Decidualisation and placentation defects are a major cause of age-related reproductive decline

Woods, Laura; Pérez-García, Vicente; Kieckbusch, Jens; Wang, Xiaoqiu; DeMayo, Francesco J.; Colucci, Francesco; Hemberger, Myriam

doi:10.1038/s41467-017-00308-x

Cited by 115 publications

(123 citation statements)

References 68 publications

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“…[123][124][125] A recent study clearly showed that abnormal embryonic development in aged female mice was associated with severe placentation defects, which resulted from major deficits in the decidualization response of the uterine stroma. 126 The same study also revealed that the defect was rooted in a blunted estrogen and P4 responsiveness of the aging uterus. Importantly, that study also demonstrated, using an embryo transfer technique, that a young uterine environment can restore normal placental and embryonic development.…”

Section: Uterine Agingmentioning

confidence: 87%

“…In addition, ovarian aging, including the follicles themselves and granulosa cells, affected the reproductive outcomes in many species, including humans . A recent study clearly showed that abnormal embryonic development in aged female mice was associated with severe placentation defects, which resulted from major deficits in the decidualization response of the uterine stroma . The same study also revealed that the defect was rooted in a blunted estrogen and P4 responsiveness of the aging uterus.…”

Section: Outstanding Issuesmentioning

confidence: 99%

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Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

Namiki

Ito

Kashiwazaki

2018

Reprod Medicine & Biology

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BackgroundHuman infertility has become a serious and social issue all over the world, especially in developed countries. Numerous types of assisted reproductive technology have been developed and are widely used to treat infertility. However, pregnancy outcomes require further improvement. It is essential to understand the cross‐talk between the uterus (mother) and the embryo (fetus) in pregnancy, which is a very complicated event.MethodsThe mammalian uterus requires many physiological and morphological changes for pregnancy‐associated events, including implantation, decidualization, placentation, and parturition, to occur. Here is discussed recent advances in the knowledge of the molecular mechanisms underlying these reproductive events — in particular, embryonic implantation and decidualization — based on original and review articles.Main findings (Results)In mice, embryonic implantation and decidualization are regulated by two steroid hormones: estrogen and progesterone. Along with these hormones, cytokines, cell‐cycle regulators, growth factors, and transcription factors have essential roles in implantation and decidualization in mice.ConclusionRecent studies using the gene manipulation of mice have given considerable insight into the molecular mechanisms underlying embryonic implantation and decidualization. However, as most of the findings are based on mice, comparative research using different mammalian species will be useful for a better understanding of the species‐dependent differences that are associated with reproductive events, including embryonic implantation.

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Section: Uterine Agingmentioning

confidence: 87%

Section: Outstanding Issuesmentioning

confidence: 99%

Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

Namiki

Ito

Kashiwazaki

2018

Reprod Medicine & Biology

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“…This may be because the aging uterus cannot provide a normal placental and uterine environment for embryonic development. A previous study showed that in older female mice, the number of live offspring declined significantly even when the number of early implantation sites was the same as that of young mice (Woods, et al 2017). Age is also an important factor causing tubal factor infertility (Maheshwari, et al 2008) .…”

Section: Discussionmentioning

confidence: 98%

“…It is suggested that in women older than 38 years, the luteinizing granulosa cells are less numerous, there are lower concentrations of sex hormones and there is increased mitochondrial damage (Vollenhoven and Hunt 2018). The impact of maternal age on the uterus also decreases the success of pregnancy (Woods, et al 2017). This may be because the aging uterus cannot provide a normal placental and uterine environment for embryonic development.…”

Section: Discussionmentioning

confidence: 99%

The effects of human umbilical cord mesenchymal stem cell transplantation on female fertility preservation in mice

Zhang

Liu

Tang

et al. 2020

Preprint

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authors contributed equally to this work. AbstractFemale fertility is the capacity to produce oocytes and achieve fertilization and pregnancy, and these outcomes are impaired by age, diseases, environment and social pressure. However, there is no effective therapy that preserves female reproductive ability. Mesenchymal stromal cells (MSCs) can exhibit multidirectional differentiation potential, and they have gained great attention as a tool for preserving female fertility.Therefore, this study uses human umbilical cords-MSCs (Huc-MSCs) to preserve and restore fertility in aging female mice and chemotherapy-damaged mice through the rescue of ovarian function and the reconstruction of the fallopian tubes and uterus. In our study, 2 mouse models were generated: aging mice (37 weeks old) and chemotherapy-damaged mice. Then, we injected Huc-MSCs into mice through the tail vein. After treatment, the effect of MSCs on the ovary, fallopian tubes and uterus was evaluated by analyzing gonadal hormone levels and by performing morphological analysis and statistical analysis. The levels of E2 and FSH exhibited a significant recovery after HUC-MSC transplantation both in aging mice and mice treated with chemotherapy. Huc-MSC treatment also increased the numbers of primordial, developing and preovulatory follicles in the ovaries of mice. Meanwhile, MSCs have been shown to rescue the morphology of the fallopian tubes and uterus through mechanisms such as regenerating the cilia in fallopian tubes and reforming glands and chorionic villi in the uterus. Therefore, it is suggested that Huc-MSCs may represent an effective potential treatment for preserving female fertility through recovery from chemotherapy damage and rescuing female reproductive organs from the effects of aging.

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“…For sPTB, the magnitude of age modification may be small but aligns with biological sciences research on aging‐related impairments in reproductive functioning. For example, analyses of both human and rodent data suggest that advanced maternal age is associated with uterine dysfunction (eg, reduced decidualization) and altered utero‐placental vascular function (eg, enhanced myogenic response), even when samples are restricted to pregnancies with normal outcomes . Consequently, older mothers may experience more severe physiologic responses to the incomplete spiral artery remodeling, imbalance of angiogenic factors, oxidative stress, and inflammation that characterizes preeclampsia, possibly worsening ischemia and/or triggering sPTB .…”

Section: Discussionmentioning

confidence: 99%

Pregnancy complications and risk of preterm birth according to maternal age: A population‐based study of delivery hospitalizations in Alberta

Scime

Chaput

Faris

et al. 2019

Acta Obstet Gynecol Scand

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Introduction Pregnancy‐related medical complications are associated with a 2‐ to 5‐fold increased risk of preterm birth (PTB), but the nature of this etiologic relation in context with maternal factors remains poorly understood. Previous studies have generally treated maternal age as a confounder but overlooked its potential as an effect modifier, whereby the magnitude of the effect of complications on PTB could differ significantly across age groups. We investigated whether advanced maternal age (≥35 years) modified the association between pregnancy complications and PTB, and compared population‐attributable fractions of PTB from complications in women older vs younger than 35 years. Material and methods We analyzed population‐based, cross‐sectional data from the Alberta Discharge Abstract Database for women aged 18‐50 years with singleton live births in hospital between 2014 and 2017 (n = 152 246). Complications were preeclampsia, gestational diabetes, and placental disorders identified using diagnostic codes. Outcomes were spontaneous (sPTB) or iatrogenic (iPTB) PTB before 37 weeks of gestation. We estimated risk ratios and risk differences using modified Poisson and log binomial regression, respectively, adjusting for confounders (pregnancy history, comorbidities). Population‐attributable fractions estimates were calculated from risk ratios. Age modification was tested using interaction terms and Z‐tests. Results Prevalence of advanced maternal age was 19.2%. Pregnancy complications and s/iPTB were more common among women aged ≥35 years. Age modified the risk of PTB from preeclampsia only, with risk differences of 9.9% (95% CI 7.2%‐12.6%) in older women vs 6.1% (95% CI 4.8%‐7.4%) in younger women (P‐interaction = 0.012) for sPTB, and 29.5% (95% CI 26.0%‐33.1%) vs 20.8% (95% CI 18.9%‐22.6%, P‐interaction <0.001) for iPTB. Population‐attributable fractions of s/iPTB types for all complications were consistently 2%‐5% larger in women aged ≥35 years, and significantly larger for preeclampsia (sPTB: 5.1% vs 2.7%, P = 0.002; iPTB: 18.8% vs 14.0%, P < 0.001) and placental disorders (sPTB: 12.5% vs 8.7%, P < 0.001; iPTB: 13.2% vs 8.9%, P < 0.001). Conclusions Of the pregnancy complications studied, advanced maternal age only modified the association between PTB and preeclampsia, such that older women with preeclampsia have a higher risk for s/iPTB than younger counterparts. Pregnancy complications contribute to a sizable proportion of PTBs in Alberta, especially among women aged ≥35 years. Findings may inform clinical risk assessment and population‐level policy targeting PTB.

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Decidualisation and placentation defects are a major cause of age-related reproductive decline

Cited by 115 publications

References 68 publications

Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

The effects of human umbilical cord mesenchymal stem cell transplantation on female fertility preservation in mice

Pregnancy complications and risk of preterm birth according to maternal age: A population‐based study of delivery hospitalizations in Alberta

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