimo; Lähteenmäki, Pekka

doi:10.1016/s0010-7824(03)00077-5

Cited by 80 publications

(63 citation statements)

References 28 publications

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“…DHP, a fish-specific progestin, is the most potent ligand to bind fish nuclear Pgr, which had been proved using an in vitro system in several fish species including zebrafish, salmon, and cod (Chen et al 2010(Chen et al , 2012(Chen et al , 2013. In previous research, the antagonism between RU486 and progestin, by competing for binding to Pgr, has been well studied in mammalian species and zebrafish (Leonhardt & Edwards 2002, Heikinheimo et al 2003, Chen et al 2010, Delgado & Davenport 2012. In this study, morphological observations revealed that RU486 treatment for 3 months resulted in the inhibition of spermatogonial cell proliferation and spermatogenic cell differentiation in XY tilapia.…”

Section: Discussionmentioning

confidence: 99%

“…RU486, an orally active compound for absorption used in FDA-approved medical treatment, binds to the progesterone receptor with twofold higher affinity than progesterone (Heikinheimo et al 2003). So far, nuclear progestin receptors have been identified and characterized in several fish species, with variable expression profiles being detected in Sertoli cells, Leydig cells, and germ cells (Chen et al 2010, 2011, Hanna et al 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Blocking of progestin action disrupts spermatogenesis in Nile tilapia (Oreochromis niloticus)

Liu¹,

Luo²,

Song³

et al. 2014

Journal of Molecular Endocrinology

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In vitro studies have indicated that the maturation-inducing hormone 17a,20b-dihydroxy-4-pregnen-3-one (17a,20b-DP, DHP), probably through nuclear progestin receptor (Pgr), might be involved in the proliferation of spermatogonial cells and the initiation of meiosis in several fish species. However, further in vivo evidence is required to elucidate the role of DHP in spermatogenesis during sexual differentiation in teleosts. In this study, we cloned pgr and analyzed its expression in Nile tilapia (Oreochromis niloticus) and treated XY fish with RU486 (a synthetic Pgr antagonist) from 5 days after hatching (dah) to determine the role of DHP in spermatogenesis. Sequence and phylogenetic analyses revealed that the Pgr identified in tilapia is a genuine Pgr. Pgr was found to be expressed in the Sertoli cells surrounding spermatogonia and spermatids in the testis of tilapia. Real-time PCR analysis revealed that the expression of pgr in the testis was significantly upregulated from 10 dah, further increased at 50 dah, and persisted until adulthood in fish. In the testis of RU486-treated fish, the transcript levels of germ cell markers and a meiotic marker were substantially reduced. However, the expression of markers in Sertoli cells remained unchanged. Moreover, the production of 11-ketotestosterone and the expression of genes encoding various steroidogenic enzymes were also not altered. In contrast, the expression of cyp17a2, encoding one of the critical steroidogenic enzymes involved in DHP biosynthesis, declined significantly, possibly indicating the inhibition of DHP production by RU486. RU486 treatment given for 2 months did not affect spermatogenesis; however, treatment given for more than 3 months resulted in a decrease in spermatogonial cell numbers and depletion of later-phase spermatogenic cells. Simultaneous excessive DHP supplementation restored spermatogenesis in RU486-treated XY fish. Taken together, our data further indicated that DHP, possibly through Pgr, might be essential for spermatogonial cell proliferation and spermatogenesis in fish.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blocking of progestin action disrupts spermatogenesis in Nile tilapia (Oreochromis niloticus)

Liu¹,

Luo²,

Song³

et al. 2014

Journal of Molecular Endocrinology

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“…After doses ranging from 50 to 100 mg, the serum concentration increases progressively, but little or no further increase is seen after doses of 100-800 mg. The concentrations of several metabolites, in contrast, increase in a dose-dependent manner and exceed that of the parent compound when large doses of RU 486 are administered (7,8). Mifepristone is highly protein bound in human serum, unlike in rats, due to the presence of a1-acid glycoprotein (orosomucoid).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Mifepristone (RU 486) in Cushing's syndrome

Johanssen¹,

Allolio²

2007

European Journal of Endocrinology

111

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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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“…There are no apparent maternal or neonatal side effects. 3 The pharmacokinetics of mifepristone is characterized by rapid absorption and a long half-life of 25-30 h. 4 Various trials employing 200mg of mifepristone resulted in shorter interval to the onset of labour and less oxytocin was required for those achieving vaginal delivery. More recently Elliot and colleagues compared the effects of 50mg and 200mg of oral mifepristone with placebo on cervical ripening and labour induction at term in primigravid women with unfavourable cervices.…”

Section: Introductionmentioning

confidence: 99%

Mifepristone: an alternate to dinoprostone in induction of labour

Sailatha

Famida

Chellaiyan

et al. 2017

Int J Reprod Contracept Obstet Gynecol

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Background: To assess and compare the efficacy, safety and fetomaternal outcome of mifepristone versus dinoprostone in priming the cervix and in inducing labour in pregnant women at term.Methods: This is a prospective comparative study done in Chettinad health and research institute, over a period of one year from October 2015 to October 2016. 50 pregnant women (Group 1) in 3rd trimester with unfavorable cervix were given 200mcg of mifepristone orally. If labour did not start or if the Bishop score remained poor at the end of 24hrs, induction was continued with 0.5mg of dinoprostone gel at a maximum of 3 gels at 6th hourly interval. Another 50 pregnant women (Group2) in 3rd trimester underwent induction according to the routine dinoprostone gel regimen of maximum 3 gels at intervals of 6hrs.Results: Improvement in Bishop score was significant with mifepristone by the end of 24hrs.But, in comparison, there was statistically significant improvement in Bishop score in favour of dinoprostone (Mean 4.7) than mifepristone (Mean 4.0). Also, the induction delivery interval was significantly less (Mean 11.5 hrs) with dinoprostone than mifepristone (Mean 20.3 hrs). Number of cases undergoing LSCS for failed induction was less in mifepristone group (4%). The rate of vaginal delivery, Caesarean sections, instrumental delivery and overall fetal outcome was comparable in both groups.Conclusions: Mifepristone is a safe, effective and suitable alternate agent for cervical ripening and initiation of labour when given 24 h before onset of labour.

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The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

Cited by 80 publications

References 28 publications

Blocking of progestin action disrupts spermatogenesis in Nile tilapia (Oreochromis niloticus)

Blocking of progestin action disrupts spermatogenesis in Nile tilapia (Oreochromis niloticus)

Mifepristone (RU 486) in Cushing's syndrome

Mifepristone: an alternate to dinoprostone in induction of labour

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