Progesterone Receptors in the Human Pregnancy Uterus: Do they Hold the Key to Birth Timing?

Mesiano, Sam; Wang, Yuguang; Norwitz, Errol R.

doi:10.1177/1933719110382922

Cited by 140 publications

(99 citation statements)

References 138 publications

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“…P 4 executes its functions via two PR isoforms, PR-A and PR-B (65,66). Analysis of promoter activity in cell culture systems suggests that while PR-A functions as a repressor, PR-B serves to increase P 4 signaling (67). Notably, the placenta does not express PR.…”

Section: Figurementioning

confidence: 99%

“…Therefore, P 4 should exert its effects via decidual or myometrial PR; which site of P 4 signaling is more important in parturition remains to be ascertained. Functional withdrawal of P 4 signaling in the myometrium has been proposed to trigger labor in humans (67). There could be several reasons for withdrawal: reduced P 4 levels, local metabolism of P 4 in the myometrium and/or decidua, an altered ratio of PR isoforms (PR-A/PR-B), or reduced transactivation or heightened transrepression due to recruitment of coactiva-tors or corepressors (68).…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P 4 ), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P 4 may help reduce the incidence of preterm birth in high-risk women.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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show abstract

“…In many species, the physiological withdrawal before parturition is due to a decline in available progesterone (Nathanielsz 1998, Norwitz 1999, Jenkin & Young 2004, Mitchell & Taggart 2009, the pregnane that is generally considered the most potent endogenous progestin and that decrease is apparent in systemic blood. Studies in women (Pieber et al 2001) and mice (Condon et al 2003, Mendelson & Condon 2005 revealed that birth is not invoked by a decline in systemic progesterone but involves a decrease in expression or function of the classic nuclear progesterone receptors (Kastner et al 1990) in target tissues (Conneely et al 2003, Mesiano et al 2011 such as myometrium. In horses, the endocrinology of pregnancy is more complex (Conley 2016, Legacki et al 2016) than other animals and the mechanisms initiating parturition are a matter of speculation (Thorburn 1993, Silver 1994, Conley & Neto 2008, Fowden et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Progestin withdrawal at parturition in the mare

Legacki¹,

Corbin²,

Ball³

et al. 2016

Reproduction

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Mammalian pregnancies need progestogenic support and birth requires progestin withdrawal. The absence of progesterone in pregnant mares, and the progestogenic bioactivity of 5α-dihydroprogesterone (DHP), led us to reexamine progestin withdrawal at foaling. Systemic pregnane concentrations (DHP, allopregnanolone, pregnenolone, 5α-pregnane-3β, 20α-diol (3β,20αDHP), 20α-hydroxy-5α-dihydroprogesterone (20αDHP)) and progesterone) were monitored in mares for 10 days before foaling (n = 7) by liquid chromatography-mass spectrometry. The biopotency of dominant metabolites was assessed using luciferase reporter assays.

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“…Clinical observations of humans have revealed that the myometrial PRA expression becomes increased relative to PRB expression at term labor, and related studies have indicated that this differential PR isoform ratio suppresses the responsiveness to myometrial progesterone, thereby triggering labor and delivery. [6][7][8][9] Yet, the mechanisms regulating the expression of the PR isoforms remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition

Chen

Luo

et al. 2014

Reprod. Sci.

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The functional interaction of progesterone receptor (PR) isoforms PRA and PRB regulates myometrial transition from the resting state to excitation-contraction to initiate parturition. However, the regulatory mechanisms responsible for maintenance and functional alteration of the PRA and PRB expression levels during human pregnancy and term labor, respectively, remain unknown. Therefore, this study was designed to investigate whether and how epigenetic DNA modifications, specifically methylations, at the PRs' promoter regions contribute to the differential expression of PRA and PRB in laboring term myometrium of humans. Comparative analysis of PRA and PRB messenger RNA (mRNA) expression levels and accompanying changes in their promoters' methylation status was carried out using human myometrial samples from women undergoing singleton, term deliveries by cesarean section, either in the absence of labor (designated as NIL for not-in-labor) or in active labor (designated as IL for in labor). The PRA gene expression was shown to be elevated significantly during labor, while PRB gene expression was unaltered, and this differential expression was accompanied by decreased DNA methylation at the PRA promoter and not at the PRB promoter. In addition, labor-related decreased mRNA expression of the DNA methyltransferase (DNMT) family members DNMT1 and DNMT3a was found, however whether the increased expression of DNMTs directly supports the functional withdrawal of progesterone needs further investigation. Collectively, these data indicate that DNA methylation might represent an important epigenetic mechanism of labor-related differential expression of PRs, thereby mediating the biological process of functional PR withdrawal at term for parturition.

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Progesterone Receptors in the Human Pregnancy Uterus: Do they Hold the Key to Birth Timing?

Cited by 140 publications

References 138 publications

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Progestin withdrawal at parturition in the mare

Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition

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