- Title
- Pathways to uterine activation at labour
- Creator
- Phung, Jason
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Preterm birth (PTB) affects approximately fifteen million babies globally every year. Approximately two thirds of all PTB occurs spontaneously or after premature rupture of membranes; whilst the remaining third are indicated PTB. The mechanism of PTB is not well characterised but has been hypothesised to occur because of premature activation of pathways responsible in term labour. There are also numerous risk factors and aetiologies that contribute to preterm birth risk; it is also not clear whether the same pathways are activated across the different aetiologies of PTB. Current understanding of myometrial transitioning during term labour highlights the importance of a functional progesterone withdrawal and estrogen activation favouring pro-inflammatory signalling which promotes the expression of contraction-associated proteins that enable myometrium to spontaneously contract during labour. These include production of prostaglandins (also important in cervical ripening and membrane rupture) and increased gap junction formation. The studies included in this thesis aim to improve the understanding of myometrial pathways in term and preterm labour. The first aim was to determine if myometrial gene expression occurring at the onset of term labour is the same as that occurring during preterm labour. The second aim was to determine if there were myometrial gene expression differences (on a transcriptomic level) occurring during preterm labour and how these signals were impacted by the presence of chorioamnionitis. The final aim was to determine if localised myometrial progesterone metabolism acted as a mechanisms of progesterone withdrawal in both term and preterm labour as a possible mechanism of labour. In the first publication, the aim was to determine if myometrial gene expression occurring at the onset of term labour is the same as that occurring during preterm labour. Using 44 genes known to be differentially expressed in term labour and representative of important biological function in labour (i.e., prostaglandin production and inflammatory signalling), this study demonstrated that preterm labouring myometrium had a distinct expression profile compared to term labouring myometrium. This was true for both singleton and twin pregnancies. This first publication concluded that preterm labour may be associated with different myometrial signals from term labour or perhaps processes outside the myometrium. In the second publication, the aim was to determine if there were myometrial gene expression differences (on a transcriptomic level) occurring during preterm labour and how these signals were impacted by the presence of chorioamnionitis. This study follows from publication one that highlighted no differences between the labouring and non-labouring preterm myometrium across 44 functionally important genes. Given only a small number of genes were assess in publication one, RNA-sequencing was used to compare non-labouring and labouring myometrium transcriptomics. Labouring myometrium was grouped by the presence or absence of chorioamnionitis a priori. Findings from the first publication were confirmed when differential gene expression analysis demonstrated no transcriptional differences in preterm non-labouring patients and preterm labouring patients without chorioamnionitis. However, additional comprehensive analyses were performed using gene set enrichment and weighted gene co-expression network analyses. Based on these additional analyses, preterm labour was associated with activation of the innate immune system and inflammation and activation of G protein-coupled receptors in both labour with and without chorioamnionitis. This study concluded that all causes of preterm labour within the study population were associated with the activation of the innate immune system, but this was more marked in the presence of chorioamnionitis. In the third publication, the aim was to determine if localised myometrial progesterone metabolism acted as a mechanisms of progesterone withdrawal in both term and preterm labour as a possible mechanism of labour. The progesterone-metabolising enzyme 20α- hydroxysteroid dehydrogenase (20α-HSD), encoded by AKR1C1, was quantified in preterm labouring and non-labouring myometrium as well as term labouring and non-labouring myometrium. AKR1C1 was found to be significantly increased with labour onset in term myometrium, but not in preterm myometrium. However, when assessing a subgroup of preterm labouring myometrium with clinical chorioamnionitis, AKR1C1 expression was significantly upregulated, suggesting that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labour in the setting of chorioamnionitis. This study also found that AKR1C1 expression was influenced by higher maternal BMI in a fetal sex-specific manner. This study concluded that localised progesterone metabolism may be a driver in term labour and a subset of PTL. This body of work highlights the important role of inflammation in both term and preterm labour within the myometrium. Gene expression differences exist between term and preterm labour. The orchestration of inflammation in preterm myometrium may not be related to a single gene, or even a small number of genes, but rather suites of genes that operate in large inflammatory networks. Finally, localised progesterone metabolism through activity of 20α-HSD may represent a mechanism of preterm labour in a subset of preterm labour.
- Subject
- preterm birth; uterine activation; localised progesterone metabolism; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1510112
- Identifier
- uon:56346
- Rights
- Copyright 2024 Jason Phung
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 10 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 196 KB | Adobe Acrobat PDF | View Details Download |