The impact of gonadotropin receptor polymorphisms on human reproductive function
Författare
Summary, in English
To date, approximately 15% of all couples worldwide suffer from infertility. The management include controlled
ovarian hyper-stimulation of the women with follicle-stimulating hormone (FSH) and semen analysis of the men,
prior to in vitro fertilization (IVF) and transfer of the fertilized embryo to the uterine cavity. Approximately 250 000
IVF cycles 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 that common 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 FSHR gene, 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 can be drawn. Therefore, the aims of this
thesis were to investigate the impact of the FSHR SNPs 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/LHCGR genotypes 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 investigated in vitro in 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 FSHR T307/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 FSHR S680/LHCGR S312. In vitro results indicated that the FSHR S680/LHCGR N312 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 FSHR T307/N680 genotype, while women homozygous
for the FSHR S680/LHCGR S312 combination more often got pregnant after IVF. In vitro results 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 may explain 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.
ovarian hyper-stimulation of the women with follicle-stimulating hormone (FSH) and semen analysis of the men,
prior to in vitro fertilization (IVF) and transfer of the fertilized embryo to the uterine cavity. Approximately 250 000
IVF cycles 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 that common 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 FSHR gene, 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 can be drawn. Therefore, the aims of this
thesis were to investigate the impact of the FSHR SNPs 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/LHCGR genotypes 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 investigated in vitro in 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 FSHR T307/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 FSHR S680/LHCGR S312. In vitro results indicated that the FSHR S680/LHCGR N312 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 FSHR T307/N680 genotype, while women homozygous
for the FSHR S680/LHCGR S312 combination more often got pregnant after IVF. In vitro results 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 may explain 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.
Avdelning/ar
Publiceringsår
2017
Språk
Engelska
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Medical and Health Sciences
Nyckelord
- FSHR
- LHCGR
- single-nucleotide polymorphism (SNP)
- in vitro fertilization (IVF)
- reproduction
- Infertility
- male fertility
- female fertility
Status
Published
Forskningsgrupp
- Molecular genetic reproductive medicine, Malmö
Handledare
- Yvonne Giwercman
- Aleksander Giwercman
- Claus Yding Andersen
ISBN/ISSN/Övrigt
- ISBN: 978-91-7619-413-3
Försvarsdatum
10 mars 2017
Försvarstid
09:00
Försvarsplats
CRC Aula, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
Opponent
- Jörg Gromoll (professor)