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13: Prevention of preterm birth with progestational agents: revealing molecular mechanisms

      Objective

      Clinically, vaginal progesterone (Vag P) and 17 alpha-hydroxyprogestreone caproate (17P) have been shown to prevent preterm birth (PTB) in high risk populations. We hypothesize these agents may be preventing PTB by altering signal transduction pathways that would promote premature cervical remodeling. Specifically, we hypothesize that progestational agents modify the mucosal immune response in the cervix through altered production of TH17 cytokines and increased expression of anti-microbial proteins.

      Study Design

      Using a mouse model, on days E14-E17 CD-1 pregnant mice were treated with either 0.1cc of 10mg/ml of 17P subcutaneously, 0.1cc of castor oil (CO) subcutaneously, 0.1 cc of 25 mg/ml of progesterone in Replens vaginally, or 0.1cc of Replens vaginally, with four dams per treatment group. Mice were sacrificed six hours after treatment on E17.5. Cervices were collected and quantitative real-time polymerase chain reaction (qPCR) was performed on the following targets: IL17, IL22, IL22R, Defensin 1, Defensin 3, Defensin 4, SLP1, and Claudin-2.

      Results

      Exposure to Vag P significantly increased the expression of Defensin 1 compared to Replens (p<0.01), CO (p<0.001), and 17P (p<0.001). Vag P also significantly increased expression of IL22R compared to CO (p<0.05) and 17P (p<0.05). Treatment with either 17P or Vag P did not have a statistically significant effect on the production of SLP1, or Claudin-2. Baseline mRNA values of IL17, IL22, Defensin 3, and Defensin 4 levels were very low; expression was not altered by any of the treatments.

      Conclusion

      These studies demonstrate that progesterone administered vaginally can alter the musical immune response. Notably, Vag P, through an increase in Defensin 1 and IL22R expression, served to boost the host mucosal immune response in the cervix. Whether these molecular changes from Vag P result in a functional effect and are a key mechanism by which Vag P prevents PTB requires further study. Importantly, 17P had no effect on these pathways in the cervix.
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