Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor

Brenner, Robert; Slayden, Ov D.; Critchley, Hilary

doi:10.1530/rep.0.1240167

Cited by 55 publications

(12 citation statements)

References 25 publications

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“…Pathway analysis is widely used to analyze gene expression data and serves as an effective tool for delineating the underlying biological processes involved in mRNA aberrations [68–71]. Biological pathways altered in the current study included: cellular growth and proliferation, lipid metabolism, tissue remodeling, ECM mineralization, inflammation, angiogenesis, and metabolic exchange.…”

Section: Discussionmentioning

confidence: 99%

Global gene expression in endometrium of high and low fertility heifers during the mid-luteal phase of the estrous cycle

et al. 2014

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BackgroundIn both beef and dairy cattle, the majority of early embryo loss occurs within the first 14 days following insemination. During this time-period, embryos are completely dependent on their maternal uterine environment for development, growth and ultimately survival, therefore an optimum uterine environment is critical to their survival. The objective of this study was to investigate whether differences in endometrial gene expression during the mid-luteal phase of the estrous cycle exist between crossbred beef heifers ranked as either high (HF) or low fertility (LF) (following four rounds of artificial insemination (AI)) using the Affymetrix® 23 K Bovine Gene Chip.ResultsConception rates for each of the four rounds of AI were within a normal range: 70–73.3%. Microarray analysis of endometrial tissue collected on day 7 of the estrous cycle detected 419 differentially expressed genes (DEG) between HF (n = 6) and LF (n = 6) animals. The main gene pathways affected were, cellular growth and proliferation, angiogenesis, lipid metabolism, cellular and tissue morphology and development, inflammation and metabolic exchange. DEG included, FST, SLC45A2, MMP19, FADS1 and GALNT6.ConclusionsThis study highlights, some of the molecular mechanisms potentially controlling uterine endometrial function during the mid-luteal phase of the estrous cycle, which may contribute to uterine endometrial mediated impaired fertility in cattle. Differentially expressed genes are potential candidate genes for the identification of genetic variation influencing cow fertility, which may be incorporated into future breeding programmes.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-234) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Global gene expression in endometrium of high and low fertility heifers during the mid-luteal phase of the estrous cycle

et al. 2014

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“…80,81 Since androgens suppress estrogen-induced endometrial proliferation, the increase in the AR could be a possible mechanism to explain the antiproliferative effects. 82 In the presence of mifepristone, receptors adopt an inactive conformation and preferentially interact with corepressors such as nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone, resulting in loss of transcriptional activity. 83 The mixed agonist/antagonist, asoprisnil (that are a selective PR modulator for gynecological therapy), partially recruits coactivators and strongly recruits corepressors, 84 which explains its mixed agonist and antagonist action.…”

Section: Genomic Pathways Of Mifepristonementioning

confidence: 99%

“…However, the increase in estrogen and PRs is also associated with an increase in the number of androgen receptor. [80][81][82] Since androgens suppress estrogeninduced endometrial proliferation, the increase in the AR could be a possible mechanism to explain the antiproliferative effects. Further evidence of the role played by androgens in this antiproliferative effect is the observation that the specific nuclear antagonist of the AR, flutamide, blocks the antiproliferative effects in the endometrium.…”

Section: Genomic Pathways Of Mifepristonementioning

confidence: 99%

Genomic and Nongenomic Effects of Mifepristone at the Cardiovascular Level: A Review

et al. 2017

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Mifepristone (RU 486) is a compound that is structurally related to steroid hormones, which is derived from the estrane progestins. This compound strongly binds the progesterone and glucocorticoid receptor and, to a lesser extent, the androgen receptor. This compound has its effects through different signaling pathways, related to genomic and nongenomic effects. The genomic effect involves the activation or blockage of nuclear or intracellular receptor, that in this case the progesterone, glucocorticoid, and androgen receptors. On the contrary, the nongenomic effect of mifepristone is independent of the activation of these receptors. Regarding the nongenomic, several authors observed that mifepristone induces higher uterine artery blood flow probably due to the decrease in serum nitric oxide level. Moreover, recently it has been demonstrated that mifepristone induces relaxation, and this effect is independent of the endothelium and due to the activation of the calcium channels. The main side effects associated with this pathway are hemorrhage and inhibition of platelet aggregation that can lead to hypovolemia or to hypotension. Concerning the genomic effect, this drug blocks progesterone, androgens, and glucocorticoids receptors and also activates the progesterone receptor and their respective effects. The most frequently reported adverse effects of mifepristone are nausea, vomiting, hypovolemia, hypotension, amenorrhea, and infertility. The main purpose of this review is to describe the genomic and nongenomic effects of mifepristone at vascular level and describe some pathologies in which mifepristone is used as a treatment.

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“…Long-term administration of low doses of antiprogestin (RU486) allowed normal ovarian cycles, but suppressed endometrial growth and decreased glandular cell proliferation in women, demonstrating that the endometrium was more sensitive to the effects of anti-progestin than were other tissues (Cameron et al 1996). In primates, the anti-progestin (ZK 137136) inhibited endometrial mitotic activity, wet mass and thickness, and suppressed endometrial growth and glandular proliferation (Brenner et al 2002), whereas in rodents, anti-progestins did not cause any anti-proliferative effects in the oviductal or vaginal epithelium (Chwalisz et al 1998). The antagonism to the action of progesterone in regression of the mammary tissue has been reported in cats developing fibroadenomatous hyperplasia, when aglepristone is given at 10 mg ⁄ kg on four to five consecutive days (Wehrend et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Anti‐Progestin Aglepristone on the Uterine Tissue of Cats Administered Medroxyprogesterone Acetate

Muphung¹,

Rungsipipat²,

Chatdarong³

2009

Reprod Domestic Animals

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The effect of aglepristone, a progesterone receptor antagonist, on feline endometrial proliferation induced by medroxyprogesterone acetate (MPA), a contraceptive progestin, was investigated. Three groups each of six cats were studied: Group A, during inter-oestrus; Group B, given 50 mg MPA; Group C, receiving 50 mg MPA followed by 10 mg/kg aglepristone twice at 24-h interval 3 weeks later. Ovariohysterectomy was performed, and uterine tissue was collected from the mid part of the horn when the cats were confirmed as being in inter-oestrus (Group A), 3 weeks after the MPA administration (Group B), or 2 weeks after aglepristone administration (Group C). Uterine weights, relative uterine weights and uterine diameters were determined. The endometrial and myometrial thicknesses and the endometrial/myometrial ratios were determined in histological sections. Histological sections were also immunostained for proliferative activity [anti-proliferative cell nuclear antigen (PCNA) antibody], and progesterone receptor (anti-hPR) and percentage of positive cells in luminal vs glandular epithelium were determined for both parameters. PCNA and all morphological parameters except endometrial thickness were increased (p < 0.05) by MPA, and progesterone receptor was decreased compared to untreated cats. Aglepristone treatment had no significant effect compared to MPA alone. However, glandular proliferative activity was usually but not significantly lower in Group C than in Group B, suggesting a potential effect of the anti-progestin that might be clinically beneficial. Alternatively, this possible effect in the aglepristone group may reflect the longer time after MPA that these animals were examined. Whether lack of significant effect of the anti-progestin was because of too high dose of MPA relative to the dose of aglepristone, the delay of 14 days in obtaining tissues after aglepristone treatment, or simply an insufficient duration of aglepristone treatment requires further study.

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Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor

Cited by 55 publications

References 25 publications

Global gene expression in endometrium of high and low fertility heifers during the mid-luteal phase of the estrous cycle

Global gene expression in endometrium of high and low fertility heifers during the mid-luteal phase of the estrous cycle

Genomic and Nongenomic Effects of Mifepristone at the Cardiovascular Level: A Review

Effects of the Anti‐Progestin Aglepristone on the Uterine Tissue of Cats Administered Medroxyprogesterone Acetate

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