Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions

Ruddock, Nicole; Shi, Shao Qing; Jain, Sangeeta; Moore, Gradie; Hankins, Gary D.V.; Romero, Roberto; Garfield, Robert E.

doi:10.1016/j.ajog.2008.06.085

Cited by 85 publications

(75 citation statements)

References 25 publications

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“…Several studies demonstrated that progesterone promotes myometrial relaxation. [43][44][45] Our finding that the absence of C5aR prevents PTD in the mouse models has important therapeutic implications. Blocking the complement cascade at C5a and CaR interaction inhibits mediators and effectors of cervical remodeling and prevents PTD, suggesting that complement might be a good target for therapy in women with PTD.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

González

Franzke

Yang

et al. 2011

The American Journal of Pathology

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157

177

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Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication. Premature birth/delivery (PTD) is one of the most significant causes of perinatal mortality and morbidity in developed countries. Preterm infants suffer morbidities including respiratory distress, intraventricular hemorrhage, and cerebral palsy, among other serious diseases.1 These outcomes can have a life-long impact and more than $25 billion is spent each year to take care of these infants. Investigations to define the causes of PTD remain a challenge in the obstetrical field. Preterm labor is a multistage biochemical and biophysical process, during which changes in the myometrium and the cervix occur.The uterine cervix is a complex organ that undergoes extensive changes through gestation and parturition. These changes are a common first step in preterm parturition.2 As a gatekeeper for pregnancy, the cervix is a structural barrier that keeps the fetus inside the uterus until the end of gestation. Collagens, elastin, proteoglycans, and hyaluronate are responsible for the full tensile strength of the cervix.2 Ripening of the cervix is an important biological and clinical event required for a normal parturition. The process is gradual during pregnancy, with a fast final remodeling of the cervix before parturition. Increased collagen degradation and synthesis, and high activity of collagenases have been observed in the human cervix during final ripening.

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Section: Discussionmentioning

confidence: 99%

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

González

Franzke

Yang

et al. 2011

The American Journal of Pathology

Self Cite

157

177

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“…9 In contrast, 17HPC did not bring a direct relaxant effect on human myometrium in vitro, 9,10 and in high concentrations stimulated the uterine tissue contractile activity. 9 One of the explanations offered by the authors for the nul or stimulating effect of 17HPC was the use of myometrium tissue samples obtained from women undergoing cesarean section late in pregnancy 9,10 and from nonpregnant participants, 10 rather than preterm myometrium, which could display a different responsiveness to 17HPC. Furthermore, Sexton and coauthors suggested that in vivo administration of 17HPC could result in the formation of a metabolite exerting an uterorelaxant effect.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of 17-Alpha-Hydroxyprogesterone Caproate by Human Placental Mitochondria

et al. 2012

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Perfusion of 17-alpha-hydroxyprogesterone caproate (17HPC) via the maternal circuit of a dually perfused human placental lobule resulted in the extensive formation of 2 metabolites. On the other hand, human placental microsomes biotransformed 17HPC into 5 monohydroxylated metabolites, which did not correspond to those formed during perfusion. The goal of this investigation was to determine the subcellular localization of the enzymes responsible for the biotransformation of 17HPC during its perfusion in human placenta. Crude subcellular fractions of the human placental tissue were utilized. Six 17HPC metabolites were formed by the placental mitochondrial fraction, of which 4 were identical to those formed by the microsomes; whereas the other 2, namely MM and M 19 , were formed by the mitochondrial fraction only. The latter metabolites were identical to those formed during 17HPC perfusion, as determined by liquid chromatography-mass spectrometry (LC-MS) analysis. Therefore, these data strongly suggest that the enzymes responsible for the biotransformation of 17HPC during its perfusion are predominantly localized in human placental mitochondria.

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“…Clinically, progesterone is the only agent shown to be effective in preventing preterm birth with efficacy proven for selected groups (Dodd et al 2008). The mechanism of action of progesterone is unknown, although there is some evidence in vitro of an acute inhibitory effect on myometrial contractions (Ruddock et al 2008). Progestogens may also act to inhibit inflammation, with inhibition of LPS-induced inflammation in human fetoplacental arteries and in myometrium (Gotkin et al 2006) and inhibition of a Inflammation in reproductive processes physiological rise in mouse myometrial CCL2 in vivo (Shynlova et al 2008).…”

Section: Complicated Labourmentioning

confidence: 99%

Inflammatory pathways in female reproductive health and disease

Jabbour¹,

Sales²,

Catalano³

et al. 2009

Reproduction

291

226

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Inflammation involves alterations to vascular and immune cell function. It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. These are orchestrated by specific molecular pathways involving a host of growth factors, cytokines, chemokines and lipid mediators. Resumption of normal reproductive function involves prompt and proper resolution of these inflammatory pathways. Recent literature confirms that resolution of inflammatory pathways involves specific biochemical events that are activated to re-establish homeostasis in the affected tissue. Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution. This review will address the role of inflammatory events in normal reproductive function and its pathologies.

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Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions

Cited by 85 publications

References 25 publications

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Metabolism of 17-Alpha-Hydroxyprogesterone Caproate by Human Placental Mitochondria

Inflammatory pathways in female reproductive health and disease

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