The rationale for use of progesterone in the prevention of preterm birth?

Abstract

Pineda-Torres and co-investigators explored the anti-inflammatory properties of progesterone (P4) using an in vitro model of choriodecidual infection. These experiments were performed to determine if progesterone can suppress an induced immune response in fetal membranes. As expected from prior work, the authors demonstrate a potent cytokine response from lipopolysaccharide (LPS) administration. The lowest dose of P4 had really no or minimal effect on the LPS-induced cytokine production. The higher doses of P4 did suppress the immune response in the choriodecidual and amniotic compartments. Notably, administering RU486 (a progesterone antagonist) abrogated the immunoprotective effect of P4, suggesting a progesterone-receptor-specific action in the ability of P4 to provide immunosuppression. Progesterone has long been believed to have immunosuppressive properties. The ability of steroids to modify the immune response through binding the glucocorticoid receptor (GR) is well described. However, the mechanisms by which progesterone exerts immunomodulatory effects are more convoluted. Progesterone typically binds the progesterone receptor (PR) to induce downstream effects; yet, progesterone can also bind GR with varying affinity (Simoncini et al. Endocrinology 2004;145:5745). Additionally, progesterone may have other non-PR or non-genomic mechanisms of action. As progesterone levels are elevated during pregnancy, it is theorised that these high levels of progesterone maintain a relative immunosuppressed state in gestational tissues. If this is indeed correct, the question remains how administering progesterone (either through an injection of 17-alpha hydroxyprogesterone caproate or via vaginal application of progesterone) further modifies the immune response in the normal gestational state and/or in one in which there is active infection or inflammation (such as may be the case in preterm birth). In fact, in vivo work in mice failed to demonstrate any key mechanisms by which progestational agents alter in the normal gestational state (Nold et al. Am J Obstet Gynecol 2013;208:223 e1). Other in vivo studies utilising mouse models of preterm birth demonstrate immunomodulatory properties of progestational agents supporting the in vitro findings presented in this paper (Elovitz et al. Am J Obstet Gynecol 2004;190:693; Elovitz et al. Am J Obstet Gynecol 2005;193:1149; Elovitz et al. J Maternal-fetal Neonatal Med 2008;21;223; Yellon et al. Reprod. Sci. 2009;16:257). However, these in vivo studies noted the most profound immunosuppressive effects from medroxyprogesterone acetate, which is known to exert downstream effects via GR and PR. The studies presented here, while adding further evidence that P4 can induce immunomodulatory properties and that those effects are mitigated by P4 via a receptor-mediated mechanism (PR or GR), cannot provide sufficient evidence to explain possible findings from use of progestational agents in the prevention of preterm birth in the clinical setting. Understanding the need to elucidate mechanisms and that such trials in humans are difficult, we remain unclear about the role of progesterone in preventing preterm birth. Although this study, and other studies, suggest that P4 can provide immunosuppression, whether the clinically used progestational agents prevent preterm birth by suppressing an immune response in the cervix, uterus, placenta or fetal membranes, remains unknown. The more that we reveal about the pathogenesis of preterm birth, the more likely we are to discover specific therapeutics that target this precise pathway and lead to greater prevention of preterm birth. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.