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Enache RM, Roşu OA, Profir M, Pavelescu LA, Creţoiu SM, Gaspar BS. Correlations Between Gut Microbiota Composition, Medical Nutrition Therapy, and Insulin Resistance in Pregnancy-A Narrative Review. Int J Mol Sci 2025; 26:1372. [PMID: 39941139 PMCID: PMC11818759 DOI: 10.3390/ijms26031372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/31/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Many physiological changes accompany pregnancy, most of them involving metabolic perturbations. Alterations in microbiota composition occur both before and during pregnancy and have recently been correlated with an important role in the development of metabolic complications, such as insulin resistance and gestational diabetes mellitus (GDM). These changes may be influenced by physiological adaptations to pregnancy itself, as well as by dietary modifications during gestation. Medical nutritional therapy (MNT) applied to pregnant women at risk stands out as one of the most important factors in increasing the microbiota's diversity at both the species and genus levels. In this review, we discuss the physiological changes during pregnancy and their impact on the composition of the intestinal microbiota, which may contribute to GDM. We also discuss findings from previous studies regarding the effectiveness of MNT in reducing insulin resistance. In the future, additional studies should aim to identify specific gut microbial profiles that serve as early indicators of insulin resistance during gestation. Early diagnosis, achievable through stool analysis or metabolite profiling, may facilitate the timely implementation of dietary or pharmaceutical modifications, thereby mitigating the development of insulin resistance and its associated sequelae.
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Affiliation(s)
- Robert-Mihai Enache
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Oana Alexandra Roşu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (O.A.R.); (M.P.); (L.A.P.)
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Monica Profir
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (O.A.R.); (M.P.); (L.A.P.)
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Luciana Alexandra Pavelescu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (O.A.R.); (M.P.); (L.A.P.)
| | - Sanda Maria Creţoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (O.A.R.); (M.P.); (L.A.P.)
| | - Bogdan Severus Gaspar
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Surgery Clinic, Bucharest Emergency Clinical Hospital, 014461 Bucharest, Romania
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Svenvik M, Raffetseder J, Brudin L, Berg G, Hellberg S, Blomberg M, Jenmalm MC, Ernerudh J. Early prediction of spontaneous preterm birth before 34 gestational weeks based on a combination of inflammation-associated plasma proteins. Front Immunol 2024; 15:1415016. [PMID: 39076980 PMCID: PMC11284114 DOI: 10.3389/fimmu.2024.1415016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/01/2024] [Indexed: 07/31/2024] Open
Abstract
Background In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population. Methods A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis. Results In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor κB (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester. Conclusion A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive.
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Affiliation(s)
- Maria Svenvik
- Department of Obstetrics and Gynecology, Region Kalmar County, Kalmar, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Johanna Raffetseder
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Lars Brudin
- Department of Clinical Physiology, Region Kalmar County, Kalmar, Sweden
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Göran Berg
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Obstetrics and Gynecology, Linköping University, Linköping, Sweden
| | - Sandra Hellberg
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Marie Blomberg
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Obstetrics and Gynecology, Linköping University, Linköping, Sweden
| | - Maria C. Jenmalm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Jan Ernerudh
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden
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Peng T, Cui J, Ni Z, Tang Y, Cao X, Li S, Cheng X, Huang J. Methyl-CpG-binding protein 2 regulates CYP27A1-induced myometrial contraction during preterm labor. Mol Hum Reprod 2024; 30:gaae016. [PMID: 38704863 DOI: 10.1093/molehr/gaae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 03/25/2024] [Indexed: 05/07/2024] Open
Abstract
Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that methyl-CpG-binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases. Herein, using RNA sequence analysis of global gene expression in human uterine smooth muscle cells (HUSMCs) following siMeCP2, we show that MeCP2 silencing caused dysregulation of the cholesterol metabolism pathway. Notably, MeCP2 silencing resulted in the upregulation of CYP27A1, the key enzyme involved in regulating cholesterol homeostasis, in HUSMCs. Methylation-specific PCR, chromatin immunoprecipitation, and dual luciferase reporter gene technology indicated that MeCP2 could bind to the methylated CYP27A1 promoter region and repress its transcription. Administration of siCYP27A1 in a lipopolysaccharide (LPS)-induced preterm labor mouse model delayed the onset of preterm labor. Human preterm myometrium and the LPS-induced preterm labor mouse model both showed lower expression of MeCP2 and increased expression of CYP27A1. These results demonstrated that aberrant upregulation of CYP27A1 induced by MeCP2 silencing is one of the mechanisms facilitating inappropriate myometrial contraction. CYP27A1 could be exploited as a novel therapeutic target for preterm birth.
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Affiliation(s)
- Ting Peng
- Department of Obstetrics, Changning Maternity & Infant Health Hospital, East China Normal University, Shanghai, China
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jiayan Cui
- Department of Pharmaceutical Sciences,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Ziyun Ni
- Department of Pharmaceutical Sciences,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yao Tang
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Xiaojing Cao
- Department of Pharmaceutical Sciences,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Sihan Li
- Department of Pharmaceutical Sciences,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xixi Cheng
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jin Huang
- Department of Pharmaceutical Sciences,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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Chen JJ, Chen XJ, She QM, Li JX, Luo QH. Clinical risk factors for preterm birth and evaluating maternal psychology in the postpartum period. World J Psychiatry 2024; 14:661-669. [PMID: 38808088 PMCID: PMC11129159 DOI: 10.5498/wjp.v14.i5.661] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/26/2024] [Accepted: 04/11/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Although the specific pathogenesis of preterm birth (PTB) has not been thoroughly clarified, it is known to be related to various factors, such as pregnancy complications, maternal socioeconomic factors, lifestyle habits, reproductive history, environmental and psychological factors, prenatal care, and nutritional status. PTB has serious implications for newborns and families and is associated with high mortality and complications. Therefore, the prediction of PTB risk can facilitate early intervention and reduce its resultant adverse consequences. AIM To analyze the risk factors for PTB to establish a PTB risk prediction model and to assess postpartum anxiety and depression in mothers. METHODS A retrospective analysis of 648 consecutive parturients who delivered at Shenzhen Bao'an District Songgang People's Hospital between January 2019 and January 2022 was performed. According to the diagnostic criteria for premature infants, the parturients were divided into a PTB group (n = 60) and a full-term (FT) group (n = 588). Puerperae were assessed by the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS), based on which the mothers with anxiety and depression symptoms were screened for further analysis. The factors affecting PTB were analyzed by univariate analysis, and the related risk factors were identified by logistic regression. RESULTS According to univariate analysis, the PTB group was older than the FT group, with a smaller weight change and greater proportions of women who underwent artificial insemination and had gestational diabetes mellitus (P < 0.05). In addition, greater proportions of women with reproductive tract infections and greater white blood cell (WBC) counts (P < 0.05), shorter cervical lengths in the second trimester and lower neutrophil percentages (P < 0.001) were detected in the PTB group than in the FT group. The PTB group exhibited higher postpartum SAS and SDS scores than did the FT group (P < 0.0001), with a higher number of mothers experiencing anxiety and depression (P < 0.001). Multivariate logistic regression analysis revealed that a greater maternal weight change, the presence of gestational diabetes mellitus, a shorter cervical length in the second trimester, a greater WBC count, and the presence of maternal anxiety and depression were risk factors for PTB (P < 0.01). Moreover, the risk score of the FT group was lower than that of the PTB group, and the area under the curve of the risk score for predicting PTB was greater than 0.9. CONCLUSION This study highlights the complex interplay between postpartum anxiety and PTB, where maternal anxiety may be a potential risk factor for PTB, with PTB potentially increasing the incidence of postpartum anxiety in mothers. In addition, a greater maternal weight change, the presence of gestational diabetes mellitus, a shorter cervical length, a greater WBC count, and postpartum anxiety and depression were identified as risk factors for PTB.
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Affiliation(s)
- Jia-Jun Chen
- Department of Clinical Laboratory, Shenzhen Bao’an District Songgang People’s Hospital, Shenzhen 518000, Guangdong Province, China
| | - Xue-Jin Chen
- Department of Otolaryngology Head and Neck Surgery Outpatient, Shenzhen Children’s Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qiu-Min She
- Department of Clinical Laboratory, Shenzhen Bao’an District Songgang People’s Hospital, Shenzhen 518000, Guangdong Province, China
| | - Jie-Xi Li
- Department of Prevention and Health Care, Shenzhen Bao’an District Songgang People’s Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qiu-Hong Luo
- Department of Obstetrics, Shenzhen Bao’an District Songgang People’s Hospital, Shenzhen 518000, Guangdong Province, China
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Tian Z, Zhang X, Yao G, Jin J, Zhang T, Sun C, Wang Z, Zhang Q. Intestinal flora and pregnancy complications: Current insights and future prospects. IMETA 2024; 3:e167. [PMID: 38882493 PMCID: PMC11170975 DOI: 10.1002/imt2.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/27/2023] [Accepted: 12/22/2023] [Indexed: 06/18/2024]
Abstract
Numerous studies have demonstrated the pivotal roles of intestinal microbiota in many physiopathological processes through complex interactions with the host. As a unique period in a woman's lifespan, pregnancy is characterized by changes in hormones, immunity, and metabolism. The gut microbiota also changes during this period and plays a crucial role in maintaining a healthy pregnancy. Consequently, anomalies in the composition and function of the gut microbiota, namely, gut microbiota dysbiosis, can predispose individuals to various pregnancy complications, posing substantial risks to both maternal and neonatal health. However, there are still many controversies in this field, such as "sterile womb" versus "in utero colonization." Therefore, a thorough understanding of the roles and mechanisms of gut microbiota in pregnancy and its complications is essential to safeguard the health of both mother and child. This review provides a comprehensive overview of the changes in gut microbiota during pregnancy, its abnormalities in common pregnancy complications, and potential etiological implications. It also explores the potential of gut microbiota in diagnosing and treating pregnancy complications and examines the possibility of gut-derived bacteria residing in the uterus/placenta. Our aim is to expand knowledge in maternal and infant health from the gut microbiota perspective, aiding in developing new preventive and therapeutic strategies for pregnancy complications based on intestinal microecology.
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Affiliation(s)
- Zhenyu Tian
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China
| | - Xinjie Zhang
- Department of Biology University College London London UK
| | - Guixiang Yao
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China
| | - Jiajia Jin
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China
| | - Tongxue Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China
| | - Chunhua Sun
- Department of Health Management Center, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan China
| | - Zhe Wang
- Department of Geriatrics Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan China
| | - Qunye Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China
- Cardiovascular Disease Research Center of Shandong First Medical University Central Hospital Affiliated to Shandong First Medical University Jinan China
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Mensah NA, Fassett MJ, Shi JM, Kawatkar AA, Xie F, Chiu VY, Yeh M, Avila CC, Khadka N, Sacks DA, Getahun D. Examining recent trends in spontaneous and iatrogenic preterm birth across race and ethnicity in a large managed care population. Am J Obstet Gynecol 2022:S0002-9378(22)02176-7. [PMID: 36403861 DOI: 10.1016/j.ajog.2022.11.1288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND For the past several decades, epidemiological studies originating from the United States have consistently reported increasing rates of preterm birth (PTB). Despite the implementation of several clinical and public health interventions to reduce PTB rates, it remains the leading cause of infant morbidity and mortality in the United States and around the world. OBJECTIVE This study aimed to examine recent trends in preterm birth and its clinical subtypes by maternal race and ethnicity among singleton births. STUDY DESIGN Kaiser Permanente Southern California electronic health records for all singleton births between 2009 and 2020 (n=427,698) were used to examine preterm birth trends and their subtypes (spontaneous and iatrogenic preterm births). Data on preterm labor triage extracted from electronic health records using natural language processing were used to define preterm birth subtypes. Maternal race and ethnicity are categorized as non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Asian or Pacific Islander. Multiple logistic regression was used to quantify the linear trend for preterm birth and its subtypes. Racial and ethnic trends were further examined by considering statistical interactions and stratifications. RESULTS From 2009 to 2020, the overall preterm birth rate decreased by 9.12% (from 8.04% to 7.31%; P<.001). The rates decreased by 19.29% among non-Hispanic Whites (from 7.23% to 5.83%; P<.001), 6.15% among Hispanics (from 7.82% to 7.34%; P=.036), and 12.60% among non-Hispanic Asian or Pacific Islanders (from 8.90% to 7.78%; P<.001), whereas a nonsignificantly increased preterm birth rate (8.45%) was observed among non-Hispanic Blacks (from 9.91% to 10.75%; P=.103). Between 2009 and 2020, overall spontaneous preterm birth rates decreased by 28.85% (from 5.75% to 4.09%; P<.001). However, overall iatrogenic preterm birth rates increased by 40.45% (from 2.29% to 3.22%; p<.001). Spontaneous preterm birth rates decreased by 34.73% among non-Hispanic Whites (from 5.44% to 3.55%; P<.001), 19.75% among non-Hispanic Blacks (from 6.82% to 5.47%; P<.001), 22.96% among Hispanics (from 5.55% to 4.28%; P<.001), and 28.19% among non-Hispanic Asian or Pacific Islanders (from 6.50% to 4.67%; P<.001). Iatrogenic preterm birth rates increased by 52.42% among non-Hispanic Whites (from 1.88% to 2.61%; P<.001), 107.89% among non-Hispanic Blacks (from 3.18% to 6.13%; P<.001), 46.88% among Hispanics (from 2.29% to 3.26%; P<.001), and 42.21% among non-Hispanic Asian or Pacific Islanders (from 2.45% to 3.44%; P<.001). CONCLUSION The overall preterm birth rate decreased over time and was driven by a decrease in the spontaneous preterm birth rate. There is racial and ethnic variability in the rates of spontaneous preterm birth and iatrogenic preterm birth. The observed increase in iatrogenic preterm birth among all racial and ethnic groups, especially non-Hispanic Blacks, is disconcerting and needs further investigation.
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Affiliation(s)
- Nana A Mensah
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Michael J Fassett
- Department of Obstetrics and Gynecology, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, CA; Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA
| | - Jiaxiao M Shi
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Aniket A Kawatkar
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Fagen Xie
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Vicki Y Chiu
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Meiyu Yeh
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Chantal C Avila
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - Nehaa Khadka
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
| | - David A Sacks
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA; Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Darios Getahun
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA.
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Kolatorova L, Vitku J, Suchopar J, Hill M, Parizek A. Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine. Int J Mol Sci 2022; 23:7989. [PMID: 35887338 PMCID: PMC9322133 DOI: 10.3390/ijms23147989] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 11/16/2022] Open
Abstract
Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles. While the discovery of its effects has a long history, over recent decades, various novel actions of this interesting steroid have been documented, of which its neuro- and immunoprotective activities are the most widely discussed. Discoveries of the novel biological activities of progesterone have also driven research and development in the field of progesterone analogues used in human medicine. Progestogen treatment has traditionally and predominately been used in maintaining pregnancy, the prevention of preterm labor, various gynecological pathologies, and in lowering the negative effects of menopause. However, there are also various other medical fields where progesterone and its analogues could find application in the future. The aim of this work is to show the mechanisms of action of progesterone and its metabolites, the physiological and pharmacological actions of progesterone and its synthetic analogues in human medicine, as well as the impacts of its production and use on the environment.
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Affiliation(s)
- Lucie Kolatorova
- Department of Steroids and Proteofactors, Institute of Endocrinology, Narodni 8, 116 94 Prague, Czech Republic; (J.V.); (M.H.)
| | - Jana Vitku
- Department of Steroids and Proteofactors, Institute of Endocrinology, Narodni 8, 116 94 Prague, Czech Republic; (J.V.); (M.H.)
| | - Josef Suchopar
- DrugAgency, a.s., Klokotska 833/1a, 142 00 Prague, Czech Republic;
| | - Martin Hill
- Department of Steroids and Proteofactors, Institute of Endocrinology, Narodni 8, 116 94 Prague, Czech Republic; (J.V.); (M.H.)
| | - Antonin Parizek
- Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General Teaching Hospital, Apolinarska 18, 128 51 Prague, Czech Republic;
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Cathey AL, Aung MT, Watkins DJ, Rosario ZY, Vélez Vega CM, Alshawabkeh AN, Cordero JF, Mukherjee B, Meeker JD. Mediation by hormone concentrations on the associations between repeated measures of phthalate mixture exposure and timing of delivery. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2022; 32:374-383. [PMID: 34987188 PMCID: PMC9124667 DOI: 10.1038/s41370-021-00408-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Phthalates are used in the manufacturing of consumer products, resulting in ubiquitous human exposure to phthalate mixtures. Previous work has suggested that phthalates display endocrine-disrupting capabilities, and exposure is associated with early delivery. OBJECTIVE To assess mediating effects of hormone concentrations on associations between phthalate mixtures and preterm birth (PTB). METHODS Repeated urinary phthalates and serum hormones were measured among 1011 women in the PROTECT Puerto Rico birth cohort from 2011-2019. We utilized ridge regression to create phthalate environmental risk scores (ERS), which represent weighted summaries of total phthalate exposure. Mediation analyses were conducted on a subset of 705 women. We additionally conducted fetal sex-specific analyses. RESULTS Free thyroxine (FT4) mediated 9.6% of the association between high molecular weight (HMW) ERS at 18 weeks and reduced gestational age at delivery (95%CI:1.07-29.9). Progesterone at 26 weeks mediated 21.1% and 16.2% of the association between HMW ERS at 18 and 22 weeks, and spontaneous PTB, respectively. Among male fetuses, corticotropin releasing hormone (CRH) at 18 weeks mediated 28.2% of the association between low molecular weight ERS and spontaneous PTB. SIGNIFICANCE We provide introductory evidence of hormone disruption on the causal pathway between phthalate exposure and early delivery. We also show differences by fetal sex, but larger sample size is necessary to validate our findings. IMPACT STATEMENT This study provides introductory evidence that an alteration of hormone concentrations occurs on the causal pathway between gestational phthalate mixture exposure and subsequent PTB. In addition to the novel application of repeated biomarker measurements and mixtures methods in causal mediation analyses, we also explored differences between classes of phthalate compounds and between fetal sexes. We show that differential endocrine pathways may be disrupted with exposures to low versus HMW phthalate compounds, and that pregnancies with a male fetus may be more susceptible to endocrine disruption than those with a female fetus.
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Affiliation(s)
- Amber L Cathey
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Max T Aung
- Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA, USA
| | - Deborah J Watkins
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Zaira Y Rosario
- Graduate School of Public Health, University of Puerto Rico, San Juan, PR, USA
| | - Carmen M Vélez Vega
- Graduate School of Public Health, University of Puerto Rico, San Juan, PR, USA
| | | | - José F Cordero
- College of Public Health, University of Georgia, Athens, GA, USA
| | - Bhramar Mukherjee
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - John D Meeker
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
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Progesterone Receptor Signaling in the Uterus Is Essential for Pregnancy Success. Cells 2022; 11:cells11091474. [PMID: 35563781 PMCID: PMC9104461 DOI: 10.3390/cells11091474] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 12/25/2022] Open
Abstract
The uterus plays an essential role in the reproductive health of women and controls critical processes such as embryo implantation, placental development, parturition, and menstruation. Progesterone receptor (PR) regulates key aspects of the reproductive function of several mammalian species by directing the transcriptional program in response to progesterone (P4). P4/PR signaling controls endometrial receptivity and decidualization during early pregnancy and is critical for the establishment and outcome of a successful pregnancy. PR is also essential throughout gestation and during labor, and it exerts critical roles in the myometrium, mainly by the specialized function of its two isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), which display distinct and separate roles as regulators of transcription. This review summarizes recent studies related to the roles of PR function in the decidua and myometrial tissues. We discuss how PR acquired key features in placental mammals that resulted in a highly specialized and dynamic role in the decidua. We also summarize recent literature that evaluates the myometrial PR-A/PR-B ratio at parturition and discuss the efficacy of current treatment options for preterm birth.
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10
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Zakaria ZZ, Al-Rumaihi S, Al-Absi RS, Farah H, Elamin M, Nader R, Bouabidi S, Suleiman SE, Nasr S, Al-Asmakh M. Physiological Changes and Interactions Between Microbiome and the Host During Pregnancy. Front Cell Infect Microbiol 2022; 12:824925. [PMID: 35265534 PMCID: PMC8899668 DOI: 10.3389/fcimb.2022.824925] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/26/2022] [Indexed: 12/20/2022] Open
Abstract
In recent years, it has become clear that microbiome play a variety of essential roles in human metabolism, immunity, and overall health and that the composition of these microbiome is influenced by our environment, diet, weight, hormones, and other factors. Indeed, numerous physiological and pathological conditions, including obesity and metabolic syndrome, are associated with changes in our microbiome, referred to as dysbiosis. As a result, it is not surprising that such changes occur during pregnancy, which includes substantial weight gain and significant changes in metabolism and immune defenses. The present review relates physiological changes during pregnancy to alterations in the microbial composition at various sites, including the gut, oral cavity, and vagina. Pregnancy has been linked to such microbial changes, and we believe that, in contrast to certain disease states, these microbial changes are vital for a healthy pregnancy, probably through their influence on the mother’s immunological, endocrinological, and metabolic status.
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Affiliation(s)
- Zain Zaki Zakaria
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
- Biomedical Research Center, Qatar University (QU), Doha, Qatar
| | - Shouq Al-Rumaihi
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Rana S. Al-Absi
- Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University (QU), Doha, Qatar
| | - Huda Farah
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Muram Elamin
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Rahaf Nader
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Salma Bouabidi
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Sara Elgaili Suleiman
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Shahd Nasr
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
| | - Maha Al-Asmakh
- Department of Biomedical Sciences, College of Health Sciences, Qatar University (QU) Health, Qatar University, Doha, Qatar
- Biomedical Research Center, Qatar University (QU), Doha, Qatar
- *Correspondence: Maha Al-Asmakh,
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11
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Chan D, Bennett PR, Lee YS, Kundu S, Teoh TG, Adan M, Ahmed S, Brown RG, David AL, Lewis HV, Gimeno-Molina B, Norman JE, Stock SJ, Terzidou V, Kropf P, Botto M, MacIntyre DA, Sykes L. Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response. Nat Commun 2022; 13:975. [PMID: 35190561 PMCID: PMC8861006 DOI: 10.1038/s41467-022-28620-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 01/28/2022] [Indexed: 01/04/2023] Open
Abstract
There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1β and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB. Gaining mechanistic insight into the microbiological and immunological factors that are associated with spontaneous preterm birth is important for the development of prevention strategies. Here authors show that the complement system in conjunction with specific vaginal microbial and associated immunological changes are contributing to this condition.
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12
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Zhao Z, Chen L, Cao M, Chen T, Huang Y, Wang N, Zhang B, Li F, Chen K, Yuan C, Li C, Zhou X. Comparison of lncRNA Expression in the Uterus between Periods of Embryo Implantation and Labor in Mice. Animals (Basel) 2022; 12:ani12030399. [PMID: 35158722 PMCID: PMC8833358 DOI: 10.3390/ani12030399] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/25/2022] [Accepted: 02/03/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Progesterone has been proven to play an important role in female mammals during pregnancy. In this study, the uteri of pregnant mice were collected to compare mRNA and lncRNA expression between periods of embryo implantation and labor. The results show that 19 known differentially expressed lncRNAs and 31 novel differentially lncRNAs were commonly expressed between the two stages, indicating that these lncRNAs’ function is related to progesterone. Abstract Uterine function during pregnancy is regulated mainly by progesterone (P4) and estrogen (E2). Serum P4 levels are known to fluctuate significantly over the course of pregnancy, especially during embryo implantation and labor. In this study, pregnant mice at E0.5, E4.5, E15.5, and E18.5 (n = 3/E) were used for an RNA-Seq-based analysis of mRNA and lncRNA expression. In this analysis, 1971 differentially expressed (DE) mRNAs, 493 known DE lncRNAs, and 1041 novel DE lncRNAs were found between E0.5 and E4.5 at the embryo implantation stage, while 1149 DE mRNAs, 192 known DE lncRNAs, and 218 novel DE lncRNAs were found between E15.5 and E18.5 at the labor stage. The expression level of lncRNA-MMP11 was significantly downregulated by P4 treatment on MSM cells, while lncRNA-ANKRD37 was significantly upregulated. Notably, 117 DE mRNAs, 19 known DE lncRNAs, and 31 novel DE lncRNAs were commonly expressed between the two stages, indicating that these mRNAs and lncRNAs may be directly or indirectly regulated by P4.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Xu Zhou
- Correspondence: (C.L.); (X.Z.)
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13
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Gao Z, Xu X, Li Y, Sun K, Yang M, Zhang Q, Wang S, Lin Y, Lou L, Wu A, Liu W, Nie B. Mechanistic Insight into PPARγ and Tregs in Atherosclerotic Immune Inflammation. Front Pharmacol 2021; 12:750078. [PMID: 34658891 PMCID: PMC8511522 DOI: 10.3389/fphar.2021.750078] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/17/2021] [Indexed: 12/19/2022] Open
Abstract
Atherosclerosis (AS) is the main pathological cause of acute cardiovascular and cerebrovascular diseases, such as acute myocardial infarction and cerebral apoplexy. As an immune-mediated inflammatory disease, the pathogenesis of AS involves endothelial cell dysfunction, lipid accumulation, foam cell formation, vascular smooth muscle cell (VSMC) migration, and inflammatory factor infiltration. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in lipid metabolism, inflammation, and apoptosis by antagonizing the Wnt/β-catenin pathway and regulating cholesterol efflux and inflammatory factors. Importantly, PPARγ-dependant fatty acid uptake is critical for metabolic programming. Activated PPARγ can exert an anti-atherosclerotic effect by inhibiting the expression of various inflammatory factors, improving endothelial cell function, and restraining the proliferation and migration of VSMCs. Regulatory T cells (Tregs) are the only subset of T lymphocytes that have a completely negative regulatory effect on the autoimmune response. They play a critical role in suppressing excessive immune responses and inflammatory reactions and widely affect AS-associated foam cell formation, plaque rupture, and other processes. Recent studies have shown that PPARγ activation promotes the recruitment of Tregs to reduce inflammation, thereby exerting its anti-atherosclerotic effect. In this review, we provide an overview of the anti-AS roles of PPARγ and Tregs by discussing their pathological mechanisms from the perspective of AS and immune-mediated inflammation, with a focus on basic research and clinical trials of their efficacies alone or in combination in inhibiting atherosclerotic inflammation. Additionally, we explore new ideas for AS treatment and plaque stabilization and establish a foundation for the development of natural PPARγ agonists with Treg recruitment capability.
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Affiliation(s)
- Zhao Gao
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China.,Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Institute of Nephrology, Guangdong Medical University, Zhanjiang, China
| | - Xinrui Xu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China
| | - Yang Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kehan Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Manfang Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qingyue Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China
| | - Shuqi Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yiyi Lin
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China
| | - Lixia Lou
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China
| | - Aiming Wu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China
| | - Weijing Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China.,Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Institute of Nephrology, Guangdong Medical University, Zhanjiang, China
| | - Bo Nie
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to BeijingUniversity of Chinese Medicine, Beijing, China.,School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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14
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Choi SJ, Kwak DW, Kil K, Kim SC, Kwon JY, Kim YH, Na S, Bae JG, Cha HH, Shim JY, Oh KY, Lee KA, Kim SM, Cho IA, Lee SM, Cho GJ, Jo YS, Choi GY, Choi SK, Hur SE, Hwang HS, Kim YJ. Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis. BJOG 2020; 127:1646-1654. [PMID: 32536019 DOI: 10.1111/1471-0528.16365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. DESIGN A multicentre, randomised, open-label, equivalence trial and a meta-analysis. SETTING Tertiary referral hospitals in South Korea. POPULATION Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). METHODS Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). MAIN OUTCOME MEASURE Preterm birth (PTB) before 37 weeks of gestation. RESULTS A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. CONCLUSION Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. TWEETABLE ABSTRACT Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.
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Affiliation(s)
- S-J Choi
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - D W Kwak
- Ajou University School of Medicine, Suwon, Korea
| | - K Kil
- Yeouido St Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - S-C Kim
- Pusan National University College of Medicine, Pusan, Korea
| | - J-Y Kwon
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Y H Kim
- Chonnam National University Medical School, Gwangju, Korea
| | - S Na
- Kangwon National University Hospital, School of Medicine Kangwon National University, Chuncheon, Korea
| | - J-G Bae
- Keimyung University School of Medicine, Daegu, Korea
| | - H-H Cha
- Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - J-Y Shim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - K Y Oh
- School of Medicine, Eulji University, Daejeon, Korea
| | - K A Lee
- Kyung Hee University School of Medicine, Seoul, Korea
| | - S M Kim
- Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - I A Cho
- Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea
| | - S M Lee
- Seoul National University College of Medicine, Seoul, Korea
| | - G J Cho
- Korea University College of Medicine, Seoul, Korea
| | - Y S Jo
- St Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - G Y Choi
- Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University, Seoul, Korea
| | - S K Choi
- College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - S E Hur
- Konyang University Hospital, Daejeon, Korea
| | - H S Hwang
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
| | - Y J Kim
- College of Medicine, Ewha Womans University, Seoul, Korea
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15
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You S, Cui AM, Hashmi SF, Zhang X, Nadolny C, Chen Y, Chen Q, Bush X, Hurd Z, Ali W, Qin G, Deng R. Dysregulation of bile acids increases the risk for preterm birth in pregnant women. Nat Commun 2020; 11:2111. [PMID: 32355283 PMCID: PMC7193585 DOI: 10.1038/s41467-020-15923-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 04/03/2020] [Indexed: 12/13/2022] Open
Abstract
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications. Bile acids are recognized as signaling molecules regulating a myriad of cellular and metabolic activities but have not been etiologically linked to PTB. In this study, a hospital-based cohort study with 36,755 pregnant women is conducted. We find that serum total bile acid levels directly correlate with the PTB rates regardless of the characteristics of the subjects and etiologies of liver disorders. Consistent with the findings from pregnant women, PTB is successfully reproduced in mice with liver injuries and dysregulated bile acids. More importantly, bile acids dose-dependently induce PTB with minimal hepatotoxicity. Furthermore, restoring bile acid homeostasis by farnesoid X receptor activation markedly reduces PTB and dramatically improves newborn survival rates. The findings thus establish an etiologic link between bile acids and PTB, and open an avenue for developing etiology-based therapies to prevent or delay PTB.
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Affiliation(s)
- Sangmin You
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Ai-Min Cui
- Nantong Maternal and Child Health Hospital, Nantong University, Nantong, China
| | - Syed F Hashmi
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Xinmu Zhang
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Christina Nadolny
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Yuan Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Qiwen Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Xin Bush
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Zachary Hurd
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Winifer Ali
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Gang Qin
- Department of Epidemiology and Biostatistics, School of Public Health, Nantong University, 226006, Nantong, Jiangsu Province, China
| | - Ruitang Deng
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA.
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16
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Fuhler GM. The immune system and microbiome in pregnancy. Best Pract Res Clin Gastroenterol 2020; 44-45:101671. [PMID: 32359685 DOI: 10.1016/j.bpg.2020.101671] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/19/2020] [Accepted: 03/05/2020] [Indexed: 01/31/2023]
Abstract
Hormonal changes during pregnancy instigate numerous physiological changes aimed at the growth and delivery of a healthy baby. A careful balance between immunological tolerance against fetal antigens and immunity against infectious agents needs to be maintained. A three-way interaction between pregnancy hormones, the immune system and our microbiota is now emerging. Recent evidence suggests that microbial alterations seen during pregnancy may help maintain homeostasis and aid the required physiological changes occurring in pregnancy. However, these same immunological and microbial alterations may also make women more vulnerable during pregnancy and the post-partum period, especially regarding immunological and infectious diseases. Thus, a further understanding of the host-microbial interactions taking place during pregnancy may improve identification of populations at risk for adverse pregnancy outcomes.
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Affiliation(s)
- G M Fuhler
- Erasmus MC University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Erasmus Medical Center, Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
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17
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Rath W, Kuon RJ. Progesterone - Effective for Tocolysis and Maintenance Treatment After Arrested Preterm Labour?: Critical Analysis of the Evidence. Geburtshilfe Frauenheilkd 2019; 79:834-843. [PMID: 31423018 PMCID: PMC6690738 DOI: 10.1055/a-0829-3992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/05/2019] [Accepted: 01/07/2019] [Indexed: 12/19/2022] Open
Abstract
Numerous experimental studies indicate that natural progesterone, through various mechanisms, exerts an inhibitory effect on uterine contractility and sensitises the myometrium for tocolytics. It was therefore appropriate to investigate the possible benefits of oral/vaginal progesterone and the synthetic progesterone derivative 17-α-hydroxyprogesterone caproate, applied intramuscularly, in clinical studies on primary tocolysis, additively to established tocolytics ("adjunctive tocolysis") and as maintenance treatment after successful tocolysis in cases of threatened preterm birth. Three studies with a small number of cases do not yield any sufficient evidence for recommending progesterone/17-α-hydroxyprogesterone caproate as primary tocolysis in women with preterm labour. There is also no evidence that progesterone or 17-α-hydroxyprogesterone caproate combined with commonly used tocolytics leads to a prolongation of pregnancy and a significant decrease in the rate of preterm birth. The data on the use of progesterone as maintenance treatment is controversial. While randomised, controlled studies with low quality showed promising results, studies with high quality did not reveal any significant differences with regard to the rate of preterm birth < 37 weeks of gestation, the latency period until delivery and in the neonatal outcome between progesterone/17-α-hydroxyprogesterone caproate and placebo or no treatment. Significant differences in the methodology, the inclusion and outcome criteria, the mode of application and the dosages of the substances as well as the inadequate statistical power as a result of low numbers of cases make interpretation and comparability of the studies difficult. Therefore, well-designed randomised, placebo-controlled, double-blind studies with uniform primary outcome criteria are needed in order to clarify whether progesterone and via which route of administration and at which dosage is of clinical benefit for patients with manifest preterm contractions and as maintenance treatment after arrested preterm labour.
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Affiliation(s)
- Werner Rath
- Medizinische Fakultät Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Ruben-J Kuon
- Universitätsklinikum Heidelberg, Abteilung für Gynäkologische Endokrinologie und Fertilitätsstörungen, Heidelberg, Germany
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18
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Sisti G, Cozzolino M. Combining pessary, cerclage and vaginal progesterone to prevent preterm birth: Why not? J Gynecol Obstet Hum Reprod 2019; 48:435-436. [PMID: 30898629 DOI: 10.1016/j.jogoh.2019.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/19/2019] [Accepted: 03/15/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Giovanni Sisti
- Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, Bronx, NY, USA.
| | - Mauro Cozzolino
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA; Rey Juan Carlos University, Department of Gynecology and Obstetrics, Avenida de Atenas s/n, 28922, Alcorcón, Madrid, Spain; IVIRMA Madrid, Avenida del Talgo 68, 28023, Aravaca, Madrid, Spain
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