Progestin treatment for the prevention of preterm birth

Lučovnik, Miha; Kuon, Ruben; Chambliss, Linda R.; Maner, William L.; Shi, Suqing; Shi, Leili; Balducci, James; Garfield, Robert E.

doi:10.1111/j.1600-0412.2011.01178.x

Cited by 25 publications

(16 citation statements)

References 82 publications

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“…Similarly, earlier studies did not find any non-genomic relaxing effect for P4 either [35], although a synthetic P4 derivative, dydrogesterone was found to inhibit the pregnant myometrial contractions by the inhibition of voltage dependent Ca-channels [33]. Some other experiments found that P4 had an ability to relax human non-pregnant or pregnant uterine tissues in high dose [36][37][38] which findings are virtually in conflict of our results. However, the findings may be a result of genomic feature of P4 since the P4 incubation period in both reported studies were more than 1 h. The specific receptor antagonists of sex hormones (flutamide for T and fulvestrant for E2) did not reduce their actions, which is further evidence that the genomic pathway is not involved in the relaxing effects of T and E2.…”

Section: Discussioncontrasting

confidence: 75%

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

et al. 2020

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The non-genomic (prompt) actions of sex steroids on pregnant uterine contractility are not fully explored yet, the aim of our study was to clarify such effects of 17-β estradiol (E2), progesterone (P4) and testosterone (T) on late (22-day) pregnant uterine contractions together with the signaling pathways in rats in vitro. Methods: The uterine effects of sex steroids on KCl-stimulated contractions were examined in the presence of genomic pathway blocker actinomycin D and cycloheximide, sex hormone receptor antagonists (flutamide, fulvestrant, mifepristone) and also after removing the endometrium. The modifications in uterine G-protein activation and cAMP levels were also detected. Results: T and E2 both relaxed the uterine contractions in the concentration range of 10 −8-10 −3 M with an increase in the activated G-protein and cAMP levels of the uterus, while P4 was ineffective. Cycloheximide, actinomycin D, antagonist for T and E2 were not able to modify the responses along with the endothelium removal. Mifepristone blocked the relaxing effects of T and E2 and reduced the activation of G-protein and the formation of cAMP. Significance: T and E2 can inhibit KCl-stimulated contractions in the late pregnant uterus in high concentrations and in a non-genomic manner. Their actions are mediated by a G-protein coupled receptor that can be blocked by mifepristone. A single and high dose of T or E2 might be considered in premature contractions, however, further preclinical and clinical studies are required for the approval of such a therapeutic intervention.

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Section: Discussioncontrasting

confidence: 75%

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

et al. 2020

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“…The route of administration may influence the efficacy of progesterone therapy during pregnancy [ 22 , 23 ]. Vaginal progesterone administration resulted in higher endometrial progesterone concentrations than those observed in patients administered oral and intramuscular progesterone [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Oral and vaginal administration routes are noninvasive, whereas intramuscular administration is invasive. Additionally, the oral and vaginal routes of administration are associated with acceptable and minimal side effects, respectively, whereas side effects were reported in one-third of pregnant women who received weekly intramuscular injections of progesterone to prevent recurrent preterm delivery [ 22 – 24 ]. Oral synthetic progestational agents, including dydrogesterone, have been developed to eliminate issues related to the variable bioavailability of natural formulations of oral progesterone [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis

Lee

Park

Kim

et al. 2017

BioMed Research International

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Objective To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion. Methods In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria. Results The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; P = 0.001; I2, 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups. Conclusion Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion.

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“…414 Studies have suggested that progestin supplementation may prevent initiation of preterm labor or treat it once it is already established. 415 Whether changes in MMPs and sex hormones could interfere with uterine relaxation and trigger uterus contraction and pre-term delivery needs to be further examined. Also, whether the potential beneficial effects of progesterone in preterm labor are mediated via modulation of MMP expression/activity warrant further investigation.…”

Section: Dysregulation Of Uterine Mmps During Preterm Labormentioning

confidence: 99%

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Chen

Khalil

2017

Progress in Molecular Biology and Translational Science

234

168

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Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor.

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Progestin treatment for the prevention of preterm birth

Cited by 25 publications

References 82 publications

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

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