A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition
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The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone–progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24–48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.
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Progesterone withdrawal is a contributing factor to initiation of parturition.
“Progesterone withdrawal is a contributing factor to initiation of parturition and the possibility exists that the baseline reduction in progesterone in our model system does not occur in a timely manner or at a level to initiate parturition60.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [60]
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- Authors
- Condon, J. C., Jeyasuria, P., Faust, J. M., Wilson, J. W., & Mendelson, C. R.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Mendelson, Carole R.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-07-28
- Volume
- 100
- Issue
- 16
- Pages
- 9518-9523
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC170950
- OpenAlex
- W1992634340
- Cited by
- 270
- References
- 42
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 16 · 2018: 8 · 2017: 11 · 2016: 18 · 2015: 11 · 2014: 12 · 2013: 21 · 2012: 20
- FWCI
- 8.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD011149, 3-P01-HD11149-25S1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Health Sciences › Medicine › Obstetrics and Gynecology › Maternal and Perinatal Health Interventions
- Keywords
- progesterone receptor, transcriptional coactivator, childbirth, labor onset, histone acetylation, histone deacetylase, CREB-binding protein, SRC-2, SRC-3, myometrium, progesterone withdrawal, trichostatin A, acetylated histone H3, term pregnancy, uterus
- MeSH terms
- Acetyltransferases, Animals, Cell Nucleus, Enzyme Inhibitors, Female, Histones, Humans, Hydroxamic Acids, Immunohistochemistry, Labor, Obstetric, Myometrium, Nuclear Proteins, Pregnancy, Progesterone, Receptors, Progesterone, RNA, Messenger, Transcription Factors, Uterus, Immunoblotting, Oncogene Proteins, Trans-Activators, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, CREB-Binding Protein, Mice, Histone Acetyltransferases, Nuclear Receptor Coactivator 2, Histone Deacetylase Inhibitors, Nuclear Receptor Coactivator 3
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