Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny

Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.

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Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency

Reproduction ◽

10.1530/rep-12-0006 ◽

2012 ◽

Vol 144 (1) ◽

pp. 91-100 ◽

Cited By ~ 17

Author(s):

Y B Ding ◽

J L He ◽

X Q Liu ◽

X M Chen ◽

C L Long ◽

...

Keyword(s):

Early Pregnancy ◽

Embryo Implantation ◽

Dna Methyltransferases ◽

Deficient Diet ◽

Mouse Uterus ◽

Dietary Folate ◽

Endometrial Cells ◽

Pregnant Mice ◽

Implantation Sites ◽

Significant Expression

We have characterized the uterine expression of DNA methyltransferases (DNMTs) during early pregnancy in mice and determined whether a folate-deficient diet (FDD) can affect DNMTs in this context. Within endometrial cells, expressions of DNMT (cytosine-5) 1 (Dnmt1),Dnmt3a, andDnmt3bwere significantly elevated during the prereceptive phase of pregnancy but generally returned to baseline levels during receptive and postimplantation periods. As such, the transcription of DNMT genes is temporally regulated during early pregnancy. When comparisons were made between implantation sites (IS) and inter-IS on day 5 of pregnancy, lower levels ofDnmt3awere detected at IS. Comparisons between IS and inter-IS did not reveal significant expression differences for other DNMT genes. When tissue sections were examined, DNMT3A was specifically lower in the stroma of IS. Reduced DNMT1 and DNMT3B levels were also observed in the luminal and glandular epithelia of IS, whereas no obvious differences in the stroma were detected. In pseudo-pregnant mice subjected to a FDD, levels ofDnmt1andDnmt3a(but notDnmt3b) were significantly upregulated in endometrial tissues, as compared with controls. When tissues from these folate-deficient mice were examined, DNMT1 levels were elevated in both the luminal and glandular epithelia, whereas DNMT3A was upregulated in the luminal epithelium and the stroma. A slight increase in DNMT3B levels was detected in the glandular epithelium. These results indicate that DNMTs may regulate the transcription of endometrial genes associated with embryo implantation and that levels of DNMTs are affected by dietary folate in mice.

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Nucleolar stress regulation of endometrial receptivity in mouse models and human cell lines

Cell Death and Disease ◽

10.1038/s41419-019-2071-6 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 5

Author(s):

Wei Hu ◽

Yu-Xiang Liang ◽

Jia-Mei Luo ◽

Xiao-Wei Gu ◽

Zi-Cong Chen ◽

...

Keyword(s):

Epithelial Cells ◽

Early Pregnancy ◽

Embryo Implantation ◽

Uterine Receptivity ◽

Positive Effects ◽

Delayed Implantation ◽

Nucleolar Stress ◽

Pregnant Mice ◽

Successful Establishment ◽

Luminal Epithelial Cells

Abstract Embryo implantation is essential to the successful establishment of pregnancy. A previous study has demonstrated that actinomycin D (ActD) could initiate the activation of mouse delayed implantation. However, the mechanism underlying this activation remains to be elucidated. A low dose of ActD is an inducer of nucleolar stress. This study was to examine whether nucleolar stress is involved in embryo implantation. We showed that nucleolar stress occurred when delayed implantation was activated by ActD in mice. ActD treatment also stimulated the Lif-STAT3 pathway. During early pregnancy, nucleolar stress was detected in the luminal epithelial cells during the receptive phase. Blastocyst-derived lactate could induce nucleolar stress in cultured luminal epithelial cells. The inhibition of nucleophosmin1 (NPM1), which was a marker of nucleolar stress, compromised uterine receptivity and decreased the implantation rates in pregnant mice. To translate these mouse data into humans, we examined nucleolar stress in human endometrium. Our data demonstrated that ActD-induced nucleolar stress had positive effects on the embryo attachment by upregulating IL32 expression in non-receptive epithelial cells rather than receptive epithelial cells. Our data should be the first to demonstrate that nucleolar stress is present during early pregnancy and is able to induce embryo implantation in both mice and humans.

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Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis

Nature Communications ◽

10.1038/s41467-021-23571-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Diana Monsivais ◽

Takashi Nagashima ◽

Renata Prunskaite-Hyyryläinen ◽

Kaori Nozawa ◽

Keisuke Shimada ◽

...

Keyword(s):

Progesterone Receptor ◽

Bone Morphogenetic Proteins ◽

Early Pregnancy ◽

Embryo Implantation ◽

Endometrial Receptivity ◽

Bmp Signaling ◽

Conditional Deletion ◽

Pregnant Mice ◽

Endometrial Epithelium

AbstractDuring early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.

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Platelet-activating factor-antagonists reduce implantation in mice at low doses only

Reproduction Fertility and Development ◽

10.1071/rd9950051 ◽

1995 ◽

Vol 7 (1) ◽

pp. 51 ◽

Cited By ~ 10

Author(s):

C O'Neill

Keyword(s):

Early Pregnancy ◽

Embryo Implantation ◽

Platelet Activating Factor ◽

Implantation Rate ◽

Corpora Lutea ◽

Detailed Knowledge ◽

Low Doses ◽

Paf Antagonists ◽

Implantation Sites ◽

Web 2086

The effects of a number of platelet-activating factor (PAF)-antagonists on embryo implantation were investigated. Mice were treated from Day 1 to Day 4 of pregnancy with three defined PAF-antagonists: SRI 63 441, BN 52021, and WEB 2086. Necroscopies were performed on Day 8 and the number of implantation sites, the implantation rate (number of implanted embryos compared with the number of corpora lutea) and the proportion of animals pregnant were determined. Each agent caused a reduction in the number of implantation sites at relatively low doses. The dose that had a maximum contragestational effect was 40 micrograms, 10 micrograms and 10 micrograms (per 30 g bodyweight per day) for SRI 63 441, WEB 2086 and BN 52021 respectively. This contragestational effect was completely lost at twice (SRI 63 441), five times (WEB 2086) and ten times (BN 52021) the most effective dose. Treatment with WEB 2086 on the day of implantation (Day 4) by intraperitoneal injection or instillation into the uterus only did not significantly reduce the implantation rate and neither did treatment after implantation (Days 5-8). The results show that the pharmacology of PAF-antagonists in early pregnancy is not simple. An understanding of the actions of these agents in early pregnancy will require a detailed knowledge of their pharmacokinetics, pharmacodynamics and targets of action in early pregnancy.

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Gain-of-function β-catenin in the uterine mesenchyme leads to impaired implantation and decidualization

Journal of Endocrinology ◽

10.1530/joe-16-0502 ◽

2017 ◽

Vol 233 (1) ◽

pp. 119-130 ◽

Cited By ~ 10

Author(s):

Amanda L Patterson ◽

Jamieson Pirochta ◽

Stephanie Y Tufano ◽

Jose M Teixeira

Keyword(s):

Epithelial Cell ◽

Early Pregnancy ◽

Embryo Implantation ◽

Junctional Complex ◽

Mullerian Duct ◽

Mesenchymal Tumors ◽

Gain Of Function ◽

Müllerian Duct ◽

Duct Development

Embryo implantation and endometrial decidualization are critical events that occur during early pregnancy in humans and mice, and perturbation in either can result in infertility. WNT signaling through the canonical β-catenin pathway plays a pivotal role in embryonic Müllerian duct development, postnatal uterine maturation and establishment of pregnancy. Loss of β-catenin in the Müllerian duct mesenchyme (MDM)-derived stroma and myometrium results in impaired decidualization and infertility, whereas gain-of-function (GOF) results in the formation of mesenchymal tumors and sub-fertility attributed to malformed oviducts. We hypothesized that GOF β-catenin further contributes to sub-fertility through improper stromal and epithelial cell signaling during embryo implantation and decidualization. We show that mice with GOF β-catenin in MDM-derived stroma and myometrium have reduced implantation sites after embryo transfer and decreased decidualization. On day 4.5 of pseudopregnancy or in mice treated with progesterone and estrogen to mimic early pregnancy, the estrogen–LIF–ERK and progesterone–IHH pathways remain predominantly intact in GOF β-catenin mice; however, JAK/STAT signaling is altered. pSTAT3 is significantly reduced in GOF β-catenin mice and expression of downstream epithelial junctional complex factors, Ctnna1 and Cldn1, is increased. We also show that purified stromal cells from GOF β-catenin uteri, when removed from epithelial cell influence and provided with the appropriate hormonal stimuli, are able to decidualize in vitro indicating that the cells are intrinsically capable of decidualization. Taken together, these results suggest that dysregulated β-catenin activity in the stroma affects epithelial cell STAT3 signaling and ultimately embryo implantation and stromal decidualization.

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Vertebral malformation in the mouse foetus caused by X-radiation of the mother during pregnancy

Development ◽

10.1242/dev.12.4.841 ◽

1964 ◽

Vol 12 (4) ◽

pp. 841-850

Author(s):

Ujihiro Murakami ◽

Yoshiro Kameyama

Keyword(s):

Early Pregnancy ◽

Vertebral Column ◽

Strain Differences ◽

In Utero ◽

Oxygen Deprivation ◽

Experimental Animals ◽

Vertebral Malformation ◽

Pregnant Mice ◽

Maternal Hypoxia ◽

In Pregnancy

Maternal hypoxia in early pregnancy can result in malformations of the vertebrae of mouse foetuses, and there is a tendency for more posterior vertebrae to be affected the later in pregnancy the oxygen deprivation occurs (Murakami & Kameyama, 1963). Ingalls et al. (1957) and Degenhardt (1954, 1959) had earlier obtained similar results. We have also exposed pregnant mice to X-radiation and studied the consequent malformations. The effects on the extremities have already been described (Murakami, Kameyama & Nogami, 1963), and in the present paper we shall describe the effects on the vertebral column. Vertebral malformations in animals irradiated in utero have been described by Job, Leibold & Fitzmaurice (1935), Warkany and Schraffenberger (1947), Russell. (1950, 1954), and Russell & Russell (1954). In order to obtain results comparable with those of our experiments with hypoxia, no less than to detect inter-strain differences, we used mice of the ddN and CF1 strains originally supplied by the Central Laboratories for Experimental Animals, Tokyo (Zikkendobutsu Chuo Kenkyujo).

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Thrombotic thrombocytopenic purpura in early pregnancy with maternal and fetal survival

Annals of Hematology ◽

10.1007/bf01738304 ◽

1992 ◽

Vol 64 (5) ◽

pp. 245-248 ◽

Cited By ~ 14

Author(s):

E. Rozdzinski ◽

B. Hertenstein ◽

T. Schmeiser ◽

E. Seifried ◽

E. Kurrle ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Early Pregnancy ◽

Thrombocytopenic Purpura ◽

Fetal Survival

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Perfluorooctanoic Acid Exposure in Early Pregnancy Induces Oxidative Stress in The Uterus and Liver in Mice

10.21203/rs.3.rs-160447/v1 ◽

2021 ◽

Author(s):

Yan Zhang ◽

Linchao Zhang ◽

JiaLu Bao ◽

LianTao Liu ◽

Xiaodan Wang

Keyword(s):

Early Pregnancy ◽

Caspase 3 ◽

Liver Toxicity ◽

Liver Weight ◽

Perfluorooctanoic Acid ◽

Control Group ◽

Dependent Manner ◽

Subsequent Increase ◽

Decidual Cells ◽

Pregnant Mice

Abstract To investigate the mechanism perfluorooctanoic acid (PFOA)’s toxicity on the uterus and liver of the mice during early pregnancy, pregnant mice were given 0, 1, 5, 10, 20, 40 mg/kg PFOA daily by gavage from gestational day (GD) 1-7, and sacrificed on GD 9. Uterus and liver weight were recorded, liver and uterine indexes were calculated, histopathological changes of the liver and uterus were examined, and levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) in liver were detected by spectrophotometric method. Expression of FAS, FASL, Bax, Bcl-2, and Caspase-3 in decidual cells were detected by immunohistochemistry and the TUNEL method was used to detect apoptotic uterine cells. Results showed that liver weight increased, and the uterus index was significantly reduced at 40 mg/kg compared with the control group. With increasing doses of PFOA, levels of SOD and GSH-PX were significantly decreased, and MDA significantly increased in liver tissue. 20 mg/kg and 40 mg/kg of PFOA caused greater harm to the uterus and congestion and resorption may occur. Expression of FAS, FASL, Bax, and Caspase-3 in decidual cells of the uterus in PFOA treatment groups significantly increased in a dose-dependent manner. The expression of Bcl-2 was down-regulated, which decreased the ratio of Bcl-2/Bax. It is therefore proposed that oxidative damage may be one of the mechanisms by which PFOA induces liver toxicity, and a subsequent increase in uterine cell apoptosis may induce embryo loss or damage.

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226.Regulated expression of adhesion and anti-adhesion molecules in mouse endometrium during early pregnancy

Reproduction Fertility and Development ◽

10.1071/srb04abs226 ◽

2004 ◽

Vol 16 (9) ◽

pp. 226 ◽

Cited By ~ 1

Author(s):

M. J. Jasper ◽

A. Stocker ◽

S. A. Robertson

Keyword(s):

Real Time ◽

Adhesion Molecules ◽

Early Pregnancy ◽

Embryo Implantation ◽

Early Embryo ◽

Luminal Epithelium ◽

Paracrine Factors ◽

Mean Values ◽

Actin Mrna ◽

Further Development

To implant and establish the connections that are vital for further development, the early embryo must attach to and then breech the barrier posed by the epithelium of the maternal tract. Expression of adhesion and anti-adhesion molecules in the luminal epithelium of the endometrium are thought to fluctuate in a temporal pattern to 'frame' the implantation site, with their expression regulated by endocrine and paracrine factors. Anti-adhesion molecules, such as members of the mucin family, provide a barrier to implantation in sites or at times unsuitable for embryo development. Expression of adhesion molecules, or specific integrins, are thought to aid in the adhesion of the embryo, allowing it to induce changes in the underlying tissue promoting embryo invasion and pregnancy. The aim of this study was to quantitate the expression of mRNA encoding the integrins αυ, α4 and β3 and MUC1 and MUC4 from Day 0 (oestrous) to Day 4 of pregnancy (implantation) using quantitative real time RT-PCR. Uterine tissues were collected at oestrous and at Days 1, 2, 3 and 4 of pregnancy (Day 1 corresponding to the presence of a vaginal plug), total RNA was extracted, DNAse treated, reverse transcribed into cDNA, and quantified by real-time PCR using SYBR Green chemistry. All specific primers were designed using GenBank sequences and data were normalised to β-actin mRNA expression. Expression of MUC1 and MUC4 mRNAs was dramatically reduced, with mean values 20-fold and 100-fold less than at oestrous respectively, by Day 4 of pregnancy. In contrast, expression of mRNAs encoding integrins αυ, α4 and β3 was detected throughout early pregnancy. These data demonstrate that adhesion and anti-adhesion molecules are differentially expressed in the murine uterus during early pregnancy and may be key mediators in embryo implantation, promoting attachment of the embryo to the luminal epithelium in an environment conducive to embryo growth and development. Supported by a Clive & Vera Ramaciotti Project Grant to MJ Jasper.

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Dydrogesterone in the treatment of the threatened and habitual miscarriage

Medical Council ◽

10.21518/2079-701x-2018-13-68-72 ◽

2018 ◽

pp. 68-72 ◽

Cited By ~ 2

Author(s):

N. K. Tetruashvili ◽

A. A. Agadzhanova

Keyword(s):

Early Pregnancy ◽

Comparative Evaluation ◽

Meta Analysis ◽

Reproductive Disorders

The article presents the findings of the studies evaluating the efficacy of gestagens in the treatment of the threatened and habitual miscarriage. It summarizes a number of meta-analysis related to the comparative evaluation of the use of various gestagens during pregnancy. The foreign societies’ guidelines for the treatment of reproductive disorders and the management of early pregnancy in women with the threatened and habitual miscarriage are outlined.

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