Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor

Narvekar, Nitish; Critchley, Hilary O. D.; Liu, Cheng; Baird, D. T.

doi:10.1093/humrep/del182

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…were upregulated, which correlates well with the described effects of Dox on collagen synthesis. Mifepristone (RU-486) is a synthetic steroid with potent antiprogesterone and antiglucocorticoid activities, being able to upregulate glucocorticoid receptors in the endometrium when used as a contraceptive (Narvekar et al, 2006). In addition to its other side effects, RU-486 has also been described as depressing the innate immune system (Miech, 2005).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Effects of Tet-On and Mifepristone-Inducible Systems in Mouse Liver

et al. 2008

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Control of transgene expression from long-term expression vectors can be achieved with inducible and regulated promoters. The two most commonly used inducible systems employ doxycycline or mifepristone as the drug activating a silent trans-activator, which is expressed from a constitutive promoter. We evaluated the alterations provoked by constitutive expression in the liver of rtTA2 S -M2 (rtTA2; second-generation reverse tetracycline-controlled trans-activator) and GLp65, which are the trans-activators of the doxycyline-and mifepristone-inducible systems, respectively. To this end we performed transcriptomic analysis of mice expressing these trans-activators in the liver over 1 month. rtTA2 expression induced alterations in a few genes (69 gene probesets; false discovery rate [FDR], ϳ0.05), whereas GLp65 caused more numerous changes (1059 gene probe-sets, an FDR of ϳ0.05). However, only 20 and 53 of the genes from the rtTA2 and GLp65 groups, respectively, showed changes (R-fold Ն 3). Functional assignments indicate that alterations were mild and of little general significance. Few additional transcriptomic changes were observed when expressing trans-activators in the presence of inducer drugs; most were due to the drugs themselves. These results and the absence of toxicity observed in treated animals indicate that the two inducible systems are well tolerated and have little impact on the liver transcriptome profile. The milder alterations found with the use of rtTA2 suggest that this system is possibly safer for gene therapy applications. 1233

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Effects of Tet-On and Mifepristone-Inducible Systems in Mouse Liver

et al. 2008

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“…Inhibition of estrogen-dependent endometrial fibroblast, epithelial and endothelial cell proliferation, modulation of extracellular matrix synthesis, and angiogenesis are highly complex, multifactorial cellular and molecular processes, in which PR clearly plays an important role (Conneely et al, 2001;Slayden and Brenner, 2004;Narvekar et al, 2006). Like other nuclear hormone receptors, PR is a ligandactivated transcription factor with domains for DNA binding, hormone binding, and transactivation.…”

Section: Discussionmentioning

confidence: 99%

The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982)

Giorgio-Miller

Bungay²,

Tutt³

et al. 2008

J Pharmacol Exp Ther

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The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognized as the potential basis for preventing gynecological conditions such as endometriosis and uterine fibroids. In this study, we examine the in vitro and in vivo properties of a nonsteroidal PR antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) in comparison with the nonselective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborization of the rabbit endometrium in a dose-dependent manner at unbound drug exposures that were commensurate with their potencies as PR antagonists in vitro. Translation of this pharmacology to a clinically relevant system was required to bridge the pharmacological gap between nonmenstruating rabbits and humans. Thus, the pharmacokinetic (PK) and pharmacodynamic (PD) data from the rabbit were combined to predict pharmacological effects on the naturally cycling cynomolgus macaque endometrium. PF-02367982 blocked the effect of progesterone on the cynomolgus macaque endometrium to the same degree as RU-486 and at exposures predicted by the rabbit PK-PD model. With such an efficacious and superior selectivity profile to the nonselective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynecological conditions such as endometriosis.The discovery of synthetic progesterone receptor (PR) modulators has underscored the important role that progesterone plays in reproductive physiology, including the menstrual cycle, endometrial growth, breast development and maintenance of pregnancy (Chabbert-Buffet et al., 2005;Spitz, 2006). RU-38486 (RU-486, mifepristone) is the founding member of steroidal PR antagonists and is approved clinically for pregnancy termination and emergency contraception. Studies with RU-486 and other PR antagonists, such as onapristone, ZK-137316 (Zelinski-Wooten et al., 1998), and ZK-230211, have revealed that these agents, as well as directly antagonizing progesterone function, can block ovarian function and also arrest the effect of estrogen on the endometrium in women and nonhuman primates (NHP) (Wolf et al., 1989;Baird et al., 2003;Brenner et al., 2005; ChabbertBuffet et al., 2005;Slayden et al., 2006).The potential usefulness of RU-486 and other PR antagonists in the treatment of pathological conditions such as endometriosis, uterine fibroids, and cancer is supported by a number of preclinical observations and clinical findings (Grow et al., 1996;Kettel et al., 1996;Baird et al., 2003;Fiscella et al., 2006). Although RU-486 has potent antiprogestagenic activity, it is also an equipotent antagonist at the glucocorticoid receptor (GR) (Heikinheimo et al., 1987). As a consequence, RU-486 suppresses the inhibition of corticotropin secretion induced by corticosteroids, limiting its wider usefu...

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“…CDB-4124 endometrial histology OB Ioffe et al microarterial thrombi of the type encountered with unopposed estrogens, high-density 'chicken-wire' microvessels seen with mifepristone, 23 and widespread vascular wall thickening reported previously for asoprisnil. 10 Two cases with endometrial vascular thrombosis involved only venules in isolated fragments that had sheet-like necrosis.…”

Section: Unblinded Review Of Histologic Changes In Cdb-4124 Treatmentmentioning

confidence: 96%

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

2009

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Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124 (also known as Proellext) for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed endometrial carcinoma or hyperplasia while on therapy. CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other progesterone receptor modulators, including cystic architecture and mixed non-physiologic epithelial changes will prevent misdiagnosis.

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Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor

Abstract: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.

Cited by 42 publications

References 52 publications

Transcriptomic Effects of Tet-On and Mifepristone-Inducible Systems in Mouse Liver

Transcriptomic Effects of Tet-On and Mifepristone-Inducible Systems in Mouse Liver

The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982)

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

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