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ABSTRACT: The aim of the study was to determine the roles of intrafollicular and systemic oxidative stress and antioxidant response in ovarian stimulation and intracytoplasmic sperm injection (ICSI) outcomes. For this purpose, 102 ICSI patients undergoing controlled ovarian stimulation were enrolled and samples were collected on the day of follicle puncture. Total peroxide (TPX) concentrations and total antioxidant response (TAR) were measured in follicular fluid and blood plasma, and an oxidative stress index (OSI) was calculated based on these two parameters. Urinary concentrations of 8-iso-prostaglandin F(2a) (F(2)IsoP) were measured. Elevated intrafollicular oxidative stress was positively correlated with ovarian stimulation outcome: less FSH per retrieved oocyte was used, more oocytes were collected and higher serum oestradiol concentrations were measured in patients with higher follicular OSI. However, high urinary F(2)IsoP related to lower embryo quality and F(2)IsoP was also elevated in smoking patients. Patients with endometriosis had lower follicular antioxidant status. Most importantly, higher systemic blood TAR was significantly favourable for achieving clinical pregnancy (P=0.03). In conclusion, the findings suggest clear associations between oxidative stress, antioxidant status and several aspects of ovarian stimulation and IVF/ICSI outcome, including pregnancy rate. Several oxygen-dependent biochemical reactions produce reactive oxygen species as by-products that may eventually lead to oxidative stress, which is detrimental to cells and tissues. Total antioxidant status, on the other hand, comprises several agents that balance the excess of these reactive oxygen species and reduce potential damage to the body. The aim of the current work was to study this balance in 102 patients participating in an ICSI programme and to examine the degree to which total peroxide content and antioxidant status influence infertility and pregnancy outcome. During the study, several tests were performed to characterize oxidative stress levels in ovarian follicular fluid, blood plasma and urine. We found a significantly higher oxidative stress environment in the ovary when compared with blood plasma. This suggests a prominent role of oxidative stress in the ovaries of these patients. The elevated oxidative stress levels were correlated to a higher number of oocytes that could be obtained via the procedure and to a lower amount of FSH needed to mature the oocytes, suggesting that oxidative stress, to some degree, is favourable for hormone stimulation outcome. A high level of lipid peroxidation products in the urine, another marker of oxidative stress, was observed in smokers and this marker was elevated in patients with embryos that had lower developmental potential. A higher overall antioxidant status in blood plasma was advantageous for achieving pregnancy.
Reproductive biomedicine online 01/2013; · 2.04 Impact Factor
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ABSTRACT: Expression of survivin, an inhibitor of apoptosis, is increased in endometriotic lesions and probably favors the survival of endometrial fragments in the peritoneal cavity. The aim of this study was to evaluate associations between survivin promoter polymorphisms and the risk of endometriosis, as well as to compare the immunoreactivity to survivin in sera of patients with and without endometriosis. We studied 149 women with endometriosis, 196 fertile women from the general population (control group A) and 47 women who had undergone diagnostic laparoscopy and had no evidence of endometriosis (control group B). There were no significant differences in the genotypic distribution of the survivin gene promoter region -241C/T, -235G/A and -31G/C single nucleotide polymorphisms (SNP) between endometriosis patients and the two control groups. In addition, also median anti-survivin autoantibody levels were similar among patients and controls (group B). However, anti-survivin antibody concentrations seemed to be influenced by cigarette smoking, being significantly lower in sera of actively smoking women compared to non-smokers (median OD: 0.019 vs. 0.155, respectively, P<0.001), and by the -235G/A SNP, as A allele carriers were significantly more frequent among women with a high antibody level (OD≥2.0) compared to those with lower concentrations (OD<2.0) (23.1% vs. 4.1%, respectively, P=0.008). Based on these results, we conclude that survivin promoter polymorphisms are not associated with susceptibility to endometriosis in the Estonian population, and though the expression of survivin is increased in endometriotic lesions, autoimmune reactivity against it is similar in women with and without the disease.
Journal of Reproductive Immunology 11/2012; · 2.97 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) act as important epigenetic posttranscriptional regulators of gene expression. We aimed to gain more understanding of the complex gene expression regulation of endometrial receptivity by analyzing miRNA signatures of fertile human endometria. We set up to analyze miRNA signatures of receptive (LH + 7, n = 4) versus prereceptive (LH + 2, n = 5) endometrium from healthy fertile women. We found hsa-miR-30b and hsa-miR-30d to be significantly upregulated, and hsa-miR-494 and hsa-miR-923 to be downregulated in receptive endometrium. Three algorithms (miRanda, PicTar, and TargetScan) were used for target gene prediction. Functional analyses of the targets using Ingenuity Pathways Analysis and The Database for Annotation, Visualization and Integrated Discovery indicated roles in transcription, cell proliferation and apoptosis, and significant involvement in several relevant pathways, such as axon guidance, Wnt/β-catenin, ERK/MAPK, transforming growth factor β (TGF-β), p53 and leukocyte extravasation. Comparison of predicted miRNA target genes and our previous messenger RNA microarray data resulted in a list of 12 genes, including CAST, CFTR, FGFR2, and LIF that could serve as a panel of genes important for endometrial receptivity. In conclusion, we suggest that a subset of miRNAs and their target genes may play important roles in endometrial receptivity.
Reproductive sciences (Thousand Oaks, Calif.) 08/2012; · 2.31 Impact Factor
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ABSTRACT: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker of infection and inflammation.
We studied serum and follicular fluid sTREM-1 in infertile patients (N = 110) utilizing enzyme-linked immunosorbent assay.
Serum and follicular sTREM-1 were in good correlation (Pearson's correlation 0.56, P < 0.0001) with higher values in follicular fluid (140.4 ± 34.4 and 115.6 ± 35.1 pg/mL, t-test, P < 0.0001). Endometriosis associated with lower follicular and serum sTREM-1 compared with male factor infertility patients (age-adjusted r = -25.7 pg/mL, P = 0.018; r = -22.1 pg/mL, P = 0.030). No associations between follicular or serum sTREM-1 and clinical parameters were found, except higher serum sTREM-1 associated with lower embryo quality in all patients (adjusted r = -0.3%, P = 0.033), with a cutoff value between 111.5 and 113.3 pg/mL (OR = 0.38, P = 0.048; OR = 0.34, P = 0.028) predicting that more than 39% of embryos would be with good quality.
Serum sTREM-1 could represent a prognostic marker for female fecundity, probably indicating impaired inflammatory reaction of immune system.
American Journal Of Reproductive Immunology 01/2012; 68(1):68-74. · 2.17 Impact Factor
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ABSTRACT: Cytokines are key modulators of the immune system and also contribute to regulation of the ovarian cycle. In this study, Bender MedSystems FlowCytomix technology was used to analyze follicular cytokines (proinflammatory: IL-1β, IL-6, IL-18, IFN-γ, IFN-α, TNF-α, IL-12, and IL-23;, and anti-inflammatory: G-CSF), chemokines (MIP-1α, MIP-1β, MCP-1, RANTES, and IL-8), and other biomarkers (sAPO-1/Fas, CD44(v6)) in 153 women undergoing in vitro fertilization (IVF). Cytokine origin was studied by mRNA analysis of granulosa cells. Higher follicular MIP-1α and CD44(v6) were found to correlate with polycystic ovary syndrome, IL-23, INF-γ, and TNF-α with endometriosis, higher CD44(v6) but lower IL-β and INF-α correlated with tubal factor infertility, and lower levels of IL-18 and CD44(v6) characterized unexplained infertility. IL-12 positively correlated with oocyte fertilization and embryo development, while increased IL-18, IL-8, and MIP-1β were associated with successful IVF-induced pregnancy.
Clinical and Developmental Immunology 01/2012; 2012:606459. · 1.84 Impact Factor
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ABSTRACT: Female fertility can be affected by diseases or dysfunctions of reproductive tract, neuroendocrine system, and immune system. Reproductive autoimmune failure can be associated with overall activation of immune system or with immune system reactions specifically directed against ovarian antigens. Majority of the antiovarian autoantibodies are directed against β-subunit of follicle stimulating hormone (anti-FSH). This paper summarizes a current clinical classification of female infertility in the context of general activation of autoimmunity and antiovarian autoimmunity by describing serum anti-FSH. The presence of naturally occurring anti-FSH in healthy women will be discussed. In addition, the putative impairment of ovarian folliculogenesis in case of increased production of those antibodies in infertile women will be characterized.
Clinical and Developmental Immunology 01/2012; 2012:762541. · 1.84 Impact Factor
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Clinical and Developmental Immunology 01/2012; 2012:408329. · 1.84 Impact Factor
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ABSTRACT: The innate immune system provides the first-line defence against genital tract pathogens and is also involved in establishing and maintaining a successful pregnancy. Genetic variation of factors regulating immune response can be associated with complications after genital tract infections and may lead to unfavourable pregnancy outcomes. This study focused on four polymorphisms in the mannose binding lectin gene (MBL2) and assessed their significance in tubal damage and female fertility by comparing genotype frequencies among 388 controls and women with tubal factor infertility (n=155) or previous ectopic pregnancy (n=178). The high-producing MBL2 genotype HYA/LYA was found to have a protective effect, while the hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to tubal factor infertility. Also, the low-producing genotypes showed association with early pregnancy loss in IVF treatment. In conclusion, these data suggest that certain MBL2 genotypes can be associated with tubal damage in patients with evidence of Chlamydia trachomatis infection and additionally may contribute to the pathogenesis of early pregnancy loss.
Journal of Reproductive Immunology 12/2011; 92(1-2):62-7. · 2.97 Impact Factor
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Signe Altmäe,
Jüri Reimand,
Outi Hovatta,
Pu Zhang,
Juha Kere,
Triin Laisk,
Merli Saare,
Maire Peters,
Jaak Vilo,
Anneli Stavreus-Evers, Andres Salumets
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ABSTRACT: A prerequisite for successful embryo implantation is adequate preparation of receptive endometrium and the establishment and maintenance of a viable embryo. The success of implantation further relies upon a two-way dialogue between the embryo and uterus. However, molecular bases of these preimplantation and implantation processes in humans are not well known. We performed genome expression analyses of human embryos (n = 128) and human endometria (n = 8). We integrated these data with protein-protein interactions in order to identify molecular networks within the endometrium and the embryo, and potential embryo-endometrium interactions at the time of implantation. For that, we applied a novel network profiling algorithm HyperModules, which combines topological module identification and functional enrichment analysis. We found a major wave of transcriptional down-regulation in preimplantation embryos. In receptive-stage endometrium, several genes and signaling pathways were identified, including JAK-STAT signaling and inflammatory pathways. The main curated embryo-endometrium interaction network highlighted the importance of cell adhesion molecules in the implantation process. We also identified cytokine-cytokine receptor interactions involved in implantation, where osteopontin (SPP1), leukemia inhibitory factor (LIF) and leptin (LEP) pathways were intertwining. Further, we identified a number of novel players in human embryo-endometrium interactions, such as apolipoprotein D (APOD), endothelin 1 (END1), fibroblast growth factor 7 (FGF7), gastrin (GAST), kringle containing trnasmembrane protein 1 (KREMEN1), neuropilin 1 (NRP1), serpin peptidase inhibitor clade A member 3 (SERPINA3), versican (VCAN), and others. Our findings provide a fundamental resource for better understanding of the genetic network that leads to successful embryo implantation. We demonstrate the first systems biology approach into the complex molecular network of the implantation process in humans.
Molecular Endocrinology 11/2011; 26(1):203-17. · 4.54 Impact Factor
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ABSTRACT: Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.
Molecular Biology Reports 09/2011; 39(4):4471-8. · 2.93 Impact Factor
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ABSTRACT: To investigate whether polymorphisms in genes involved in biosynthesis and signalling of sex steroids influence susceptibility to endometriosis and to infertility associated with it.
Patients with endometriosis (n = 150) and fertile controls (n = 199) were genotyped for polymorphisms in oestrogen receptor genes ESR1 (rs2234693 - T/C single nucleotide polymorphism (SNP), dinucleotide (TA)(n) repeat) and ESR2 (dinucleotide (CA)(n) repeat), progesterone receptor gene PGR (rs10895068 - G/A SNP, 306-bp Alu-insertion), 17β-hydroxysteroid dehydrogenase type 1 gene HSD17B1 (rs605059 - A/G SNP), and aromatase gene CYP19A1 (rs10046 - C/T SNP, (TTTA)(n) tetranucleotide repeat, 3-bp TCT insertion/deletion polymorphism).
The HSD17B1 A/G SNP A allele increased overall endometriosis risk and the risk of stage I-II disease, while ESR1 longer (TA)(n) repeats only correlated with susceptibility to stage I-II endometriosis. When considering patients' fertility status, HSD17B1 A/G SNP A allele and ESR1 longer (TA)(n) repeats were associated with endometriosis accompanied by infertility, while ESR2 shorter (CA)(n) repeats were linked with endometriosis without infertility. Other polymorphisms were distributed similarly among patients and controls.
Genetic variants in ESR1, ESR2, and HSD17B1 genes could modify susceptibility to endometriosis and might influence the fertility status in endometriosis patients.
Gynecological Endocrinology 06/2011; 27(6):425-33. · 1.58 Impact Factor
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ABSTRACT: The aim of this study was to investigate tissue factor (TF) and its inhibitors TFPI and TFPI2 in secretory endometrium of fertile women and in women with unexplained infertility in relation to endometrial receptivity. In addition, common variation in the regulatory area of TF and TFPI genes was studied. Immunostaining of TF and TFPI, together with the appearance of pinopodes, revealed similar expression pattern in fertile endometrium throughout the secretory phase, being highest at the time of implantation. When compared protein expression levels at the time of implantation, infertile women demonstrated significantly higher TFPI expression in luminal epithelium. Furthermore, polymorphism TF -603 A/G was associated with the endometrial protein level in infertile women, being highest in women with GG genotype, and variation TFPI -287 T/C was associated with unexplained infertility, where infertile women presented more frequently T allele than fertile women. Contrary to TF and TFPI, TFPI2 showed different mRNA and protein expression patterns in fertile endometrium, and no differences between fertile and infertile women were detected. We conclude that the TF pathway is involved in normal endometrial maturation, where TF and TFPI seem to have important roles at the time of embryo implantation. Higher TFPI expression level during the time of embryo implantation and TFPI -287 T allele could be risk factors for unexplained infertility. No distinct involvement of TFPI2 in the regulation of endometrial receptivity and unexplained infertility was found.
Reproductive sciences (Thousand Oaks, Calif.) 03/2011; 18(7):666-78. · 2.31 Impact Factor
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ABSTRACT: Male factor infertility is a growing problem worldwide. Considering that a male factor is involved in at least 20% of infertility cases, there is a need for better predictive markers of sperm function. The traditional sperm analysis based on sperm count and motility has been used for the diagnosis of male fertility for several decades, however, a significant number of men with normal sperm features remain unable to reach pregnancy. This fact clearly indicates the need to develop new male infertility tests to accurately diagnose the sperm samples from these individuals. Furthermore, the classic spermiogram has limited predictive power to predict pregnancy in assisted reproductive techniques. Microarray technology is a powerful tool for detecting gene expression of thousands of genes at the same time. There is a great interest in the sperm transcriptome as a source from which to develop markers of male infertility. This commentary discusses the current advances in the microarray technology and sperm quality. It is believed that microarray-based fertility testing of sperm potential in infertility treatment could be close at hand.
Reproductive biomedicine online 02/2011; · 2.04 Impact Factor
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ABSTRACT: Upper genital tract infections can inflict inadequate immune response and cause Fallopian tube damage and concomitant female infertility. However, the exact role of host genetic variation in the development of tubal factor infertility remains unclear. We selected nine genetic variations in four genes involved in immune response modulation (CCR5, TLR2, TLR4 and MBL2) and assessed their association with tubal factor infertility by comparing genotype frequencies among 163 women with tubal factor infertility and 400 control individuals. The CCR5, TLR2 and TLR4 genotypes were not associated with tubal factor infertility, although the TLR4 Asp299Gly and Thr399Ile heterozygosity was associated with a decreased incidence of pathogens associated with genital tract infections in tubal factor infertility patients. In contrast, MBL2 low-producing genotypes were associated with an increased incidence of such pathogens. In addition, hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to tubal factor infertility, while a protective effect was associated with the high-producing MBL2 genotype HYA/LYA. Overall, these data suggest that polymorphisms in TLR4 and MBL2 play a role in receptiveness to pathogens causing genital tract infections, while MBL2 genotypes contribute to susceptibility to tubal factor infertility.
Journal of Reproductive Immunology 12/2010; 87(1-2):74-81. · 2.97 Impact Factor
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Eneli Oitmaa,
Maire Peters,
Kadri Vaidla,
Reidar Andreson,
Reedik Mägi,
Georgi Slavin,
Agne Velthut,
Neeme Tõnisson,
Tiia Reimand,
Maido Remm,
Marion Schneider,
Katrin Ounap, Andres Salumets,
Andres Metspalu
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ABSTRACT: To develop a new rapid and high-throughput microarray-based prenatal diagnostic test for the detection of trisomy 21 (T21).
The T21 arrayed primer extension-2 (APEX-2) assay discriminates between trisomy and euploid DNA samples by comparing the signal intensities of allelic fractions of heterozygous single nucleotide polymorphisms (SNPs) after APEX reaction. After preliminary validation using DNA samples from Down syndrome patients, we analyzed DNA samples from cultured and uncultured amniocytes and chorionic villus for 90 SNPs with high heterozygosity from the 21(q21.1q22.2) region. Differences in allelic ratios of heterozygous SNPs in normal and T21 individuals were verified by t-test.
Analysis of the T21 APEX-2 assay results revealed that 90 SNPs were sufficient for reliable discrimination between T21 and euploid DNA samples (P≤0.05 for one or both strands). Using 134 clinical samples from cultured or uncultured fetal cells, both the sensitivity and the specificity of the assay were 100%.
Our study provides a proof of principle demonstration of the use of the modified APEX-2 assay as a new, fast and reliable method for prenatal diagnosis of fetal T21.
Prenatal Diagnosis 12/2010; 30(12-13):1170-7. · 2.11 Impact Factor
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ABSTRACT: To determine plausible associations between endometriosis and vascular endothelial growth factor gene (VEGF -2578 A/C, -1154 G/A, -634 G/C and 936 C/T), also angiotensin I-converting enzyme gene (ACE -240 A/T and 2350 A/G) single nucleotide polymorphisms (SNPs), as well as their respective haplotypes.
PCR-based restriction fragment length polymorphism analysis was used to detect SNPs in VEGF and ACE genes in 150 Estonian women with endometriosis and 199 control subjects.
The CC genotype of the VEGF -2578 A/C SNP was correlated with a decreased risk of endometriosis (OR=0.40, 95% CI 0.20-0.78). Other VEGF and ACE SNPs and haplotypes were not associated with endometriosis.
This case-control study demonstrated that the VEGF -2578 A/C SNP may influence susceptibility to endometriosis in the Estonian population, while associations between endometriosis and other VEGF and ACE SNPs, as well as the respective haplotypes are unlikely.
European journal of obstetrics, gynecology, and reproductive biology 11/2010; 153(1):85-9. · 1.97 Impact Factor
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ABSTRACT: we examined the influence of the androgen receptor gene (AR) CAG microsatellite (AR-CAG) repeat polymorphism and X-chromosome inactivation (XCI) pattern on ovarian reserve markers (follicle stimulating hormone (FSH) and antral follicle count on menstrual cycle day 3-5) and disease etiology in patients with polycystic ovarian syndrome (PCOS) or premature ovarian failure (POF).
case-control study. Population. In all, 32 women with PCOS, 26 women with POF and 79 controls were investigated.
AR-CAG and XCI were analyzed using polymerase chain reaction-based assays following DNA digestion with the methylation-sensitive restrictase HpaII.
distribution of AR-CAG alleles and XCI patterns.
POF patients had shorter AR-CAG microsatellites than controls. AR-CAG microsatellite length was negatively associated with serum dehydroepiandrosterone sulfate level. The magnitude of XCI skewing was negatively and positively correlated with luteinizing hormone (LH) and FSH serum levels, respectively, during the early follicular phase, but showed no correlation with the number of early antral follicles.
our results suggest that AR-CAG variations and XCI pattern exert an effect on FSH and LH values, and also have the potential to influence the etiopathogenesis of POF.
Acta Obstetricia Et Gynecologica Scandinavica 11/2010; 89(12):1557-63. · 1.77 Impact Factor
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ABSTRACT: In this case-control study, we investigated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis in women of caucasian origin. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more common in control group.
Fertility and sterility 09/2010; 94(4):1560-3. · 3.97 Impact Factor
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ABSTRACT: Female infertility patients with diverse etiologies show increased production of autoantibodies.
Immunoblot analysis of sera from patients with endometriosis and tubal factor infertility (TFI) and mass spectrometry identification of candidate antigens.
The immunoblot results demonstrated the presence of IgA and IgG anti-endometrial antibodies (AEA) to various antigens at molecular weights ranging from 10 to 200 kDa. Differences were detected in certain AEA reactions between the patients' groups and particular AEA were associated with in vitro fertilization (IVF) implantation failure. IgA AEA to a 47-kDa protein were more prevalent in TFI patients and were associated with unsuccessful IVF treatment. This antigen was subsequently identified as alpha-enolase.
Determination of the presence and spectra of AEA in patients with endometriosis and TFI undergoing IVF may be a useful marker to predict their pregnancy outcome.
American Journal Of Reproductive Immunology 05/2010; 63(5):349-57. · 2.17 Impact Factor
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ABSTRACT: This review summarizes current knowledge of the effect of folate-mediated one-carbon metabolism and related genetic variants on female fertility and pregnancy viability. Insufficient folate status disrupts DNA methylation and integrity and increases blood homocysteine levels. Elevated levels of follicular fluid homocysteine correlate with oocyte immaturity and poor early embryo quality, while methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with lower ovarian reserves, diminished response to follicular stimulation, and reduced chance of live birth after in vitro fertilization. Embryos carrying multiple MTHFR variants appear to have a selective disadvantage; however, the heterozygous MTHFR 677CT genotype in the mother and fetus provides the greatest chance for a viable pregnancy and live birth, possibly due to a favorable balance in folate cofactor distribution between methyl donor and nucleotide synthesis. The results of previous studies clearly emphasize that imbalances in folate metabolism and related gene variants may impair female fecundity as well as compromise implantation and the chance of a live birth.
Nutrition Reviews 02/2010; 68(2):99-113. · 4.47 Impact Factor
