Prevention of preterm birth by progestational agents: What are the molecular mechanisms?

Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: .
American journal of obstetrics and gynecology (Impact Factor: 4.7). 03/2013; 208(3):223.e1-7. DOI: 10.1016/j.ajog.2013.01.020
Source: PubMed


Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogesterone caproate (17P) have been shown to prevent preterm birth (PTB) in high-risk populations. We hypothesize that treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling.
Using a mouse model, on embryonic day (E)14-E17 CD-1 pregnant mice were treated with: (1) 0.1 mL of 25 mg/mL of 17P subcutaneously; (2) 0.1 mL of castor oil subcutaneously; (3) 0.1 mL of 10 mg/mL of progesterone in a long-lasting Replens (Lil' Drug Store Products, Inc., Cedar Rapids, IA); or (4) 0.1 mL of the same Replens, with 4 dams per treatment group. Mice were sacrificed 6 hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis.
Exposure to VP significantly increased the expression of defensin 1 compared to Replens (P < .01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone-mediated regulators of uterine quiescence, microRNA involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix.
Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study.

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    • "Ultrasonic cervical length has been the standard measure used to identify cervical insufficiency and to identify women who should receive preventive progestogen therapy to prevent preterm birth (Cahill et al. 2010; Campbell 2011; Romero et al. 2013; Werner et al. 2011). Progestogen therapy has been promising in preventing preterm birth in women with cervical shortening or a history of preterm birth (DeFranco et al. 2007; Fonseca et al. 2007), although the mechanisms underlying its prevention of preterm birth are poorly understood (Nold et al. 2013). Cervical length assessment has become a widely used clinical measure for identifying women at high risk for preterm birth; however, it has low positive predictive value in low-risk women because the majority of individuals identified with a short cervix still deliver at term (Berghella et al. 2009; Romero et al. 2013). "
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    ABSTRACT: The purpose of this study was to determine whether cervical ultrasonic attenuation could identify women at risk of spontaneous preterm birth. During pregnancy, women (n = 67) underwent from one to five transvaginal ultrasonic examinations to estimate cervical ultrasonic attenuation and cervical length. Ultrasonic data were obtained with a Zonare ultrasound system with a 5- to 9-MHz endovaginal transducer and processed offline. Cervical ultrasonic attenuation was lower at 17-21 wk of gestation in the SPTB group (1.02 dB/cm-MHz) than in the full-term birth groups (1.34 dB/cm-MHz) (p = 0.04). Cervical length was shorter (3.16 cm) at 22-26 wk in the SPTB group than in the women delivering full term (3.68 cm) (p = 0.004); cervical attenuation was not significantly different at this time point. These findings suggest that low attenuation may be an additional early cervical marker to identify women at risk for SPTB. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Ultrasound in medicine & biology
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    • "A growing literature also demonstrates that age as well as gender may profoundly influence TBI-related functional deficits and histopathology [20]–[24]. Although progesterone has been given at the high end of the dose range (25 mg/kg) to prevent pre-term birth (see for example [25], [26]), the literature suggesting its use as a potential neuroprotective treatment for pediatric TBI is very limited. It has already been shown that exogenous progesterone can treat seizures [27], [28] and alter the pathology of neonatal brain injury [7], [29], [30], but if given too early in development (e.g. in PND 7 and PND 14 animals), it can exacerbate injury. "
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    ABSTRACT: Controlled cortical impact (CCI) models in adult and aged Sprague-Dawley (SD) rats have been used extensively to study medial prefrontal cortex (mPFC) injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI) in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury. Twenty-eight-day old (PND 28) male Sprague Dawley rats received sham (n = 24) or CCI (n = 47) injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight) or vehicle injections on post-injury days (PID) 1-7, subjected to behavioral testing from PID 9-27, and analyzed for lesion size at PID 28. The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats. Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "It is possible that progestins may manifest different anti-inflammatory properties in humans, but any possible action is not believed to be exerted through anti-inflammatory mechanisms involving downregulation of nuclear factor-kappa B.82 The exact pathway via which progestins suppress the inflammatory influences leading to parturition remains a key unanswered question. Adding to the mystery is the recent report in a murine model that neither vaginal progesterone nor 17OH-PC has any effect on pathways known to be involved in uterine contractility/quiescence or cervical remodeling.83 "
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    ABSTRACT: Prevention of preterm delivery is a major desiderate in contemporary obstetrics and a societal necessity. The means to achieve this goal remain elusive. Progesterone has been used in an attempt to prevent preterm delivery since the 1970s, but the evidence initially accumulated was fraught by mixed results and was based on mostly underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. More recent randomized controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone may favorably influence the rate of preterm delivery. Preterm delivery is a complex disorder and consequently it is unlikely that one generalized prevention strategy will be effective in all patients. Further, an additional impediment in accepting progesterone as the "magic bullet" in the prevention of preterm delivery is that its mechanism of action is not fully understood and the optimal formulations, route of administration, and dose have yet to be established. We have concerned ourselves in this review with the most recent status of 17 alpha-hydroxyprogesterone caproate (17OH-PC) supplementation for prevention of preterm delivery. Our intention is to emphasize the efficacy, safety, and patient acceptability of this intervention, based on a comprehensive and unbiased review of the available literature. Currently there are insufficient data to suggest that 17OH-PC is superior or inferior to natural progesterone. Based on available evidence, we suggest a differential approach giving preferential consideration to either 17OH-PC or other progestins based on obstetric history and cervical surveillance. Progestin therapy for risk factors other than a history of preterm birth and/or a short cervix in the current pregnancy is not currently supported by the published evidence. The experience to date with 17OH-PC indicates that there are population subgroups that may be harmed by administration of 17OH-PC. Therefore, extending the use of 17OH-PC to unstudied populations or for indications that are not evidence-based is inadvisable outside of a research protocol.
    Preview · Article · Jul 2013 · Patient Preference and Adherence
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