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  • 1. Aghajanova, L.
    et al.
    Altmae, S.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Giudice, L. C.
    Stanniocalcin-1 in Human Endometrium2015In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 103, no 2, p. E6-E7Article in journal (Other academic)
  • 2. Aghajanova, Lusine
    et al.
    Bjuresten, Kerstin
    Altmäe, Signe
    Landgren, Britt-Marie
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    HB-EGF but not amphiregulin or their receptors HER1 and HER4 is altered in endometrium of women with unexplained infertility2008In: Reproductive Sciences, ISSN 1933-7191, Vol. 15, no 5, p. 484-92Article in journal (Refereed)
    Abstract [en]

    Heparin-binding, epidermal growth factor-like growth factor (HB-EGF) and its receptors (HER I and HER4) play a role in the human implantation process. Amphiregulin is a member of the EGF family but with unknown function in human fertility. It has been suggested that some women with unexplained infertility have defective endometrial development. The aim of this study is to determine the presence of amphiregulin and the receptors HER1 and HER4 in normal human endometrium throughout the menstrual cycle. In addition) the present study aims to compare endometrium from women with unexplained infertility with endometrium from women with male factor infertility and healthy fertile controls. Immunohistochemistry and real-time polymerase chain reaction were used to determine the expression of HB-EGF, HER 1, HER4, and amphiregulin. The stromal staining of HER I and the epithelial staining of HER4 were most intense in the mid- and late-secretory-phase endometrium. Amphiregulin did not vary during the menstrual cycle. In the mid-secretory phase, the protein expression of HB-EGF was lower in endometrium from women with unexplained infertility versus normal endometrium and endometrium from women with malefactor infertility. HB-EGF and HER4 mRNA expression in mid-secretory endometrium of women with unexplained and malefactor infertility were increased compared with normal controls. Impaired endometrial expression of certain members of the EGF family may contribute to infertility in some women with unexplained infertility.

  • 3. Aghajanova, Lusine
    et al.
    Mahadevan, S
    Altmäe, Signe
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Regan, L
    Sebire, N
    Dixon, P
    Fisher, R A
    Van den Veyver, I B
    No evidence for mutations in NLRP7, NLRP2 or KHDC3L in women with unexplained recurrent pregnancy loss or infertility2015In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 30, no 1, p. 232-238Article in journal (Refereed)
    Abstract [en]

    STUDY QUESTION: Are mutations in NLRP2/7 (NACHT, LRR and PYD domains-containing protein 2/7) or KHDC3L (KH Domain Containing 3 Like) associated with recurrent pregnancy loss (RPL) or infertility?

    SUMMARY ANSWER: We found no evidence for mutations in NLRP2/7 or KHDC3L in unexplained RPL or infertility.

    WHAT IS KNOWN ALREADY: Mutations in NLRP7 and KHDC3L are known to cause biparental hydatidiform moles (BiHMs), a rare form of pregnancy loss. NLRP2, while not associated with the BiHM pathology, is known to cause recurrent Beckwith Weidemann Syndrome (BWS).

    STUDY DESIGN, SIZE, AND DURATION: Ninety-four patients with well characterized, unexplained infertility were recruited over a 9-year period from three IVF clinics in Sweden. Blood samples from 24 patients with 3 or more consecutive miscarriages of unknown etiology were provided by the Recurrent Miscarriage Clinic at St Mary's Hospital, London, UK.

    PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were recruited into both cohorts following extensive clinical studies. Genomic DNA was isolated from peripheral blood and subject to Sanger sequencing of NLRP2, NLRP7 and KHDC3L. Sequence electropherograms were analyzed by Sequencher v5.0 software and variants compared with those observed in the 1000 Genomes, single nucleotide polymorphism database (dbSNP) and HapMap databases. Functional effects of non-synonymous variants were predicted using Polyphen-2 and sorting intolerant from tolerant (SIFT).

    MAIN RESULTS AND THE ROLE OF CHANCE: No disease-causing mutations were identified in NLRP2, NLRP7 and KHDC3L in our cohorts of unexplained infertility and RPL.

    LIMITATIONS, REASONS FOR CAUTION: Due to the limited patient size, it is difficult to conclude if the low frequency single nucleotide polymorphisms observed in the present study are causative of the phenotype. The design of the present study therefore is only capable of detecting highly penetrant mutations.

    WIDER IMPLICATIONS OF THE FINDINGS: The present study supports the hypothesis that mutations in NLRP7 and KHDC3L are specific for the BiHM phenotype and do not play a role in other adverse reproductive outcomes. Furthermore, to date, mutations in NLRP2 have only been associated with the imprinting disorder BWS in offspring and there is no evidence for a role in molar pregnancies, RPL or unexplained infertility.

    STUDY FUNDING/COMPETING INTERESTS: This study was funded by the following sources: Estonian Ministry of Education and Research (Grant SF0180044s09), Enterprise Estonia (Grant EU30020); Mentored Resident research project (Department of Obstetrics and Gynecology, Baylor College of Medicine); Imperial NIHR Biomedical Research Centre; Grant Number C06RR029965 from the National Center for Research Resources (NCCR; NIH). No competing interests declared.

  • 4.
    Aghajanova, Lusine
    et al.
    Dept of Clinical Science, Karolinska Institutet, Stockholm, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lindeberg, Maria
    Dept of Clinical Science, Karolinska Institutet, Stockholm, Sweden.
    Landgren, Britt-Marie
    Dept of Clinical Science, Karolinska Institutet, Stockholm, Sweden.
    Skjöldebrand Sparre, Lottie
    Hovatta, Outi
    Dept of Clinical Science, Karolinska Institutet, Stockholm, Sweden.
    Thyroid-stimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 95, no 1, p. 230-237Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the expression, distribution, and function of thyroid-stimulating hormone receptor (TSHR) and thyroid hormone receptors (TR) alpha1, alpha2, and beta1 in human endometrium. DESIGN: Experimental clinical study. SETTING: University hospital. PATIENT(S): 31 fertile women. INTERVENTION(S): Endometrial biopsy samples obtained throughout the menstrual cycle. MAIN OUTCOME MEASURE(S): Real-time reverse transcriptase polymerase chain reaction, immunohistochemistry and Western blot to study the expression of TSHR, TRalpha1, TRalpha2, and TRbeta1 messenger RNA (mRNA) and proteins in human endometrium. RESULT(S): We found TSHR, TRalpha1, TRalpha2 and TRbeta1 mRNA and proteins expressed in human endometrium. Immunostaining for TSHR in the luminal epithelium and TRalpha1 and beta1 in the glandular and luminal epithelium increased statistically significantly on luteinizing hormone (LH) days 6 to 9, coinciding with appearance of pinopodes. Endometrial stromal and Ishikawa cells expressed mRNA for TSHR, TR, and iodothyronine deiodinases 1-3. After 48 hours, TSH significantly increased leukemia inhibitory factor (LIF) and LIF receptor (LIFR) messenger RNA (mRNA) in endometrial stromal cells, but decreased their expression in Ishikawa cells. Glucose transporter 1 mRNA was up-regulated by TSH in Ishikawa cells. We found that TSH statistically significantly increased secretion of free triiodothyronine (T(3)) and total thyroxin (T(4)) by Ishikawa cells compared with nonstimulated cells. CONCLUSION(S): Thyroid hormones are directly involved in endometrial physiology.

  • 5.
    Akram, Frida Hosseini
    et al.
    Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Johansson, Bengt
    Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Mollerstrom, Gunnar
    Oxback Clin, Sodertalje, Sweden..
    Landgren, Britt-Marie
    Karolinska Inst, CLINTEC, Stockholm, Sweden..
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Skjoldebrand-Sparre, Lottie
    Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Incidence of Subclinical Hypothyroidism and Hypothyroidism in Early Pregnancy2017In: Journal of Women's Health, ISSN 1540-9996, E-ISSN 1931-843X, Vol. 26, no 11, p. 1231-1235Article in journal (Refereed)
    Abstract [en]

    Background: Untreated and subclinical hypothyroidism (SCH) has been associated with adverse pregnancy complications such as increased risk of miscarriage, hypertension, preeclampsia, and preterm delivery. However, in Sweden, screening for thyroid dysfunction during pregnancy is only recommended for women with a high risk of thyroid disease. Therefore, the aim of this study was to determine the incidence of clinical and SCH in women in the first trimester of pregnancy.

    Materials and Methods: In this prospective study, 1298 pregnant women were divided into three groups: one unselected general screening group (n=611), one low-risk group comprising women without risk factors for thyroid disorder (n=511), and one high-risk group comprising women with an inheritance or suspicion of thyroid disease or undergoing treatment for thyroid disease (n=88). Serum was obtained up to gestational week 13, and thyrotropin (TSH) was analyzed.

    Results: The incidences of thyroid dysfunction in the three screening groups were 9.8% in the general screening group, 9.6% in the low-risk group, and 10.2%, p=0.948, in the high-risk group. In the women with known hypothyroidism on levothyroxine treatment, 50.6% had serum TSH levels above 2.0mIU/L.

    Conclusions: High-risk screening is not useful in predicting which women are at risk of thyroid disease in early pregnancy since approximate to 10% of women with SCH or hypothyroidism could not be diagnosed in this way.

  • 6. Altmae, Signe
    et al.
    Reimand, Jueri
    Hovatta, Outi
    Zhang, Pu
    Kere, Juha
    Laisk, Triin
    Saare, Merli
    Peters, Maire
    Vilo, Jaak
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Salumets, Andres
    Interactome of Human Embryo Implantation: Identification of Gene Expression Pathways, Regulation, and Integrated Regulatory Networks2012In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 26, no 1, p. 203-217Article in journal (Refereed)
    Abstract [en]

    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 humanembryos (n = 128) andhumanendometria (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.

  • 7.
    Altmae, Signe
    et al.
    Competence Ctr Hlth Technol, Tartu, Estonia.;Univ Granada, Sch Med, Dept Paediat, Granada, Spain..
    Tamm-Rosenstein, Karin
    Tallinn Univ Technol, Dept Gene Technol, EE-19086 Tallinn, Estonia..
    Esteban, Francisco J.
    Univ Jaen, Dept Expt Biol, Jaen, Spain..
    Simm, Jaak
    Tallinn Univ Technol, Dept Gene Technol, EE-19086 Tallinn, Estonia..
    Kolberg, Liis
    Univ Tartu, Inst Comp Sci, Ulikooli 18, EE-50090 Tartu, Estonia..
    Peterson, Hedi
    Univ Tartu, Inst Comp Sci, Ulikooli 18, EE-50090 Tartu, Estonia.;Quretec Ltd, Tartu, Estonia..
    Metsis, Madis
    Competence Ctr Hlth Technol, Tartu, Estonia.;Tallinn Univ, Sch Nat Sci & Hlth, EE-10120 Tallinn, Estonia..
    Haldre, Kai
    West Tallinn Cent Hosp Womens Clin, Ctr Reprod Med, Tallinn, Estonia..
    Horcajadas, Jose A.
    Hosp Miguel Servet, Araid I CS, Zaragoza, Spain..
    Salumets, Andres
    Competence Ctr Hlth Technol, Tartu, Estonia.;Univ Tartu, Dept Obstet & Gynaecol, Ulikooli 18, EE-50090 Tartu, Estonia..
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Endometrial transcriptome analysis indicates superiority of natural over artificial cycles in recurrent implantation failure patients undergoing frozen embryo transfer2016In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 32, no 6, p. 597-613Article in journal (Refereed)
    Abstract [en]

    Little consensus has been reached on the best protocol for endometrial preparation for frozen embryo transfer (FET). It is not known how, and to what extent, hormone supplementation in artificial cycles influences endometrial preparation for embryo implantation at a molecular level, especially in patients who have experienced recurrent implantation failure. Transcriptome analysis of 15 endometrial biopsy samples at the time of embryo implantation was used to compare two different endometrial preparation protocols, natural versus artificial cycles, for FET in women who have experienced recurrent implantation failure compared with fertile women. IPA and DAVID were used for functional analyses of differentially expressed genes. The TRANSFAC database was used to identify oestrogen and progesterone response elements upstream of differentially expressed genes. Cluster analysis demonstrated that natural cycles are associated with a better endometrial receptivity transcriptome than artificial cycles. Artificial cycles seemed to have a stronger negative effect on expression of genes and pathways crucial for endometrial receptivity, including ESR2, FSHR, LEP, and several interleukins and matrix metalloproteinases. Significant overrepresentation of oestrogen response elements among the genes with deteriorated expression in artificial cycles (P < 0.001) was found; progesterone response elements predominated in genes with amended expression with artificial cycles (P = 0.0052).

  • 8. Altmael, S.
    et al.
    Martinez-Conejero, J. A.
    Esteban, F. J.
    Horcajadas, J. A.
    Salumets, A.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Endometrial gene expression analysis in infertile women in natural and hormone replacement cycles2012In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 27, no Suppl. 2, p. O-243-Article in journal (Other academic)
  • 9. Altmäe, Signe
    et al.
    Esteban, Francisco J
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Simón, Carlos
    Giudice, Linda
    Lessey, Bruce A
    Horcajadas, Jose A
    Macklon, Nick S
    D'Hooghe, Thomas
    Campoy, Cristina
    Fauser, Bart C
    Salamonsen, Lois A
    Salumets, Andres
    Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium2013In: Human Reproduction Update, ISSN 1355-4786, E-ISSN 1460-2369, Vol. 20, no 1, p. 12-28Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND 'Omics' high-throughput analyses, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, are widely applied in human endometrial studies. Analysis of endometrial transcriptome patterns in physiological and pathophysiological conditions has been to date the most commonly applied 'omics' technique in human endometrium. As the technologies improve, proteomics holds the next big promise for this field. The 'omics' technologies have undoubtedly advanced our knowledge of human endometrium in relation to fertility and different diseases. Nevertheless, the challenges arising from the vast amount of data generated and the broad variation of 'omics' profiling according to different environments and stimuli make it difficult to assess the validity, reproducibility and interpretation of such 'omics' data. With the expansion of 'omics' analyses in the study of the endometrium, there is a growing need to develop guidelines for the design of studies, and the analysis and interpretation of 'omics' data.

    METHODS Systematic review of the literature in PubMed, and references from relevant articles were investigated up to March 2013.

    RESULTS The current review aims to provide guidelines for future 'omics' studies on human endometrium, together with a summary of the status and trends, promise and shortcomings in the high-throughput technologies. In addition, the approaches presented here can be adapted to other areas of high-throughput 'omics' studies.

    CONCLUSION A highly rigorous approach to future studies, based on the guidelines provided here, is a prerequisite for obtaining data on biological systems which can be shared among researchers worldwide and will ultimately be of clinical benefit.

  • 10.
    Altmäe, Signe
    et al.
    Division of Obstetrics and Gynaecology, Dept of Clinical Science, Karolinska University Hospital Huddinge, Sweden.
    Hovatta, O.
    Division of Obstetrics and Gynaecology, Dept of Clinical Science, Karolinska University Hospital Huddinge, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Salumets, A.
    Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia.
    Genetic predictors of controlled ovarian hyperstimulation: where do we stand today?2011In: Human Reproduction Update, ISSN 1355-4786, E-ISSN 1460-2369, Vol. 17, no 6, p. 813-828Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND

    Nowadays, the use of IVF has improved the prospects of infertility treatment. The expected outcome of IVF depends greatly on the effectiveness of controlled ovarian hyperstimulation (COH), where exogenous gonadotrophins are used to induce folliculogenesis. The response to stimulation varies substantially among women and is difficult to predict. Several predictive markers of COH outcome have been proposed (e.g. maternal age and ovarian reserve), but the search for optimal predictors is ongoing. Pharmacogenetic studies demonstrate the effects of individual genetic variability on COH outcome and the potential for customizing therapy based on the patient's genome.

    METHODS

    MEDLINE, EMBASE, DARE, CINAHL and the Cochrane Library, and references from relevant articles were investigated up to February 2011 regarding any common genetic variation and COH/IVF outcome.

    RESULTS

    Several polymorphisms in genes involved in FSH signalling, estrogen biosynthesis, folliculogenesis, folate metabolism and other aspects influence the response to exogenous gonadotrophin administration, resulting in differences in COH and IVF outcomes. Nevertheless, the most studied polymorphism FSHR Asn680Ser is practically the only genetic marker, together with ESR1 PvuII T/C, that could be applied in clinical tests.

    CONCLUSIONS

    Although data are accumulating with evidence suggesting that the ovarian response to COH is mediated by various polymorphisms, the optimal biomarkers and the efficacy of the tests still remain to be evaluated.

  • 11.
    Altmäe, Signe
    et al.
    Dept of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fridén, Barbro
    Dept of Women´s and Children´s Health, Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Variation in Hyaluronan-Binding Protein 2 (HABP2) Promoter Region is Associated With Unexplained Female Infertility2011In: Reproductive Sciences, ISSN 1933-7191, Vol. 18, no 5, p. 485-492Article in journal (Refereed)
    Abstract [en]

    We set up to analyze polymorphisms in hyaluronan-binding protein 2 (HABP2) gene in healthy fertile women (n = 158) and in women with unexplained infertility (n = 116) and to investigate the potential role of HABP2 in receptive endometrium. Minor rs1157916 A and the major rs2240879 A alleles together with AA genotypes were significantly less frequent in infertile women than in controls. Immunohistochemistry analysis of endometrial HABP2 expression at the time of implantation identified significantly lower HABP2 protein level in infertile women in stroma and vessels than in fertile women. Migration assay analysis of cultured trophoblast and endothelial cells toward HABP2 protein referred to the function of HABP2 in endometrial endothelial cells. In conclusion, our results indicate that polymorphisms in the regulatory region of HABP2 gene could influence gene expression levels in the receptive endometrium and could thereby be one reason for infertility complications in women with unexplained infertility. Additionally, HABP2 protein involvement in endometrial angiogenesis is proposed.

  • 12.
    Altmäe, Signe
    et al.
    Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia.
    Martinez-Conejero, José A
    IVIOMICS, Valencia, Spain.
    Esteban, Francisco J
    Department of Experimental Biology, University of Jaen, Jaen, Spain.
    Ruiz-Alonso, Maria
    IVIOMICS, Valencia, Spain.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Horcajadas, José A
    Araid at IþCS, Hospital Miguel Servet, Zaragoza, Spain.
    Salumets, Andres
    Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia.
    MicroRNAs miR-30b, miR-30d, and miR-494 Regulate Human Endometrial Receptivity2013In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 20, no 3, p. 308-317Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Altmäe, Signe
    et al.
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Salumets, Andres
    Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia.
    Bjuresten, Kerstin
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Landgren, Britt-Marie
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Hovatta, Outi
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tissue Factor and Tissue Factor Pathway Inhibitors TFPI and TFPI2 in Human Secretory Endometrium - Possible Link to Female Infertility2011In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 18, no 7, p. 666-678Article in journal (Refereed)
    Abstract [en]

    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.

  • 14.
    Arnadottir, Ragnheidur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hudecova, Miriam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kunovac-Kallak, Theodora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Poromaa, Inger Sundstrom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Steroid hormone receptor expression, proliferative activity and microvessel density in the endometrium of women with polycystic ovary syndrome2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, p. 64-64Article in journal (Other academic)
  • 15.
    Baumgart, J
    et al.
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Nilsson, K
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Stavreus Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kushnir, M M
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Pathology, University of Utah School of Medicine, Salt Lake City, USA.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Androgen levels during adjuvant endocrine therapy in postmenopausal breast cancer patients2014In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 17, no 1, p. 48-54Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate plasma steroid hormone levels in postmenopausal breast cancer patients with and without adjuvant endocrine therapy and in healthy postmenopausal women.

    Methods

    Steroid hormone levels in postmenopausal breast cancer patients treated with aromatase inhibitors (n = 32) were compared with breast cancer patients treated with tamoxifen (n = 34), breast cancer patients without adjuvant endocrine therapy (n = 15), and healthy postmenopausal women (n = 56). Pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone (DHEA), androstenedione, total testosterone, dihydrotestosterone, estrone and estradiol were measured using liquid chromatography-tandem mass spectrometry. Sex hormone binding globulin was measured by solid-phase chemiluminescent immunometric assays, and the free androgen index was calculated.

    Results

    Aromatase inhibitor users did not differ in dihydrotestosterone, total testosterone, androstenedione, DHEA, or free androgen index levels from healthy controls or untreated breast cancer patients. The highest total testosterone levels were found in tamoxifen-treated women, who had significantly higher plasma concentrations than both women treated with aromatase inhibitors and breast cancer patients without adjuvant treatment. Concentrations of cortisol and cortisone were significantly greater in aromatase inhibitor users as well as tamoxifen users, in comparison with healthy controls and untreated breast cancer patients. Aromatase inhibitor users had lower estrone and estradiol plasma concentrations than all other groups.

    Conclusion

    Adjuvant treatment with aromatase inhibitors or tamoxifen was associated with increased cortisol and cortisone plasma concentrations as well as decreased estradiol concentrations. Androgen levels were elevated in tamoxifen-treated women but not in aromatase inhibitor users.

  • 16.
    Baumgart, Juliane
    et al.
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro.
    Nilsson, Kerstin
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer2013In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 20, no 2, p. 162-168Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    The goal of this study was to investigate sexual function in postmenopausal breast cancer patients treated with aromatase inhibitors.

    METHODS:

    A population-based, cross-sectional study was conducted among postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched controls with and without estrogen treatment. Sexual function was assessed with a standardized questionnaire.

    RESULTS:

    In all, 42.4% of aromatase inhibitor-treated breast cancer patients were dissatisfied with their sex life in general, and 50.0% reported low sexual interest; this was significantly more common than in tamoxifen-treated patients and controls (P < 0.05). Aromatase inhibitor-treated patients reported insufficient lubrication in 73.9% and dyspareunia in 56.5% of cases, which were significantly more common than in controls, irrespective of hormonal use (P < 0.05). Tamoxifen-treated patients reported significantly more dyspareunia (31.3%; P < 0.05) but resembled controls in all other concerns.

    CONCLUSIONS:

    Our findings suggest that sexual dysfunction in aromatase inhibitor-treated women is a greatly underestimated problem.

  • 17.
    Baumgart, Juliane
    et al.
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Kerstin
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kask, Kristiina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Villman, Kenneth
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kallak, Theodora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer2011In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 204, no 1, p. 26.e1-7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects (P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P < .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials.

  • 18.
    Bjuresten, Kerstin
    et al.
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm.
    Landgren, Britt-Marie
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm.
    Hovatta, Outi
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Luteal phase progesterone increases live birth rate after frozen embryo transfer2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 95, no 2, p. 534-537Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To see if progesterone support has a beneficial effect on live birth rate after frozen embryo transfer in natural cycles. DESIGN: Prospective randomized controlled trial. SETTING: University-based hospital. SUBJECT(S): Four hundred thirty-five women undergoing embryo transfer in natural cycles. INTERVENTION(S): The women received either vaginal progesterone, 400 mg twice a day from the day of embryo transfer in natural cycles, or no progesterone support. MAIN OUTCOME MEASURE(S): Live birth rate, biochemical pregnancy rate, pregnancy rate, and spontaneous abortion rate. RESULT(S): Live birth rate were significantly greater in women receiving vaginal progesterone as luteal phase support after frozen-thawed embryo transfer in natural cycles compared with those who did not take progesterone. There were no differences in biochemical pregnancy rate, pregnancy rate, or spontaneous abortion rate. CONCLUSION(S): Progesterone supplementation improves live birth rate after embryo transfer in natural cycles.

  • 19. Bremer, Susanne
    et al.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knudsen, Lisbeth Ehlert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mathisien, Line
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Pazos, Patricia
    Pellizzer, Cristian
    Paulesu, Luana Ricci
    Schaefer, Wolfgang
    Schwarz, Michael
    Staud, Frantisek
    Stavreus-Evers, Anneli
    Dept Clinical Science, Intervention and Technology, Karolinska Institutet, Hospital Huddinge, Stockholm, Sweden.
    Vähänkangas, Kirsi
    In vitro tests for detecting chemicals affecting the embryo implantation process: The report and recommendations of ECVAM workshop 62 - a strategic workshop of the EU ReProTect project2007In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 35, no 4, p. 421-439Article, review/survey (Refereed)
  • 20.
    Elenis, Evangelia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Lindgren, Karin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Karypidis, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hosseini, Frida
    Bremme, Katarina
    Landgren, Britt-Marie
    Skjoldebrand-Sparre, Lottie
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study2014In: Reproductive Biology and Endocrinology, ISSN 1477-7827, E-ISSN 1477-7827, Vol. 12, p. 70-Article in journal (Refereed)
    Abstract [en]

    Background: Histidine-rich Glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage. Methods: The study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP. Results: The results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p < 0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p < 0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p < 0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p < 0.05). Conclusions: Women who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

  • 21.
    Granfors, Michaela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Karypidis, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hosseini, Frida
    Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institutet and Danderyd Hospital, Stockholm, Sweden.
    Skjöldebrand-Sparre, Lottie
    Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institutet and Danderyd Hospital, Stockholm, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bremme, Katarina
    Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden.
    Landgren, Britth-Marie
    Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Akerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study.2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 121-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage. METHODS: The study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction. RESULTS: No difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p = 0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01 - 2.64, p = 0.045) and G/G (AOR 1.52, 95% CI 1.02 - 2.27, p = 0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained. CONCLUSIONS: Our findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.

  • 22.
    Hambiliki, Fredwell
    et al.
    Department of Clinical Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hreinsson, Julius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Glycoprotein 130 promotes human blastocyst development in vitro2013In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 99, no 6, p. 1592-U444Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the efficacy of leukemia inhibitory factor (LIF) and/or glycoprotein 130 (gp130) on in vitro growth of human embryos. Design: Laboratory study. Setting: University hospital-based IVF clinic. Patient(s): A total of 164 frozen embryos that survived thawing were cultured in media supplemented with LIF and/or gp130 or control media. Intervention(s): Morphological development was evaluated by light microscopy. Protein expression profiles of single blastocysts were evaluated using matrix-assisted laser desorption/ionization time of flight-based intact cell mass spectrometry. Main Outcome Measure(s): Embryo development and protein content. Result(s): Addition of gp130 to culture media improved blastocyst formation (73% vs. 43%). Addition of LIF to the culture media did not improve embryo development. Protein fingerprint spectra were obtained that revealed significant intensity changes for multiple molecular species including thymosin beta-10, thymosin beta-4, histone H2A, histone H2B, histone H4, ubiquitin, ubiquitin-T, and acyl-CoA binding protein. Conclusion(s): Glycoprotein 130, but not LIF, seems to be beneficial for preimplantation embryo development, implicating a physiological role in regulating preimplantation development in humans and thus ought to be included in culture media designed for embryo culture to the blastocyst stage. Furthermore, these findings highlight the great potential of matrix-assisted laser desorption/ionization time of flight mass spectrometry and intact cell mass spectrometry as a versatile tool in reproductive medicine research.

  • 23.
    Hambiliki, Fredwell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ström, Susanne
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Zhang, Pu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Co-localization of NANOG and OCT4 in human pre-implantation embryos and in human embryonic stem cells2012In: Journal of Assisted Reproduction and Genetics, ISSN 1058-0468, E-ISSN 1573-7330, Vol. 29, no 10, p. 1021-1028Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    NANOG and OCT4 are required for the maintenance of pluripotency in embryonic stem cells (ESCs). These proteins are also expressed in the inner cell mass (ICM) of the mouse pre-implantation embryo.

    METHODS:

    Immunohistochemistry was used to show the presence of NANOG and OCT4 protein, and in situ hybridization was used to localize NANOG mRNA in human embryos from two-cell to blastocyst stage, and in human ESCs (hESCs).

    RESULTS:

    Nanog and Oct4 were co-localized in human embryos from morula and blastocyst stages. NANOG mRNA was detected in a group of cells in the morula, in cells of the ICM of blastocysts, and evenly in hESCs. All non-differentiated hESCs expressed NANOG and OCT4 protein. Pluripotent cells expressing NANOG and Oct4 were eccentrically localized, probably in polarized cells in a human compacted morula, which appears to be different from expression in murine embryos.

    CONCLUSION:

    In this study, we demonstrate that whole mount in situ hybridization is amenable to localization of mRNAs in human development, as in other species.

  • 24. Haroun, Sally
    et al.
    Altmäe, Signe
    Karypidis, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kuningas, Maris
    Landgren, Britt-Marie
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skjöldebrand-Sparre, Lottie
    Hosseini, Frida
    Bremme, Katarina
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Association between trefoil factor 3 gene variants and idiopathic recurrent spontaneous abortion2014In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 29, no 6, p. 737-44Article in journal (Refereed)
    Abstract [en]

    Trefoil factor 3 (TFF3) gene is an inflammatory mediator expressed in human endometrium during the window of implantation. The aim of this study was to evaluate the possible genetic association of TFF3 variants in recurrent spontaneous abortion. Women with a history of recurrent spontaneous abortion (n = 164) and healthy pregnant women (n = 143) were genotyped for five TFF3 polymorphisms (rs225439 G/A, rs533093 C/T, rs225361 A/G, rs11701143 T/C and rs77436142 G/C). In addition, haplotypes formed within the gene were analysed. Within the recurrent spontaneous abortion group, women who at some point had given birth and childless women had 4.19 ± 1.75 and 5.34 ± 3.42 consecutive spontaneous abortions, respectively. Women who had experience recurrent spontaneous abortions had a lower allele frequency of the rs11701143 promoter region minor C allele compared with fertile women (0.02 versus 0.05, P = 0.015). Patients with rs225361 AG genotype had significantly more successful pregnancies before spontaneous abortion than those with homozygous AA and GG genotypes (P = 0.014). No significant differences in haplotype frequencies between patients and controls were detected. Possible genetic risk factors identified that might contribute to the pathogenesis of idiopathic recurrent spontaneous abortion were TFF3 gene variants.

  • 25.
    Haroun, Sally
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Altmäe, Signe
    Kuningas, Maris
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    The association of trefoil factor 3 gene polymorphisms and haplotypes with unexplained female infertility: Molecular insights into TFF3 regulation in receptive phase endometrium2013In: Human Fertility, ISSN 1464-7273, E-ISSN 1742-8149, Vol. 16, no 4, p. 291-298Article in journal (Refereed)
    Abstract [en]

    This study examined the genetic variation within the gene trefoil factor 3 (TFF3) in relation to unexplained female infertility in a group of women where aberrant endometrial maturation was suspected. The study consisted of 113 women with a diagnosis of unexplained infertility and 289 healthy fertile volunteers. Five single nucleotide polymorphisms rs225439, rs533093, rs225361, rs11701143, and rs77436142 within TFF3 gene were analyzed using real-time PCR. The formed haplotype pattern within the TFF3 gene in relation to infertility was also assessed. TFF3 protein localization and expression in receptive stage endometrium at the time of implantation was measured in a subset of fertile (n = 7) and infertile (n = 12) women. Allele and genotype frequencies did not differ significantly between fertile and infertile women, nor did the formed haplotypes. TFF3 protein was expressed in all cell types in receptive stage endometria in fertile and infertile women. No significant association was observed between protein expression and analyzed genotypes. A significantly higher TFF3 expression in luminal epithelial cells was detected in women with unexplained infertility (p = 0.003).

  • 26.
    Helmestam, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Andersson, Helén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tamoxifen Modulates Cell Migration and Expression of Angiogenesis-Related Genes in Human Endometrial Endothelial Cells2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 6, p. 2527-2535Article in journal (Refereed)
    Abstract [en]

    The selective estrogen receptor modulator tamoxifen is used for the prevention and treatment of breast cancer. The adverse effects of tamoxifen include vaginal endometrial bleeding, endometrial hyperplasia, and cancer, conditions associated with angiogenesis. The aim of this study was to examine the effects of tamoxifen on cell migration and angiogenesis-related gene expression in human endometrial endothelial cells (HEECs). The regulatory effects of tamoxifen on endometrial stromal cells and HEECs were also examined. HEECs and stromal cells were isolated and grown In monocultures or co-cultures, and incubated with 0.1 to 100 mu mol/L tamoxifen for 48 hours. Quantitative PCR demonstrated that tamoxifen decreased the mRNA expression of vascular endothelial growth factor-A (VEGF-A) and increased the mRNA expression of VEGF receptor-1 and placental growth factor (PLGF) in HEECs. Tamoxifen's effects on VEGF-A were inhibited when HEECs were co-cultured with stromal cells. In addition, tamoxifen reduced VEGF-induced HEEC migration. The tamoxifen-metabolizing enzymes CYP1A1 and CYP1B1 were detected by immunohistochemistry in and around endometrial blood vessels and by quantitative PCR in HEECs. Our data suggest that tamoxifen changes the regulation of angiogenesis in the endometrium, likely by reducing angiogenic activity. The results also indicate that endometrial stromal cells regulate some of tamoxifen's effects in HEECs, and the presence of tamoxifen-metabolizing enzymes suggests tamoxifen bioactivation in the endometrial vasculature in vivo. These findings may help to elucidate the mechanism of the bleeding disturbances associated with tamoxifen treatment.

  • 27.
    Helmestam, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Davey, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anne Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bisphenol A affects human endometrial endothelial cell angiogenic activity in vitro2014In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 46, p. 69-76Article in journal (Refereed)
    Abstract [en]

    The widespread Bisphenol A (BPA) is classified as an endocrine-disrupting chemical (EDC) with estrogenic properties. Human endometrial endothelial cells (HEECs) play a key role in the endometrial angiogenesis that is under the control of estradiol. The hypothesis was that BPA may affect endometrial angiogenesis by disturbing some functional properties of the HEEC. To study this, primary HEECs were exposed to environmentally relevant doses of BPA. The HEECs were co-cultured with primary endometrial stromal cells to create conditions as similar to the in vivo situation as possible. The effects of BPA were evaluated by proliferation and viability assays, tube-formation assays, quantitative PCRs, Western blots and ELISAs. BPA slightly increased HEEC tube formation and VEGF-D protein expression compared with vehicle, without affecting HEEC viability or proliferation. Bisphenol A thus caused changes in HEEC activities in vitro, and may therefore have disturbing effects on endometrial angiogenesis. (C) 2014 Elsevier Inc. All rights reserved.

  • 28.
    Helmestam, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Lindgren, Karin Elvine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Mifepristone exposure of human endometrial endothelial cells in vitro2014In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 21, no 3, p. 408-414Article in journal (Refereed)
  • 29. Hildenbrand, Anna
    et al.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lalitkumar, P G L
    Nielsen, Soren
    Mints, Miriam
    Gemzell-Danielsson, Kristina
    Aquaporin 1 is expressed in the human endometrium during normal cycle and increases after mifepristone treatment.2008In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 22, no 1, p. 49-53Article in journal (Refereed)
    Abstract [en]

    Aquaporin-1 (AQP1) is involved in the angiogenesis and structural modifications of microvessels and possibly also in the pathogenesis of idiopathic menhorrhagia, where a reduced AQP1 expression is seen in the endometrium. Mifepristone treatment induces reduced menstrual bleeding and amenorrhea and also has a direct effect on endometrial arterioles. Administered with gestagen-only contraceptive methods, antiprogestins improve the bleeding pattern. The objective of this study was to evaluate the AQP1 expression in endometrial blood vessels during normal cycle and after mifepristone treatment. Localization and expression of AQP1 was determined using immunohistochemistry and reverse transcriptase chain reaction (RT-PCR) in 43 biopsies from human endometrium taken during a normal cycle and after mifepristone treatment. AQP1 expression in human endometrial vessels is not cycle dependent and is stronger in capillaries and arteries than in veins. After mifepristone treatment the staining intensity was increased, but not the number of stained vessels. The presence of AQP1 was also confirmed using RT-PCR. The changes in AQP1 expression could contribute to the reduced bleeding seen following mifepristone treatment and could be an effect of either antagonizing progesterone or cortisol.

  • 30.
    Jansson, Caroline
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Volgsten, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Huffman, Carolyn
    College of Health Sciences, Appalachian State University, USA.
    Skoog Svanberg, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Swanson, Kristen M
    School of Nursing, Seattle University, Seattle, WA, USA.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Validation of the Revised Impact of Miscarriage Scale for Swedish conditions and comparison between Swedish and American couples' experiences after miscarriage2017In: European journal of contraception & reproductive health care, ISSN 1362-5187, E-ISSN 1473-0782, Vol. 22, no 6, p. 412-417Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: There is a lack of knowledge in women's and men's experience of miscarriage. The Revised Impact of Miscarriage Scale (RIMS) has been used in United States to measure the experiences after miscarriage. The first objective was to test the consistency of RIMS for Swedish conditions. The second purpose of this study was to compare Swedish and American couples' experience of miscarriage by use of the RIMS.

    METHODS: Forward and back translation was used for translating RIMS into Swedish. This is a hospital-based comparative study including Swedish couples (n = 70) and American couples (n = 70). The couples were matched by the women's age, week of miscarriage and number of children. All participants answered socio-demographic, fertility and depression-scale questions in addition to RIMS.

    RESULTS: Cronbach's alpha analysis was above 0.650, the mean value was 0.824. There was no significant difference between the Swedish and American participants on the factors 'Isolation/Guilt' and 'Devastating event', but the Swedish women and men scored significantly lower on the factor 'Loss of baby' than the American women and men. The men, Swedish and American combined, scored lower than the women in all factors but the correlation within the couples was similar for both Swedish and American couples.

    CONCLUSIONS: The high consistency between the countries suggests that the RIMS questionnaire is reliable for both women and men to be used in both countries and two of three factors were similar between the two countries.

  • 31.
    Kallak, Theodora K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Baumgart, Juliane
    Nilsson, Kerstin
    Poromaa Sundström, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Treatment with aromatase inhibitor acts indirectly through the estrogen receptor pathway causing decreased junction plakoglobin mRNA expression and vaginal atrophy2013In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 20, no 12, p. 1328-1328Article in journal (Other academic)
  • 32.
    Kallak, Theodora Kunovac
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Baumgart, J.
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Moby, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kask, Kristiina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Norjavaara, E.
    Gothenburg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Sweden .
    Kushnir, M. M.
    ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, USA.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Nilsson, K.
    The School of Health and Medical Sciences, Örebro University, Sweden.
    Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients2012In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 15, no 5, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Objective

    Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. 

    Methods

    Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment. 

    Results

    By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups(p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001).  

    Conclusion

    Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.

  • 33.
    Kallak, Theodora Kunovac
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Baumgart, Juliane
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Göransson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nilsson, Kerstin
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors2013In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 21, no 4, p. 383-390Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women.

    METHODS: This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH.

    RESULTS: Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH.

    CONCLUSIONS: Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.

  • 34. Kartberg, A-J
    et al.
    Hambiliki, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Arvidsson, T
    Stavreus-Evers, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Svalander, P
    Vitrification with DMSO protects embryo membrane integrity better than solutions without DMSO2008In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 17, no 3, p. 378-384Article in journal (Refereed)
    Abstract [en]

    Vitrification has become common for cryopreservation of embryos. However, the most Optimal protocol for Vitrification is still to be found. Two vitrification protocols with similar osmolarities were compared: Protocol A. containing dimethyl sulphoxide (DMSO), propane-2-diol, and ethylene glycol. and Protocol B. containing propane-2-diol and ethylene glycol. Viability and the importance of specific incubation times for early embryo recovery. survival. and cleavage were studied. For assessment of cryodamage, embryos were labelled with Alexa Fluor 488-conjugated annexin V and propidium iodide. Vitrification Studies Oil early mouse embryos were followed Up with studies oil human embryos,. The two vitrification protocols did not differ ill embryo survival rates and were equally efficient ill both mouse and human embryo models. Morphological assessment of embryos directly after vitrification was not a useful tool for assessing survival in this study. Extended exposure of embryos with both vitrification protocols showed that the DMSO-containing vitrification solutions did not lead to cell membrane damage and death as quickly as the DMSO-free vitrification solutions. To assess embryo viability, the authors recommend that vitrification of early embryos should be combined with extended culture and assessment of normal blastocyst development before transferring to patients.

  • 35.
    Kunovac Kallak, Theodora
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Baumgart, Juliane
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Kerstin
    Department of Obstetrics & Gynecology, School of Medicine, Faculty of Health and Medicine, Örebro University, Sweden..
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Staverus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Vaginal gene expression during treatment with aromatase inhibitors2015In: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666, Vol. 15, no 6, p. 527-535Article in journal (Refereed)
    Abstract [en]

    Vaginal gene expression in aromatase inhibitor-treated women was compared with postmenopausal control women treated with vaginal estrogen therapy. Vaginal tissue from aromatase inhibitor-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion, and associated with vaginal discomfort. The presence of vaginal aromatase suggests that this is the result of local and systemic aromatase inhibition. Background: Aromatase inhibitor (AI) treatment suppresses estrogen biosynthesis and causes genitourinary symptoms of menopause such as vaginal symptoms, ultimately affecting the quality of life for many postmenopausal women with breast cancer. Thus, the aim of this study was to examine vaginal gene expression in women during treatment with AIs compared with estrogen-treated women. The secondary aim was to study the presence and localization of vaginal aromatase. Patients and Methods: Vaginal biopsies were collected from postmenopausal women treated with AIs and from age-matched control women treated with vaginal estrogen therapy. Differential gene expression was studied with the Affymetrix Gene Chip Gene 1.0 ST Array (Affymetrix Inc, Santa Clara, CA) system, Ingenuity pathway analysis, quantitative real-time polymerase chain reaction, and immunohistochemistry. Results: The expression of 279 genes differed between the 2 groups; AI-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion. Some differentially expressed genes were found to interact indirectly with the estrogen receptor alpha. In addition, aromatase protein staining was evident in the basal and the intermediate vaginal epithelium layers, and also in stromal cells with a slightly stronger staining intensity found in AI-treated women. Conclusion: In this study, we demonstrated that genes involved in cell differentiation, proliferation, and cell adhesion are differentially expressed in AI-treated women. The expression of vaginal aromatase suggests that this could be the result of local and systemic inhibition of aromatase. Our results emphasize the role of estrogen for vaginal cell differentiation and proliferation and future drug candidates should be aimed at improving cell differentiation and proliferation. (C) 2015 Elsevier Inc. All rights reserved.

  • 36.
    Laanpere, M
    et al.
    Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
    Altmäe, Signe
    Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, Sweden.
    Kaart, T
    Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, Tartu, Estonia.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Nilsson, T K
    Department of Clinical Chemistry, Örebro University Hospital, Sweden.
    Salumets, A
    Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
    Folate-metabolizing gene variants and pregnancy outcome of IVF2011In: RBM Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 22, no 6, p. 603-614Article in journal (Refereed)
    Abstract [en]

    There is growing evidence that folate status and variation in folate-metabolizing genes are involved in female reproductive functions. This study evaluated the influence of maternal blood folate, vitamin B(12), homocysteine and 10 folate pathway gene variants on IVF outcome. Also, the prevalence of these polymorphisms was compared in 439 female IVF patients and 225 fertile controls. MTHFR 677 CT heterozygotes had a higher proportion of good-quality embryos and an increased chance of pregnancy. MTHFR 1793 GA heterozygosity was associated with a lower percentage of previously failed IVF treatments. Heterozygosity for FOLR1 1816 C/delC and 1841 G/A was associated with a raised risk of pregnancy loss. The CTH 1208 GT genotype was associated with an increased chance of pregnancy and a smaller number of previously failed IVF cycles and the genotype frequency was lower in IVF patients with three or more previously failed IVF treatments compared with fertile controls. SLC19A1 80 GA heterozygotes had a decreased number of previously failed IVF treatments and were more prevalent among fertile controls. In conclusion, polymorphisms in folate-metabolizing genes may affect ovarian stimulation and pregnancy outcome of IVF, and heterozygous individuals, rather than the wild-type homozygotes, appeared to have more favourable outcomes.

  • 37. Lalitkumar, P. G. L
    et al.
    Lalitkumar, S
    Meng, C. X
    Stavreus-Evers, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hambiliki, F
    Bentin-Ley, U
    Gemzell-Danielsson, Kristina
    Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model2007In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 22, no 11, p. 3031-3037Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of fertility regulating drugs is limited among various socio-ethnic groups due to limited knowledge about their mechanism of action. This study investigates the effect of levonorgestrel and mifepristone on attachment of human embryos to an in vitro endometrial construct. METHOD: Three-dimensional endometrial constructs were established by co-culturing early luteal phase human endometrial stromal and epithelial cells. Expression of endometrial receptivity markers in this construct were examined by immunohistochemistry. Effects of mifepristone and levonorgestrel on viability and attachment of human blastocysts were investigated. RESULTS: Endometrial constructs expressed the factors involved in endometrial receptivity: estrogen receptor, progesterone receptor, vascular endothelial growth factor, leukemia inhibitory factor, interleukin-1, COX-2, MUC-1 and integrin-alpha(V)beta(3). None of the 15 embryos cultured with mifepristone attached to the endometrial construct (P < 0.01), whereas 10/17 in control, and 6/14 in levonorgestrel, groups attached. The attachment was confirmed by the positive expression of cytokeratin 7 at the attachment site. CONCLUSION: Mifepristone inhibits blastocyst attachment. Levonorgestrel did not impair the attachment of human embryos to the in vitro endometrial construct. This model could be used to understand endometrial receptivity and embryo-endometrial dialog and to develop new fertility regulating substances.

  • 38.
    Lindgren, Karin E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kårehed, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Karypidis, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hosseini, Frida
    Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institute, Danderyd Hospital.
    Bremme, Katarina
    Department of Women′s and Children′s Health, Karolinska Institute.
    Landgren, Britt-Marie
    Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Skjoldebrand-Sparre, Lottie
    Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institute, Danderyd Hospital.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Histidine-rich glycoprotein gene polymorphism in patients with recurrent miscarriage2013In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 92, no 8, p. 974-977Article in journal (Refereed)
    Abstract [en]

    Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage.

  • 39.
    Ljunger, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cnattingius, Sven
    Clinical Epidemiology Unit, Dept of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ekbom, Anders
    Lundin, Catarina
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ultrasonographic findings in spontaneous miscarriage: relation to euploidy and aneuploidy2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 95, no 1, p. 221-224Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a possible correlation between transvaginal ultrasound findings in miscarriages and cytogenetic analyses from chorionic villi obtained by dilatation and curettage. DESIGN: Prospective, population-based study. SETTING: University-based hospital. PATIENT(S): Five hundred seventy-six women with spontaneous miscarriage diagnosed between 6 and 12 completed pregnancy weeks. INTERVENTION(S): Transvaginal ultrasonography and dilatation and curettage. MAIN OUTCOME MEASURE(S): Cytogenetic analyses and ultrasound measurement of embryonic pole. RESULT(S): The mean gestational age was 9.5 weeks. Chromosomal analyses were successful in 259 cases, 159 with cytogenetic abnormalities and 100 euploidy. Empty gestational sacs were equally often found in euploidy and aneuploidy, whereas small embryonic or fetal poles were significantly more often associated with aneuploidy. CONCLUSION(S): A smaller than expected fetal size when a miscarriage is diagnosed during the first trimester is significantly associated with a chromosomal aberration.

  • 40.
    Murto, Tiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bjuresten, Kerstin
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
    Landgren, Britt-Marie
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Predictive value of hormonal parameters for live birth in women with unexplained infertility and male infertility2013In: Reproductive Biology and Endocrinology, ISSN 1477-7827, E-ISSN 1477-7827, Vol. 11, p. 61-Article in journal (Refereed)
    Abstract [en]

    Background: Infertile women might get pregnant sometime after fertility treatment, but today, there is no prediction model on who will eventually have children. The objective of the present study was to characterize hormone levels in an arbitrary menstrual cycle in women with unexplained infertility and male infertility, and to determine the predictive value for long-term possibility of live birth. Methods: In this cross-sectional study, with 71 infertile women with diagnosis unexplained infertility and male infertility, blood samples were obtained during the proliferative and secretory phases of an arbitrary menstrual cycle. Serum concentrations of FSH, LH, AMH, inhibin B, estradiol, progesterone, PRL and TSH were determined. The predictive value of ovulation and hormonal analysis was determined by identifying the proportion of women with at least one live birth. Mann Whitney U test, chi2 test and Spearman's correlation were used for statistical analysis. A value of p < 0.05 was considered statistically significant. Results: There were no differences in hormone values and live birth rates between women with unexplained infertility and male infertility. The best sole predictors of live birth were age of the women, followed by ovulatory cycle, defined as serum progesterone concentration of greater than or equal to 32 nmol/L, and a serum TSH concentration of less than or equal to 2.5 mIU/L. Combining the age with the ovulatory cycle and serum TSH less than or equal to 2.5 mIU/L or serum AMH greater than or equal to 10 pmol/L the predictive value was close to 90%. Conclusions: Age in combination with the presence of an ovulatory cycle and serum TSH or serum AMH is predictive for long-term live birth. The advantage of serum AMH compared with serum TSH is the very little variation throughout the menstrual cycle, which makes it a useful tool in infertility diagnosis.

  • 41.
    Murto, Tiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kunovac Kallak, Theodora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hoas, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Altmäe, Signe
    University of Granada, Competence Centre on Reproductive Medicine and Biology, Tartu.
    Salumets, Andres
    University of Tartu, Competence Centre on Reproductive Medicine and Biology, Tartu.
    Nilsson, Torbjörn K
    Umeå University.
    Skoog Svanberg, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Yngve, Agneta
    Örebro University, Karolinska Institutet.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Folic acid supplementation and methylenetetrahydrofolate reductase (MTHFR)gene variations in relation to IVF pregnancy outcome2015In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 1, p. 65-71Article in journal (Refereed)
    Abstract [en]

    Objective:

    To study folic acid intake, folate status and pregnancy outcome afterinfertility treatment in women with different infertility diagnoses in relation tomethylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C and 1793G>A genevariations. Also the use of folic acid supplements, folate status and the frequency ofdifferent gene variations were studied in women undergoing infertility treatment andfertile women.

    Design:

    Observational study. Setting: University hospital. Population:Women undergoing infertility treatment and healthy, fertile, non-pregnant women.

    Methods:

    A questionnaire was used to assess general background data and use ofdietary supplements. Blood samples were taken to determine plasma folate andhomocysteine levels, and for genomic DNA extraction. A meta-analysis of four studieswas performed to assess pregnancy outcome in relation to MTHFR 677 TT vs. CC, and1298 CC vs. AA polymorphisms.

    Main outcome measures:

    Folic acid supplementintake, and plasma folate, homocysteine and genomic assays.

    Results:

    Women in theinfertility group used significantly more folic acid supplements and had better folatestatus than fertile women, but pregnancy outcome after fertility treatment was notdependent on folic acid intake, folate status or MTHFR gene variations. However, ameta-analysis demonstrated that MTHFR 1298AA polymorphism was related topregnancy outcome.

    Conclusion:

    Folic acid supplementation seems to play only a minorrole in the context of pregnancy outcome after in vitro fertilisation, and other variablesin folate metabolism are of more importance. In particular, MTHFR 1298AA genevariation appears to have a positive association with the success of fertility treatment

  • 42.
    Murto, Tiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skoog Svanberg, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Yngve, Agneta
    Örebro University, Karolinska Institutet.
    Nilsson, Torbjörn K
    Umeå University.
    Altmäe, Signe
    University of Granada, Competence Centre on Reproductive Medicine and Biology, Tartu.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Salumets, Andres
    University of Tartu, Competence Centre on Reproductive Medicine and Biology, Tartu.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility2014In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 28, no 6, p. 766-772Article in journal (Refereed)
    Abstract [en]

    Folic acid supplements are commonly used by infertile women and lead to a positive folate status. However, the effect of folic acid supplements on pregnancy outcome in women with unexplained infertility has not been well investigated. This study evaluated folic acid supplement use and folate status in women with unexplained infertility in relation to pregnancy outcome. In addition, use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile, nonpregnant control women. Women with unexplained infertility used significantly more folic acid supplements and had higher median total folic acid intake from supplements compared with fertile control women (both P < 0.001). Women with unexplained infertility also had significantly higher median plasma folate and lower median plasma homocysteine concentrations than fertile women (both P < 0.001), but folic acid supplementation or folate status were not related to pregnancy outcome in women with unexplained infertility. In conclusion, folic acid supplementation or good folate status did not have a positive effect on pregnancy outcome following infertility treatment in women with unexplained infertility.

  • 43.
    Murto, Tiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Yngve, Agneta
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Food, Nutrition and Dietetics.
    Skoog Svanberg, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Altmäe, Signe
    Competence Ctr Hlth Technol, Tartu, Estonia.
    Salumets, Andres
    Competence Ctr Hlth Technol, Tartu, Estonia;Univ Tartu;Univ Helsinki;Helsinki Univ Hosp.
    Wånggren, Kjell
    Karolinska Inst.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Compliance to the recommended use of folic acid supplements for women in Sweden is higher among those under treatment for infertility than among fertile controls and is also related to socioeconomic status and lifestyle2017In: Food & Nutrition Research, ISSN 1654-6628, E-ISSN 1654-661X, Vol. 61, article id 1334483Article in journal (Refereed)
    Abstract [en]

    Background: Folate has been discussed in relation to fertility among women, but studies on women under treatment for infertility are lacking.

    Objective: The objective of this study was to investigate folic acid supplement use and folate status among women under treatment for infertility (hereafter infertile) and fertile women also in regard to socioeconomic and lifestyle factors.

    Design: Lifestyle and dietary habits, and use of dietary supplements were assessed using a questionnaire. Blood samples were obtained for analysis of folate status. 24-hour recall interviews were also performed.

    Results: Highly educated, employed and infertile women were most prone to using folic acid supplements. The infertile women had a significantly better folate status than the fertile women. Folate status did not correlate with socioeconomic or lifestyle factors. The infertile women were physically more active, smoked less and were employed. Our questionnaire data had only fair agreement with the data from 24-hour recalls, but the folate status data was clearly correlated to our questionnaire results.

    Conclusions: Infertile women were most prone to using folic acid supplements and had better folate status than the controls. High educational and employment status were found to be key factors for high compliance to the recommended use folic acid supplements.

  • 44.
    Nordqvist, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kårehed, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hambiliki, Fredwell
    Department of Clinical Science, Karolinska Institutet, Stockholm, Sweden.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    The Presence of Histidine-Rich Glycoprotein in the Female Reproductive Tract and in Embryos2010In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 17, no 10, p. 941-947Article in journal (Refereed)
    Abstract [en]

    A well-regulated angiogenesis is crucial for proper embryo implantation, embryogenesis, and pregnancy development. Monitoring the presence and distribution of angiogenic regulators in the female reproductive tract and in the early embryo is important for a broader understanding of the molecular aspects of fertility, embryogenesis, and pregnancy. Histidine-rich glycoprotein (HRG) is a glycoprotein involved in angiogenesis. Its presence in the female reproductive tract or in embryos has not previously been studied. Follicular fluid, culture medium, and embryos were obtained from patients undergoing in vitro fertilization (IVF). Biopsies from inner genitalia and placenta were collected at surgery. Histidine-rich glycoprotein presence was investigated by immunohistochemistry and Western blot. Polymerase chain reaction (PCR) was used to determine HRG expression in tissues or by embryos. We identified HRG in follicular fluid, the female reproductive tract, and placenta, as well as in the embryos. Moreover, HRG expression was observed in blastocysts. Thus, the angiogenic properties of HRG might affect fertility.

  • 45.
    Nordqvist, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kårehed, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Histidine-Rich Glycoprotein Polymorphism and Pregnancy Outcome: a pilot study2011In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 23, no 2, p. 213-219Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRG) is involved in fibrinolysis and coagulation, the immune system and angiogenesis. These processes are all crucial in establishing and maintaining pregnancy. The primary aim of this pilot study was to determine if HRG affects pregnancy outcome. The secondary aim was to investigate if a specific genetic polymorphism (rs9898 C/T) in the HRG gene is associated with pregnancy results. The polymorphism leads to expression of either a serine or proline residue at position 186 in the protein sequence. In this study, women undergoing IVF were included. The genetic polymorphism in the HRG gene was analysed by Western blot and single nucleotide polymorphism analysis. None of the women homozygous for the serine at residue 186 became pregnant whereas the women homozygous for proline at residue 186 had higher than expected pregnancy rates. As far as is known,this is the first study to show that a specific genetic polymorphism in the HRG gene of a woman affects her chances of becoming pregnant after IVF. The results may be essential in improving advice and IVF treatment for couples with unexplained infertility.

    We have found a new test which might potentially improve advice and treatment for infertile couples considering IVF treatment. Histidine-rich glycoprotein (HRG) is involved in the system preventing blood clots or excess bleeding, the immune system and the system regulating blood vessel formation. Tight regulation of these processes is necessary for a pregnancy to be successful. This study examines how a specific genetic variant of HRG can affect pregnancy rates after IVF. The genetic polymorphism leads to expression of two different protein variations. One variation has a serine amino acid attached at position 186 and the other variation has a proline amino acid attached at the same position. Which variation a women produces is inherited co-dominantly. In this study, women undergoing IVF were included. To determine which variation each woman had, two different methods were used: Western blot and single nucleotide polymorphism analysis. The experimental results were then related to the woman’s medical records. None of the women who only produced the variation of HRG with a serine attached became pregnant, whereas the women who produced only the proline variation had higher than expected pregnancy rates. We show for the first time that the genetic background of a woman may affect her chances of becoming pregnant after IVF. The results might be essential in improving advice and IVF treatment for infertile couples.

  • 46. Parn, Triin
    et al.
    Ruiz, Raul Grau
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ruiz, Jonatan R.
    Davey, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hreinsson, Julius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Salumets, Andres
    Sjostrom, Michael
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ortega, Francisco B.
    Altmae, Signe
    Physical activity, fatness, educational level and snuff consumption as determinants of semen quality: findings of the ActiART study2015In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 31, no 1, p. 108-119Article in journal (Refereed)
    Abstract [en]

    In this study, the association between physical activity and other potential determinants, objectively measured by accelerometry, was examined. Sixty-two men attending an infertility clinic participated in the study. Obese men (body mass index >= 30) and those with a waist circumference 102 cm or more had lower semen volume than the other men (P < 0.05). Higher values in sperm parameters were observed in participants who completed university studies and those who did not consume snuff, compared with the other participants (P < 0.05). Finally, men who spent an average number of 10 min-bouts of moderate-to-vigorous physical activity had significantly better semen quality than those who engaged in low or high numbers of bouts of activity (P < 0.05). No associations were found for sedentary or moderate-to-vigorous physical activity time when it was not sustained over 10 min, i.e. not in bouts. Men who have average levels of physical activity over sustained periods of 10 min are likely to have better semen quality than men who engage in low or high levels of such activity. Similarly, high levels of total and central adiposity, low educational level and snuff consumption are negatively related to semen quality.

  • 47.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ek, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Human Prostasomes Express Glycolytic Enzymes with Capacity for ATP Production2013In: Andrology, ISSN 2047-2919, Vol. 1, no S2, p. 76-76Article in journal (Other academic)
  • 48.
    Ronquist, Göran K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Prostasomes are heterogeneous regarding size and appearance but affiliated to one DNA-containing exosome family2012In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 72, no 16, p. 1736-1745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostate acinar epithelial cells release microvesicles (prostasomes) that possess pleiotropic biological effects relevant for successful fertilization. Prostasomes are formed in a similar way as exosomes but are heterogeneous as regards size and appearance. Like exosomes they are thought to be mediators of intercellular communication.

    METHODS:

    We prepared seminal prostasomes in accordance with the prevailing protocol for exosome preparation including passage through a 0.2 µm filter and centrifugation in a sucrose gradient.

    RESULTS:

    We compared the "filterable prostasomes" with those trapped on the filter ("nonfilterable prostasomes") and, qualitatively, no conspicuous differences were apparent regarding ultrastructure and SDS-PAGE banding pattern. Moreover, both types of prostasomes contained DNA fragments and Western blot revealed presence of prostate specific membrane antigen (PSMA), CD38, and annexin A1.

    CONCLUSIONS:

    Reasonably, prostasomes could be included in the exosome family and be regarded as one entity containing chromosomal DNA.

  • 49.
    Ronquist, K Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ek, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Morrell, Jane
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ström Holst, Bodil
    Humblot, Patrice
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Prostasomes from four different species are able to produce extracellular adenosine triphosphate (ATP)2013In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1830, no 10, p. 4604-4610Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostasomes are extracellular vesicles. Intracellularly they are enclosed by another larger vesicle, a so called "storage vesicle" equivalent to a multivesicular body of late endosomal origin. Prostasomes in their extracellular context are thought to play a crucial role in fertilization.

    METHODS:

    Prostasomes were purified according to a well worked-out schedule from seminal plasmas obtained from human, canine, equine and bovine species. The various prostasomes were subjected to SDS-PAGE separation and protein banding patterns were compared. To gain knowledge of the prostasomal protein systems pertaining to prostasomes of four different species proteins were analyzed using a proteomic approach. An in vitro assay was employed to demonstrate ATP formation by prostasomes of different species.

    RESULTS:

    The SDS-PAGE banding pattern of prostasomes from the four species revealed a richly faceted picture with most protein bands within the molecular weight range of 10-150kDa. Some protein bands seemed to be concordant among species although differently expressed and the number of protein bands of dog prostasomes seemed to be distinctly fewer. Special emphasis was put on proteins involved in energy metabolic turnover. Prostasomes from all four species were able to form extracellular adenosine triphosphate (ATP). ATP formation was balanced by ATPase activity linked to the four types of prostasomes.

    CONCLUSION:

    These potencies of a possession of functional ATP-forming enzymes by different prostasome types should be regarded against the knowledge of ATP having a profound effect on cell responses and now explicitly on the success of the sperm cell to fertilize the ovum.

    GENERAL SIGNIFICANCE:

    This study unravels energy metabolic relationships of prostasomes from four different species.

  • 50.
    Ronquist, K Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ek, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human prostasomes express glycolytic enzymes with capacity for ATP production2013In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 304, no 6, p. E576-E582Article in journal (Refereed)
    Abstract [en]

    Prostasomes are prostate-derived, exosome-like microvesicles that transmit signaling complexes between the acinar epithelial cells of the prostate and sperm cells. A vast majority of prostasomes has a diameter of 30 - 200 nm and they are generally surrounded by a classical membrane bilayer. Using a selected proteomic approach, it became increasingly clear that prostasomes harbor distinct subsets of proteins that may be linked to adenosine triphosphate (ATP) metabolic turnover that in turn might be of importance in the role of prostasomes as auxiliary instruments in the fertilization process. Among the 21 proteins identified most of the enzymes of anaerobic glycolysis were represented and three of the glycolytic enzymes present are among the ten top proteins found in most exosomes, once again linking prostasomes to the exosome family. Other prostasomal enzymes involved in ATP turnover were adenylate kinase, ATPase, 5'-nucleotidase and hexose transporters. The identified enzymes in their prostasomal context were operational for ATP formation when supplied with substrates. The net ATP production was low due to a high prostasomal ATPase activity that could be partially inhibited by vanadate that was utilized in order to profile the ATP forming ability of prostasomes. Glucose and fructose were equivalent as glycolytic substrates for prostasomal ATP formation and the enzymes involved were apparently surface-located on prostasomes, since an alternative substrate not being membrane-permeable (glyceraldehyde 3-phosphate) was operative, too. There is no clear cut function linked to this subset of prostasomal proteins but some possible roles are discussed.

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