12: Preventing cervical ripening: The primary mechanism by which progestational agents prevent preterm birth?

Article Outline

• Objective
• Study design
• Results
• Conclusion
• Copyright

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Objective 

Two recent randomized trials demonstrated that progestational agents (PAs) prevent preterm birth (PTB). More recent clinical data suggests that these agents may delay PTB in patients with advanced cervical ripening (AJOG 2007). These studies sought to assess whether PAs may prevent PTB through modulation of known and unknown pathways involved in cervical ripening.

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Study design 

In experiment #1, E15 dams were injected with MPA(1mg/dam) or vehicle on E15 and cervical tissues were collected 48 hours later. RNA was extracted and used for microarray analysis using Affymetrix Gene Chip. Data and cluster analyses were performed using SAM. Pathway analysis was performed using DAVID. In experiment #2, E15 dams were treated with MPA (1mg/dam, n=6), Progesterone (P) (2mg/dam, n=6), dexamethasone (DEX, n=6) or vehicle (n=3). Cervices were collected 24 hrs later. QPCR was performed on cervical tissues from time points.

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Results 

94 genes in the cervix were differentially regulated2 fold 48 hours after treatment of MPA. Based on significance and pathway analysis, select target genes were assessed by QPCR. The HAS-2 and Claudin-2 mRNA expression were significantly differentially regulated by PAs (TABLE).

Fold change in mRNA expression by PA

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Conclusion 

HAS-2, already implicated in cervical ripening, is significantly inhibited by PAs.The up-regulation of Claudin-2 by PAs would serve to increase tight cell junctions and may represent a novel target for PA action. These molecular studies suggest that PAs, used clinically in humans, may serve to modulate genes involved in cervical ripening thus prevent cervical change and inhibit PTB.