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Biological Markers of Fertility
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infertility affects 15 % of couples, which corresponds to 60 - 80 million worldwide. The microenvironments in which the oocyte, embryo and fetus mature are vital to the establishment and development of a healthy pregnancy. Different biological systems, such as angiogenesis, the immune system and apoptosis need to be adequately regulated for pregnancy to occur and progress normally. The overall aim of this thesis was to investigate the impact of Histidine-rich glycoprotein (HRG) and Src homology 2 domain-containing adapter protein B (SHB) on human female fertility.

HRG is a plasma protein that regulates angiogenesis, the immune system, coagulation/fibrinolysis and apoptosis, by building complexes with various ligands. The impact of HRG on fertility is studied here for the first time. HRG is present in follicular fluid, the Fallopian tube, endometrium, myometrium and placenta. HRG distribution within embryo nuclei depends on developmental stage. Blastocysts express and secrete HRG. The HRG C633T single nucleotide polymorphism (SNP) appears to affect the chance of pregnancy and, correspondingly, parameters associated with pregnancy in IVF. Additionally, this HRG genotype may increase the risk in IVF of only developing embryos unfit for transfer.

SHB is an adaptor protein involved in intracellular signaling complexes that regulate angiogenesis, the immune system and cell proliferation/apoptosis. Shb knockout mice have altered oocyte/follicle maturation and impaired embryogenesis. The impact of three SHB polymorphisms (rs2025439, rs13298451 and rs7873102) on human fertility is studied for the first time. The SNP prevalences did not differ between infertile and fertile women. BMI, gonadotropin dosages, the percentage of immature oocytes, the number of fertilized oocytes, the percentage of good-quality embryos and the day of embryo transfer seems to be affected by SHB genotype.

In conclusion, HRG and SHB appear to influence female fertility. They are potential biomarkers that might be used for predicting pregnancy chance in infertile women. Knowledge of these genotypes may improve patient counseling and individualization of treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1048
Keyword [en]
angiogenesis, embryogenesis, female reproductive tract, fertility, fertilization, Histidine-rich glycoprotein, intron, in vitro fertilization, oocyte, ovarian response, pregnancy, single nucleotide polymorphism, Src homology 2 domain-containing adapter protein B
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-234067ISBN: 978-91-554-9085-0 (print)OAI: oai:DiVA.org:uu-234067DiVA: diva2:756869
Public defence
2014-12-05, Sal IX, Universitetshuset, Övre Slottsgatan 2, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-11-14 Created: 2014-10-14 Last updated: 2015-02-03Bibliographically approved
List of papers
1. The Presence of Histidine-Rich Glycoprotein in the Female Reproductive Tract and in Embryos
Open this publication in new window or tab >>The Presence of Histidine-Rich Glycoprotein in the Female Reproductive Tract and in Embryos
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2010 (English)In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 17, no 10, 941-947 p.Article in journal (Refereed) Published
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.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-234506 (URN)10.1177/1933719110374366 (DOI)000282003100008 ()20639474 (PubMedID)
Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved
2. Histidine-Rich Glycoprotein Polymorphism and Pregnancy Outcome: a pilot study
Open this publication in new window or tab >>Histidine-Rich Glycoprotein Polymorphism and Pregnancy Outcome: a pilot study
2011 (English)In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 23, no 2, 213-219 p.Article in journal (Refereed) Published
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.

Keyword
angiogenesis, fertility, histidine-rich glycoprotein, IVF, polymorphism, pregnancy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-159556 (URN)10.1016/j.rbmo.2011.04.004 (DOI)000303044500009 ()21665544 (PubMedID)
Available from: 2011-10-04 Created: 2011-10-04 Last updated: 2017-12-08Bibliographically approved
3. Ovarian Response is Affected by a Specific Histidine-Rich Glycoprotein Polymorphism: a preliminary study
Open this publication in new window or tab >>Ovarian Response is Affected by a Specific Histidine-Rich Glycoprotein Polymorphism: a preliminary study
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2015 (English)In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 30, no 1, 74-81 p.Article in journal (Refereed) Published
Abstract [en]

Genetic polymorphisms involved in angiogenesis, apoptosis and chemokine signalling are associated with varying ovarian response and oocyte quality. The protein, histidine-rich glycoprotein (HRG), is involved in these processes, but its effect on ovarian response in IVF has not been previously studied. A single nucleotide polymorphism (SNP) in the HRG gene (C633T) seems to affect pregnancy results in IVF. Women with the C/C genotype had higher pregnancy rates, C/T had moderate rates and none of those in the T/T group conceived. The aim of this study was to investigate if the HRG C633T SNP affects ovarian response. The HRG C633T SNP genotype of 67 women with unexplained infertility undergoing IVF was analysed and related to medical data. The T/T genotype obtained fewer oocytes, including mature oocytes, despite higher dosages of FSH administered. Additionally, the highest proportion of women who had exclusively poor-quality embryos was in the T/T group. No differences in demographic factors known to affect these parameters were found. The results suggest that the HRG C633T SNP influences ovarian response. Further studies of this SNP may increase knowledge about the biological processes involved in oocyte development and, furthermore, improve predicted ovarian response and fertilization.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-234490 (URN)10.1016/j.rbmo.2014.09.016 (DOI)000347102400011 ()
Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved
4. The Effect of SHB Gene Polymorphisms on Ovarian Response and Oocyte Maturation in IVF
Open this publication in new window or tab >>The Effect of SHB Gene Polymorphisms on Ovarian Response and Oocyte Maturation in IVF
2014 (English)In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990Article in journal (Refereed) Submitted
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-234492 (URN)
Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved

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