The Journal of Steroid Biochemistry and Molecular Biology
New insights into the molecular endocrinology of parturition☆
Introduction
The mechanisms leading to parturition have remained one of the great unsolved mysteries in biology. During ∼95% of human pregnancy, the uterus is maintained in a relatively quiescent state by elevated circulating levels of progesterone [1]. In most pregnant mammals, uterine quiescence ends and parturition is initiated in association with a decrease in circulating progesterone [2]. By contrast in humans, levels of progesterone in maternal plasma do not decline prior to the onset of labor and progesterone receptor (PR) levels in myometrium remain elevated. However, a critical role for functional inactivation of PR in the initiation of labor in women is suggested by the finding that the PR antagonist RU486 enhances cervical ripening and can initiate labor [3]. In consideration of the high affinity of progesterone for PR, it is possible that the decline in circulating progesterone in other mammals is not sufficient to compromise its actions at receptors within the uterus and cervix. In this regard, the finding that mice carrying a targeted deletion in the gene coding for 5α-reductase type 1 fail to undergo cervical ripening at term [4] suggests that local metabolism of progesterone within the cervix also is required for progesterone withdrawal and spontaneous labor.
In recent studies, we observed that parturition in humans and mice is associated with a pronounced decline in uterine levels of a number of coactivators known to interact with the PR, as well as a marked decrease in histone acetylation [5]. By use of semi-quantitative and real-time RT-PCR, immunohistochemistry and immunoblotting, expression of coactivators CBP, SRC-2 and SRC-3 were found to be decreased in uterine tissue of women in-labor. We also found marked decreases in SRC and CBP coactivator levels in uterine tissues of pregnant mice at term. Levels of acetylated histone H3 also were decreased in uterine tissues of humans and mice, at term. Interestingly, administration of trichostatin A (TSA), a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed parturition by 24–48 h [5]. This suggests that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR regulation of genes that maintain uterine quiescence and increase sensitivity of the uterus to contractile stimuli. We suggest that in pregnant women and other mammals, uterine quiescence is maintained by increased PR transcriptional activity, while spontaneous labor is initiated by a series of molecular events that negatively impact PR function. The cellular mechanisms that trigger these events have not yet been determined.
Section snippets
Parturition and the inflammatory response
A growing body of evidence suggests that the initiation of parturition is associated with an intrauterine inflammatory response. It is estimated that infection is manifest in ∼30% of pregnancies ending in preterm labor (with intact membranes) [6]. Furthermore, even in those cases of preterm labor in which there are no clinical symptoms, there is suggested to be a “silent” infection [7]. This is exemplified by the findings that both preterm and term labor in women are associated with increased
The signal for parturition may arise from the fetal lung
We have recently tested the hypothesis that augmented surfactant production by the maturing fetal lung and the subsequent secretion of surfactant lipids and proteins into amniotic fluid, provides the key signal for the uterine inflammatory response that leads to parturition at term. Pulmonary surfactant, a developmentally regulated, phospholipid-rich lipoprotein produced by lung type II cells, reduces surface tension at the alveolar air–liquid interface and is essential for normal breathing [13]
Conclusions
Based on these findings, we propose that the fetus provides an important signal for the initiation of parturition through augmented secretion of pulmonary surfactant into amniotic fluid during late gestation. Using the mouse as a model, we observed that the major surfactant protein, SP-A, a C-type lectin that functions as a component of the innate immune system [16], [18], is secreted by the fetal lung into amniotic fluid at high concentrations near term. The secreted SP-A has the capacity to
Acknowledgements
This research was supported by National Institutes of Health Grants 3-P01-HD11149-25S1 and 1-R01-HL078824, and by Advanced Research Program Grant 010019-0123-2001 from the Texas Higher Education Coordinating Board.
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Cited by (73)
Evaluation of serum C-reactive protein concentration as a marker of impending parturition and correlation with progesterone profile in peri-partum bitches
2019, Animal Reproduction ScienceCitation Excerpt :In the past, the analysis of CRP and other APP concentrations was proposed as an approach for early pregnancy diagnosis in the bitch (Evans and Anderton, 1992; Vannucchi et al., 2002). Although the exact mechanisms responsible for parturition are still to be elucidated, the presence of an inflammatory response in the myometrium occurs in women (Thomson et al., 1999; Mendelson and Condon, 2005; Leong et al., 2008) and could also occur in other mammalian species. When measured before, during and after women give birth to a child, assessments of CRP and another acute-phase protein, serum amyloid A, confirmed there was a physiological occurrence of a major acute-phase response (De Villiers et al., 1990; Cicarelli et al., 2004).
Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data
2018, American Journal of Obstetrics and GynecologyCitation Excerpt :Progesterone is critical for pregnancy maintenance, and a withdrawal of progesterone action is believed to be central to the initiation of parturition in most mammalian species, including primates.124-131 Progesterone exerts biological effects in the myometrium,132-136 chorioamniotic membranes,137 and uterine cervix (ie, control of cervical remodeling).138,139 Progesterone withdrawal (in rats, rabbits, and sheep) or a decline in progesterone action (in guinea pigs and primates)129 has been proposed as a key control mechanism for cervical ripening by Xu et al,140 Nold et al,141 Mahendroo et al,142,143 Word et al,144 Kirby et al,145 Yellon et al,146,147 and Chwalisz et al.148-150 Thus, a large body of evidence supports a role for progesterone in cervical remodeling.151-158
Role of collectins and complement protein C1q in pregnancy and parturition
2016, ImmunobiologyReview of the reproductive endocrinology of the pregnant and parturient mare
2016, TheriogenologyCitation Excerpt :The current review has focused on events and potential mechanisms of parturition that are detectable in systemic steroid concentrations, such as progestin withdrawal itself, but changes at the tissue and cellular level will no doubt help to explain phenomena induced locally to differing degrees among species. These might include expression of different forms of the PR that are antagonistic [187–190], local metabolism of progesterone [54,191,192], and/or direct effects progesterone or DHP metabolites (neurosteroids) on myometrium and other excitable membranes [54] that are not mediated through the PR [193]. These may be less important in species, such as the horse where progestin withdrawal is signaled by decreasing concentrations of pregnanes in the maternal circulation a few days before delivery [195].
The great obstetrical syndromes and the placenta
2023, BJOG: An International Journal of Obstetrics and Gynaecology
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Proceedings of the 16th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology, ‘Recent Advances in Steroid Biochemistry and Molecular Biology’, Seefeld, Tyrol, Austria, 5–8 June 2004.