Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

The role of the hedgehog (HH) signaling pathway in implantation was studied in mice in which the HH signal transducer, smoothened (SMO), was conditionally deleted in the stromal compartment of the uterus, using CRE recombinase expressed through the Amhr2cre allele. In Amhr2cre/+Smonull/flox-mutant mice, Smo mRNA in uterine stroma was reduced 49% compared to that in Amhr2+/+Smonull/flox control mice, while levels in the luminal epithelium were not different. Litter size was reduced 60% in mutants compared with controls, but ovulation rate and the number of implantation sites on day 7 of pregnancy did not differ. The number of corpora lutea was equivalent to the number of implantation sites, indicating that most ovulations resulted in implanted embryos. However, on days 13 to 15, the rate of embryo resorption was elevated in mutants. In control mice, on day 5, implantation sites were present and blastocysts were well-attached. In contrast, blastocysts were readily flushed from uteri of mutant mice on day 5 and implantation sites were rare. On days 5.5 and 6, implantation sites were present in mutant mice, and by day 6 embryos could not be flushed from the uterus. The weight of implantation sites on day 7 was decreased by 42% in mutant mice, consistent with delayed development. Signaling through SMO in the endometrial stroma is required for optimal timing of implantation, and deferred implantation leads to defective embryo development and subsequent pregnancy loss.

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Preconception antiphospholipid antibodies and risk of subsequent early pregnancy loss

Lupus ◽

10.1177/0961203318776089 ◽

2018 ◽

Vol 27 (9) ◽

pp. 1437-1445 ◽

Cited By ~ 4

Author(s):

K J Gibbins ◽

S L Mumford ◽

L A Sjaarda ◽

D W Branch ◽

N J Perkins ◽

...

Keyword(s):

Early Pregnancy ◽

Antiphospholipid Antibodies ◽

Pregnancy Loss ◽

Cardiac Activity ◽

Subsequent Pregnancy ◽

Early Pregnancy Loss ◽

Case Control Studies ◽

Clinical Trial Registration ◽

Live Births ◽

Embryonic Loss

Objectives To prospectively estimate the association of preconception antiphospholipid antibodies (aPL) with subsequent pregnancy loss using a cohort design. aPL have been associated with recurrent early pregnancy loss (EPL) prior to 10 weeks in previous case-control studies. Prospective ascertainment of pregnancy loss is challenging, as most women do not seek care prior to EPL. Methods Secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial of preconception low-dose aspirin. Preconception anticardiolipin (aCL) and anti-β2-glycoprotein-I (a-β2-I) were assessed in 1208 women with one or two prior pregnancy losses and no more than two prior live births. Comparison cohorts were defined by positive aPL (+aPL) or negative aPL (–aPL) status. All women were followed for six menstrual cycles while trying to conceive; if successful, they underwent an ultrasound at 6–7 weeks’ gestation. EPL was defined as loss prior to 10 weeks’ gestation; embryonic loss was loss after visualization of an embryo but prior to 10 weeks; clinical loss was any loss after visualization of an embryo (with or without fetal cardiac activity detected). Results In total, 14/1208 (1%) tested positive for +aPL. 786/1208 (65%) women had positive human chorionic gonadotropin during the study period, of which 9/786 (1%) had +aPL. Of the 786 pregnant women, 589 (75%) had live births and 24% had pregnancy losses. Women with +aPL experienced EPL at similar rates as women with –aPL, 44% vs 21% (aRR 2.4, 95% confidence interval (CI) 0.5–10.9). Embryonic loss was more common in women with +aCL IgM (aRR 4.8, 95% CI 1.0–23.0) and in women with two positive aPL. Clinical pregnancy loss was more common in women with positive a-β2-I IgM (50% vs 16.5%, aRR 3.7, 95% CI 1.3–10.8). Conclusion Positive levels of aPL are rare in women with one or two prior pregnancy losses and are not clearly associated with an increased rate of subsequent loss. Clinical trial registration The original source study was registered at ClinicalTrials.gov (#NCT00467363).

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ZUR BEDEUTUNG DES HYPOPHYSÄREN LUTEINISIERUNGSHORMONS FÜR SCHWANGERSCHAFT, GEBURT UND LACTATION BEI DER RATTE

Acta Endocrinologica ◽

10.1530/acta.0.065s005 ◽

1970 ◽

Vol 65 (3_Suppl) ◽

pp. S5-S32 ◽

Cited By ~ 2

Author(s):

K. Loewit

Keyword(s):

Luteinizing Hormone ◽

Early Pregnancy ◽

Hydroxysteroid Dehydrogenase ◽

The State ◽

Termination Of Pregnancy ◽

Progesterone Level ◽

Corpora Lutea ◽

Regulatory Properties ◽

Duration Of Pregnancy

ABSTRACT The role of luteinizing hormone (LH) for the maintenance of pregnancy, parturition and lactation was investigated by immunological and histochemical methods in the rat. Neutralisation of endogenous rat-LH with Rabbit-Anti-Bovine-LH-Serum (selective hypophysectomy) from days 7-12 of pregnancy resulted in reabsorption of the foetuses and the reappearance of strong 20α-hydroxysteroid-dehydrogenase (20α-OHSD) activity in the corpora lutea (CL) of pregnancy, which normally show no such activity at that time. This effect could be prevented in part by concurrent pregnenolone administration and fully by progesterone, but was not influenced by oestrogen or prolactin. It is concluded that in early pregnancy LH is the main luteotrophic hormone in the rat even though prolactin might act synergistically with it. Antiserum treatment after the 12th day of gestation had no influence on the state or duration of pregnancy or on parturition. LH-injections during the first half of pregnancy had no luteolytic effects i. e. they did not activate 20α-OHSD activity. After day 16 they advanced the reappearance of the enzyme, but delayed parturition or resulted in stillbirths. Neither LH nor antiserum seemed to alter lactation. Since progesterone prevented both the termination of pregnancy and the recurrence of 20α-OHSD activity, it should have some regulatory properties on the enzyme. It is discussed whether the gonadotrophin-dependent progesterone level could regulate the 20α-OHSD activity rather than result from it.

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Production of interferon by red deer (Cervus elaphus) conceptuses and the effects of roIFN-tau on the timing of luteolysis and the success of asynchronous embryo transfer

Reproduction ◽

10.1530/reprod/118.2.387 ◽

2000 ◽

pp. 387-395 ◽

Cited By ~ 6

Author(s):

KJ Demmers ◽

HN Jabbour ◽

DW Deakin ◽

AP Flint

Keyword(s):

Embryo Transfer ◽

Early Pregnancy ◽

Cervus Elaphus ◽

Pregnancy Loss ◽

Red Deer ◽

Interferon Tau ◽

Recombinant Interferon ◽

Uterine Flushing ◽

Calving Rate

The role of interferon in early pregnancy in red deer was investigated by (a) measuring production of interferon by the conceptus, (b) testing the anti-luteolytic effect of recombinant interferon-tau in non-pregnant hinds, and (c) treatment of hinds with interferon after asynchronous embryo transfer. Blastocysts were collected from 34 hinds by uterine flushing 14 (n = 2), 16 (n = 2), 18 (n = 8), 20 (n = 13) or 22 (n = 9) days after synchronization of oestrus with progesterone withdrawal. Interferon anti-viral activity was detectable in uterine flushings from day 16 to day 22, and increased with duration of gestation (P < 0.01) and developmental stage (P < 0.01). When interferon-tau was administered daily between day 14 and day 20 to non-pregnant hinds to mimic natural blastocyst production, luteolysis was delayed by a dose of 0.2 mg day(-1) (27.3 +/- 1.3 days after synchronization, n = 4 versus 21 +/- 0 days in control hinds, n = 3; P < 0.05). Interferon-tau was administered to hinds after asynchronous embryo transfer to determine whether it protects the conceptus against early pregnancy loss. Embryos (n = 24) collected on day 6 from naturally mated, superovulated donors (n = 15) were transferred into synchronized recipients on day 10 or day 11. Interferon-tau treatment (0.2 mg daily from day 14 to 20) increased calving rate from 0 to 64% in all recipients (0/11 versus 7/11, P < 0.005), and from 0 to 67% in day 10 recipients (0/8 versus 6/9, P < 0.01). The increased success rate of asynchronous embryo transfer after interferon-tau treatment in cervids may be of benefit where mismatched embryo-maternal signalling leads to failure in the establishment of pregnancy.

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Effect of Exposure to Mixture of Heavy Metals Arsenic, Cadmium and Lead on Reproductive Function and Oxidative Stress in Female Rats

INTERNATIONAL JOURNAL OF TOXICOLOGICAL AND PHARMACOLOGICAL RESEARCH ◽

10.25258/ijtpr.v9i03.9075 ◽

2017 ◽

Vol 9 (03) ◽

Author(s):

Choudhuri D. ◽

Bhattacharjee T.

Keyword(s):

Oxidative Stress ◽

Heavy Metals ◽

Ascorbic Acid ◽

Reproductive Function ◽

Reproductive Organs ◽

Female Rats ◽

Corpora Lutea ◽

Oestrus Cycle ◽

Implantation Sites ◽

Live Fetus

Background : Toxicological consequences arising from exposure to mixtures of heavy metals especially at low, chronic and environmentally relevant doses are poorly recognised. In the present study, we evaluated effects of chronic exposure to combinations of three metals arsenic (As), cadmium (Cd) and lead (Pb) present frequently in drinking water on reproductive function and oxidative damage caused to reproductive organs of female rats. Method : Female rats were exposed to mixture of metals (As, Cdand Pb) for 90 consecutive days. The gain in body weight and weight of reproductive organs were recorded following autopsy on 91 stday. The oestrus cycle were monitored during entire treatment period. Numbers of corpora lutea, implantation sites, live fetus and survival of the fetus were evaluated in rats mated successfully with untreated male after completion of their respective treatment. Ovarian cholesterol, protein, ascorbic acid and enzyme Δ 5 -3β HSD levels were estimated. Serum levels of steroid hormones oestrogen and progesterone were estimated. Histopathological picture of both ovary and uterus were assessed. Levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidise (GPX) activity, amount of reduced glutathione (GSH) and malondyaldehyde (MDA) in blood, ovary and uterus were measured as biomarkers of oxidative stress. Results : The treated rats showed reduced body weight gain and reduction in the weight of ovary and uterus. Oestrus cycle was disrupted with continuous diestrous in treated animals. Number of corpora lutea, implantation sites and live fetus and the survival of fetus evaluate were reduced significantly in treated groups. The levels of ovarian cholesterol and ascorbic acid increased in treated rats with decrease Δ5 -3β HSD level. There was reduction in serum level of both the ovarian steroid hormones oestrogen and progesterone. The protein levels did not differ between the groups. There was a significant increase in levels of MDA and decrease in levels of all the antioxidant enzymes in treated group. Conclusion : The results revealed there was disruption to reproductive functions with decrease in stereoidogenic activity and associated oxidative stress in female rats treated with combination of mixture of metals (Cd, As and Pb) at low dose for 90 consecutive days.

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Idiopathic recurrent pregnancy loss - role of pre implantation genetic screening

10.26226/morressier.5912d9ead462b802923861f0 ◽

2017 ◽

Author(s):

Venkata Vellanki

Keyword(s):

Genetic Screening ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss

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Mice with mutations in Trpm1, a gene in the locus of 15q13.3 microdeletion syndrome, display pronounced hyperactivity and decreased anxiety-like behavior

Molecular Brain ◽

10.1186/s13041-021-00749-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tesshu Hori ◽

Shohei Ikuta ◽

Satoko Hattori ◽

Keizo Takao ◽

Tsuyoshi Miyakawa ◽

...

Keyword(s):

Visual Impairment ◽

Wide Spectrum ◽

Genetic Disorder ◽

Mutant Mice ◽

Chromosome 15 ◽

Microdeletion Syndrome ◽

Visual Transduction ◽

The Central Nervous System ◽

Null Mutant Mice

AbstractThe 15q13.3 microdeletion syndrome is a genetic disorder characterized by a wide spectrum of psychiatric disorders that is caused by the deletion of a region containing 7 genes on chromosome 15 (MTMR10, FAN1, TRPM1, MIR211, KLF13, OTUD7A, and CHRNA7). The contribution of each gene in this syndrome has been studied using mutant mouse models, but no single mouse model recapitulates the whole spectrum of human 15q13.3 microdeletion syndrome. The behavior of Trpm1−/− mice has not been investigated in relation to 15q13.3 microdeletion syndrome due to the visual impairment in these mice, which may confound the results of behavioral tests involving vision. We were able to perform a comprehensive behavioral test battery using Trpm1 null mutant mice to investigate the role of Trpm1, which is thought to be expressed solely in the retina, in the central nervous system and to examine the relationship between TRPM1 and 15q13.3 microdeletion syndrome. Our data demonstrate that Trpm1−/− mice exhibit abnormal behaviors that may explain some phenotypes of 15q13.3 microdeletion syndrome, including reduced anxiety-like behavior, abnormal social interaction, attenuated fear memory, and the most prominent phenotype of Trpm1 mutant mice, hyperactivity. While the ON visual transduction pathway is impaired in Trpm1−/− mice, we did not detect compensatory high sensitivities for other sensory modalities. The pathway for visual impairment is the same between Trpm1−/− mice and mGluR6−/− mice, but hyperlocomotor activity has not been reported in mGluR6−/− mice. These data suggest that the phenotype of Trpm1−/− mice extends beyond that expected from visual impairment alone. Here, we provide the first evidence associating TRPM1 with impairment of cognitive function similar to that observed in phenotypes of 15q13.3 microdeletion syndrome.

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The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta-analysis

Taiwanese Journal of Obstetrics and Gynecology ◽

10.1016/j.tjog.2020.11.001 ◽

2021 ◽

Vol 60 (1) ◽

pp. 1-8

Author(s):

Fangfei Jiang ◽

Xiuying Hu ◽

Kang Jiang ◽

Hongxia Pi ◽

Qiyao He ◽

...

Keyword(s):

Systematic Review ◽

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Meta Analysis ◽

Low Molecular Weight

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Pineal denervation by cervical sympathetic ganglionectomy suppresses the role of photoperiod on pregnancy or pseudopregnancy, body weight and moulting periods in the mink (Mustela vison)

Journal of Endocrinology ◽

10.1677/joe.0.1070031 ◽

1985 ◽

Vol 107 (1) ◽

pp. 31-39 ◽

Cited By ~ 19

Author(s):

L. Martinet ◽

D. Allain ◽

Y. Chabi

Keyword(s):

Body Weight ◽

Environmental Factors ◽

Prolactin Secretion ◽

Corpora Lutea ◽

Progesterone Secretion ◽

Cervical Ganglion ◽

Cervical Sympathetic ◽

Implantation Period ◽

Short Days

ABSTRACT In mink, termination of the delayed implantation period, following reactivation of the corpora lutea, and onset of the spring moult are associated with a rise in prolactin secretion triggered by increasing daylength, while decreasing daylength induces the autumn moult. To establish whether suppression of the function of the pineal rendered the mink unresponsive to daylength changes, the superior cervical ganglion was removed bilaterally 2–4 weeks before mating. Intact and operated females were then left outdoors or were put under a lighting regime of either 15 h light: 9 h darkness (15L: 9D) or 8L: 16D. In July, at the end of the spring moult, the 15L: 9D lighting regime was changed to one of 8L: 16D. Under artificial photoperiods ganglionectomy suppressed the stimulatory role of long days and the inhibitory role of short days on prolactin secretion, and consequently on progesterone secretion and spring moult. Neither was the autumn moult, induced early in intact females by the change to a short photoperiod, advanced in ganglionectomized females, showing that the latter were unresponsive to the artificial modification of the photoperiod. However, in animals kept outdoors, prolactin and progesterone secretion and spring moult were not changed by ganglionectomy. Increase in body weight and autumn moult were only slightly delayed by the operation suggesting that other environmental factors had replaced the synchronizing effect of the daylength changes. Alternatively the desynchronization between intact females responsive to photoperiodism and those rendered unresponsive may be too slow to be observed soon after ganglionectomy. J. Endocr. (1985) 107, 31–39

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The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples

Thrombosis and Haemostasis ◽

10.1160/th-09-04-0224 ◽

2009 ◽

Vol 102 (10) ◽

pp. 656-667 ◽

Cited By ~ 9

Author(s):

Pascale Fabbro-Peray ◽

Pierre Marès ◽

Patrick Mismetti ◽

Géraldine Lissalde-Lavigne ◽

Éva Cochery-Nouvellon ◽

...

Keyword(s):

Protein C ◽

Pregnancy Loss ◽

Receptor Gene ◽

Coagulation Factor ◽

Factor V ◽

Endothelial Protein C Receptor ◽

Foetal Loss ◽

Factor Ii ◽

Embryonic Loss ◽

Factor V Gene

SummaryThe endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10th week ≥ foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.

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