Recurrent pre-clinical pregnancy loss is unlikely to be a 'cause' of unexplained infertility
ABSTRACT A proportion of women with 'unexplained' infertility may present with subfertility because their pregnancies fail before they are clinically recognized. In order to test whether pre-clinical early pregnancy losses (EPL) occur more frequently in women with unexplained infertility, serial urinary hCG concentrations were measured to compare EPL per cycle rates following spontaneous conception in patients with unexplained infertility versus healthy volunteers.
Sixty patients under 39 years of age with unexplained infertility and 60 healthy controls, who were trying to conceive spontaneously, participated in this study. All participants were asked to collect daily urine samples from cycle day 14 until menstruation for three consecutive cycles or until a positive pregnancy test was obtained. Urinary hCG and creatinine levels were measured by immunoassay. Implantation was detected when urinary hCG levels rose above reference levels constructed from samples obtained from 12 women not attempting to conceive. EPL rates were determined by a linear mixed model using logarithmically transformed hCG/creatinine data.
In the 133 cycles of 60 women with unexplained infertility, just one implantation was detected, which became an ongoing pregnancy. In contrast, in 103 such cycles in 46 control patients, 30 implantations were detected (24 clinical pregnancies, 6 cases of EPL). The odds ratio for EPL/cycle in the unexplained versus control group was 0 (95% confidence interval: 0-0.795, P = 0.026).
Our data do not support the hypothesis that recurrent EPL may present as unexplained infertility. Post-implantation failure is therefore unlikely to contribute significantly to the presentation of subfertility.
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ABSTRACT: Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive, however recent studies have revealed alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure; one of the altered miRs is miR-145. We assessed the role of miR-145 and its target, IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. QPCR, western blotting and 3'UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF-I-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. miR-145/IGF1R target protectors prevented miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.
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ABSTRACT: Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions. To develop our hypothesis, we modeled this process in the mouse after inactivation of protein BubR1, one of the key players of SAC. We found that soon after implantation, more than 50 % of cells of BubR1 (-/-) embryos were aneuploid and had an increased level of premature sister chromatid separation (PSCS). Aneuploid cells do not have a predominant gain or loss of some specific chromosomes, but they have mosaic variegated aneuploidy (MVA), which is characterised by random mixture of different chromosomes. MVA leads to growth retardation, stochastic massive apoptosis, disruption of bilateral symmetry, and embryo death between embryonic days 7.5 to 13.5. Analysis published human data revealed that human recurrent pregnancy loss (RPL) embryos and rare infant patients carrying BubR1 mutations that have been described so far have the PSCS and MVA as in BubR1 deficient/insufficient mice. Based on this data, we predict that deficiency/insufficiency of BubR1 and other components of the SAC in human are responsible for a significant fraction of both early and late RPLs.Chromosome Research 07/2014; 22(3). DOI:10.1007/s10577-014-9432-x · 2.69 Impact Factor
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ABSTRACT: Background/Aims: Recent investigations in both males and females show that there may also be some genetic risk factors associated with infertility, and endothelial nitric oxide synthase (eNOS) has important functions in implantation. We aimed to investigate the association of three different polymorphisms of eNOS (promoter -786T/C, exon 894 G/T and intron G10T) with unexplained female infertility. Materials and Methods: Two groups of patients were included in the study: (1) women with unexplained infertility and (2) healthy, fertile women with normal menstrual cycles. eNOS polymorphisms were studied in genomic DNA of each patient by polymerase chain reaction-restriction fragment length polymorphism method. Results: Forty-one women with unexplained infertility and 40 fertile women were included. Baseline physical characteristics and hormonal parameters of the two groups were similar. For eNOS exon 894 G/T polymorphism, the GG homozygotes were significantly lower and the heterozygotes GT were significantly higher in the infertile group than in the control group (p < 0.05). eNOS gene polymorphism both for promoter and intron were similar in the two groups (p > 0.05). Conclusion: Altered eNOS protein caused by eNOS exon 894 G/T polymorphism might cause implantation failure, which may be a possible cause of unexplained female infertility. © 2014 S. Karger AG, Basel.Gynecologic and Obstetric Investigation 02/2014; 77(2). DOI:10.1159/000357442 · 1.25 Impact Factor