Ida Lindgren Webb_kappa

96 Pages·2017·4.77 MB·English

The impact of gonadotropin receptor polymorphisms on human reproductive function
Lindgren, Ida
2017
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Citation for published version (APA):
Lindgren, I. (2017). The impact of gonadotropin receptor polymorphisms on human reproductive function.
[Doctoral Thesis (compilation), Department of Translational Medicine]. Lund University: Faculty of Medicine.
Total number of authors:
1
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The impact of gonadotropin receptor
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The impact of gonadotropin receptor op
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Ida Lindgren holds a MSc in Biomedicine from Lund to
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University, Sweden, since 2010. The focus of her the- p
sis is the effect of polymorphisms in the gonadotro- oly
pin receptor genes on human reproductive function. m
The main results are that FSH receptor polymorp- o
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hisms have an effect on male reproductive hormone h
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levels and sperm parameters, and that in women, s
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a combination of FSH receptor and LHCG receptor s
polymorphisms predict the pregnancy chance after on
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Lund University, Faculty of Medicine
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Doctoral Dissertation Series 2017:32 13
4
Department of Translational Medicine 19
Division of Molecular Genetic Reproductive Medicine 6
7
ISBN 978-91-7619-413-3 91
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ISSN 1652-8220 7 32
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The impact of gonadotropin receptor
polymorphisms on human
reproductive function

Ida Lindgren

DOCTORAL DISSERTATION
by due permission of the Faculty of Medicine, Lund University, Sweden.
To be defended at CRC Aula, Jan Waldenströms gata 35, Malmö.
Friday 10th of March 2017 at 9.00.

Faculty opponent

Professor Jörg Gromoll
Centre of Reproductive Medicine and Andrology,
Faculty of Medicine, Münster University, Münster, Germany
Organization Document name
LUND UNIVERSITY DOCTORAL DISSERTATION
Faculty of Medicine Date of issue
Department of Translational Medicine March 10th2017
Division ofMolecular Genetic
Reproductive Medicine
Author: Ida Lindgren Sponsoring organization
Title: The impact of gonadotropin receptor polymorphismson human reproductive function
Abstract
To date,approximately 15% of all couples worldwide suffer from infertility. The management include controlled
ovarianhyper-stimulation of the women withfollicle-stimulating hormone(FSH)and semen analysis of the men,
prior to in vitrofertilization (IVF)and transfer of the fertilized embryo to the uterine cavity. Approximately 250000
IVFcycles are performed worldwide each year, and as a result more than 5 million babies have been born since
the technique was developed in 1978. It has been shown thatcommon genetic variations, called single-nucleotide
polymorphisms(SNPs), affect the reproductive ability of both men and women, and also the outcome of the IVF
treatment. Especially the gene encoding the receptor to which FSH binds, the FSHRgene,has been investigated,
since FSH is an essential hormone in both female and male repoductive function. However, since conflicting
results have been produced from previous studies,no firm conclusions canbe drawn. Therefore, the aims of this
thesis were to investigate the impact of the FSHRSNPs T307A and N680S on male reproductive function in a
cohort of homogenous Swedish men (n=313) from the general population, study the connection between the
FSHR N680S and the LHCGR N312S SNPs in relation to outcomes after IVF in unselected women (n=617)
attending an IVF clinic and explore the activity of the different FSHR and LHCGR variants in vitro.The FSHR
genotypes of the men and FSHR/LHCGRgenotypes of the women were associated with clinical parameters, and
in the case of the women also associated with outcomes after IVF. The activity of the different receptor variants
were investigatedin vitroin granulosa cells from women undergoing IVF and in monkey kidney cells, by means of
the level of the produced downstream signaling molecule cAMP, measured by ELISA, in response to FSH
treatment.Swedish men from the general population that were homozygous for the FSHRT307/N680 genotype
displayed a lower serum FSH concentration, as well as higher estradiol, sex hormone-binding globulin and
testosterone concentrations, and also higher sperm counts and larger testicles. Women undergoing IVF got
pregnant to a higher extent (four-fold in IVF cycle 1 and two-fold in IVF cycle 2 and 3) if they were homozygous for
the combination of FSHRS680/LHCGR S312. In vitroresultsindicated that the FSHRS680/LHCGRN312 variant
was superior in terms of cAMP production.In conclusion, the results from this thesis show favourable reproductive
hormonal status and sperm parameters of men with the FSHRT307/N680 genotype, while women homozygous
for the FSHRS680/LHCGRS312 combination more often got pregnant after IVF. In vitroresults corroborated the
observed higher pregnancy rate for women with the FSHR S680/LHCGR S312 genotype, in terms of a higher
cAMP level in response to FSH treatment for this receptor combination.A gender difference mayexplain why the
same pattern was not observed in men, since several differences in the hormonal regulation between the female
and male reproductive system exist. In general, this knowledge may be utilized in the development of
individualized treatments of infertile men and women.
Key words
FSHR, LHCGR, single-nucleotide polymorphism (SNP), in vitrofertilization (IVF), reproduction, infertility, female
fertility, male fertility
Classification system and/or index terms (if any)
Supplementary bibliographical information Language
English
ISSN and key title: 1652-8220 ISBN: 978-91-7619-413-3
Recipient’s notes Number of pages 93 Price
Security classification
I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all
reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation.
Signature Date
The impact of gonadotropin receptor
polymorphisms on human
reproductive function

Ida Lindgren
Front cover picture “Min familj” by my nephew Alfred Anefur, 6 years old.
Back cover photo by Björn Martinsson.

Copyright © Ida Lindgren

Faculty of Medicine
Department of Translational Medicine

ISBN 978-91-7619-413-3
ISSN 1652-8220

Printed in Sweden by Media-Tryck, Lund University
Lund 2017
Till Tor

PREFACE
This thesis comprises two parts. In the first part, an overview of the field is
presented, starting with an introduction, followed by a materials and
methods section and the overall results obtained. Subsequently, a general
discussion of the scientific papers of which the thesis is built on is
presented, and finally a general conclusion and some future perspectives are
drawn. The second part of the thesis covers the three scientific papers (I-III)
upon which the thesis is based.