Dataset Information

Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.

ABSTRACT:

Objective

Seventeen-alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB.

Study design

We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB.

Results

A total of 380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. In all, 61.1% of women were African American. Multivariable logistic regression demonstrated significant treatment-genotype interactions (either a beneficial or harmful treatment response) for African Americans delivering<37 weeks' gestation for rs471767 and rs578029, and for Hispanics/Caucasians delivering<37 weeks' gestation for rs500760 and <32 weeks' gestation for rs578029, rs503362, and rs666553.

Conclusion

The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms.

SUBMITTER: Manuck TA

PROVIDER: S-EPMC3210889 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Publications

Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.

Manuck Tracy A TA Lai Yinglei Y Meis Paul J PJ Dombrowski Mitchell P MP Sibai Baha B Spong Catherine Y CY Rouse Dwight J DJ Durnwald Celeste P CP Caritis Steve N SN Wapner Ronald J RJ Mercer Brian M BM Ramin Susan M SM

American journal of obstetrics and gynecology 20110408 2

<h4>Objective</h4>Seventeen-alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB.<h4>Study design</h4>We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an inte ...[more]

PMID: 21600550

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Project description:OBJECTIVE:Progestogen (vaginal progesterone or 17-alpha-hydroxyprogesterone caproate [17OHP-C]) administration to patients at risk for preterm delivery is widely used for the prevention of preterm birth (PTB). The mechanisms by which these agents prevent PTB are poorly understood. Progestogens have immunomodulatory functions; therefore, we investigated the local effects of vaginal progesterone and 17OHP-C on adaptive and innate immune cells implicated in the process of parturition. STUDY DESIGN:Pregnant C57BL/6 mice received vaginal progesterone (1 mg per 200 ?L, n = 10) or Replens (control, 200 ?L, n = 10) from 13 to 17 days postcoitum (dpc) or were subcutaneously injected with 17OHP-C (2 mg per 100 ?L, n = 10) or castor oil (control, 100 ?L, n = 10) on 13, 15, and 17 dpc. Decidual and myometrial leukocytes were isolated prior to term delivery (18.5 dpc) for immunophenotyping by flow cytometry. Cervical tissue samples were collected to determine matrix metalloproteinase (MMP)-9 activity by in situ zymography and visualization of collagen content by Masson's trichrome staining. Plasma concentrations of progesterone, estradiol, and cytokines (interferon [IFN]?, interleukin (IL)-1?, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, keratinocyte-activated chemokine/growth-related oncogene, and tumor necrosis factor-?) were quantified by enzyme-linked immunosorbent assays. Pregnant mice pretreated with vaginal progesterone or Replens were injected with 10 ?g of an endotoxin on 16.5 dpc (n = 10 each) and monitored via infrared camera until delivery to determine the effect of vaginal progesterone on the rate of PTB. RESULTS:The following results were found: (1) vaginal progesterone, but not 17OHP-C, increased the proportion of decidual CD4+ regulatory T cells; (2) vaginal progesterone, but not 17OHP-C, decreased the proportion of decidual CD8+CD25+Foxp3+ T cells and macrophages; (3) vaginal progesterone did not result in M1?M2 macrophage polarization but reduced the proportion of myometrial IFN?+ neutrophils and cervical active MMP-9-positive neutrophils and monocytes; (4) 17OHP-C did not reduce the proportion of myometrial IFN?+ neutrophils; however, it increased the abundance of cervical active MMP-9-positive neutrophils and monocytes; (5) vaginal progesterone immune effects were associated with reduced systemic concentrations of IL-1? but not with alterations in progesterone or estradiol concentrations; and (6) vaginal progesterone pretreatment protected against endotoxin-induced PTB (effect size 50%, P = 0.011). CONCLUSION:Vaginal progesterone, but not 17OHP-C, has local antiinflammatory effects at the maternal-fetal interface and the cervix and protects against endotoxin-induced PTB.

Project description:Background17-alpha Hydroxyprogesterone caproate for prevention of recurrent preterm birth is recommended for use in the United States.ObjectiveWe sought to assess the clinical effectiveness of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth ≤35 weeks compared to similar births in our obstetric population prior to the implementation of 17-alpha hydroxyprogesterone caproate.Study designThis was a prospective cohort study of 17-alpha hydroxyprogesterone caproate in our obstetric population. The primary outcome was the recurrence of birth ≤35 weeks for the entire study cohort compared to a historical referent rate of 16.8% of recurrent preterm birth in our population. There were 3 secondary outcomes. First, did 17-alpha hydroxyprogesterone caproate modify a woman's history of preterm birth when taking into account her prior number and sequence of preterm and term births? Second, was recurrence of preterm birth related to 17-alpha hydroxyprogesterone caproate plasma concentration? Third, was duration of pregnancy modified by 17-alpha hydroxyprogesterone caproate treatment compared to a prior preterm birth?ResultsFrom January 2012 through March 2016, 430 consecutive women with prior births ≤35 weeks were treated with 17-alpha hydroxyprogesterone caproate. Nearly two thirds of the women (N = 267) began injections ≤18 weeks and 394 (92%) received a scheduled weekly injection within 10 days of reaching 35 weeks or delivery. The overall rate of recurrent preterm birth was 25% (N = 106) for the entire cohort compared to the 16.8% expected rate (P = 1.0). The 3 secondary outcomes were also negative. First, 17-alpha hydroxyprogesterone caproate did not significantly reduce the rates of recurrence regardless of prior preterm birth number or sequence. Second, plasma concentrations of 17-alpha hydroxyprogesterone caproate were not different (P = .17 at 24 weeks; P = .38 at 32 weeks) between women delivered ≤35 weeks and those delivered later in pregnancy. Third, the mean (±SD) interval in weeks of recurrent preterm birth before 17-alpha hydroxyprogesterone caproate use was 0.4 ± 5.3 weeks and the interval of recurrent preterm birth after 17-alpha hydroxyprogesterone caproate treatment was 0.1 ± 4.7 weeks (P = .63). A side effect of weekly 17-alpha hydroxyprogesterone caproate injections was an increase in gestational diabetes. Specifically, the rate of gestational diabetes was 13.4% in 17-alpha hydroxyprogesterone caproate-treated women compared to 8% in case-matched controls (P = .001).Conclusion17-alpha Hydroxyprogesterone caproate was ineffective for prevention of recurrent preterm birth and was associated with an increased rate of gestational diabetes.

Dataset Information

Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.

Objective

Study design

Results

Conclusion

Publications

Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.

Similar Datasets

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