TY - THES
T1 - The impact of gonadotropin receptor polymorphisms on human reproductive function
AU - Lindgren, Ida
N1 - Defence details
Date: 2017-03-10
Time: 09:00
Place: CRC Aula, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
External reviewer(s)
Name: Gromoll, Jörg
Title: professor
Affiliation: Centre of Reproductive Medicine and Andrology, Munster University.
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ISSN: 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:32
PY - 2017
Y1 - 2017
N2 - To date, approximately 15% of all couples worldwide suffer from infertility. The management include controlledovarian 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 000IVF cycles are performed worldwide each year, and as a result more than 5 million babies have been born sincethe technique was developed in 1978. It has been shown that common genetic variations, called single-nucleotidepolymorphisms (SNPs), affect the reproductive ability of both men and women, and also the outcome of the IVFtreatment. 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 conflictingresults have been produced from previous studies, no firm conclusions can be drawn. Therefore, the aims of thisthesis were to investigate the impact of the FSHR SNPs T307A and N680S on male reproductive function in acohort of homogenous Swedish men (n=313) from the general population, study the connection between theFSHR 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 FSHRgenotypes of the men and FSHR/LHCGR genotypes of the women were associated with clinical parameters, andin the case of the women also associated with outcomes after IVF. The activity of the different receptor variantswere investigated in vitro in granulosa cells from women undergoing IVF and in monkey kidney cells, by means ofthe level of the produced downstream signaling molecule cAMP, measured by ELISA, in response to FSHtreatment. Swedish men from the general population that were homozygous for the FSHR T307/N680 genotypedisplayed a lower serum FSH concentration, as well as higher estradiol, sex hormone-binding globulin andtestosterone concentrations, and also higher sperm counts and larger testicles. Women undergoing IVF gotpregnant to a higher extent (four-fold in IVF cycle 1 and two-fold in IVF cycle 2 and 3) if they were homozygous forthe combination of FSHR S680/LHCGR S312. In vitro results indicated that the FSHR S680/LHCGR N312 variantwas superior in terms of cAMP production. In conclusion, the results from this thesis show favourable reproductivehormonal status and sperm parameters of men with the FSHR T307/N680 genotype, while women homozygousfor the FSHR S680/LHCGR S312 combination more often got pregnant after IVF. In vitro results corroborated theobserved higher pregnancy rate for women with the FSHR S680/LHCGR S312 genotype, in terms of a highercAMP level in response to FSH treatment for this receptor combination. A gender difference may explain why thesame pattern was not observed in men, since several differences in the hormonal regulation between the femaleand male reproductive system exist. In general, this knowledge may be utilized in the development ofindividualized treatments of infertile men and women.
AB - To date, approximately 15% of all couples worldwide suffer from infertility. The management include controlledovarian 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 000IVF cycles are performed worldwide each year, and as a result more than 5 million babies have been born sincethe technique was developed in 1978. It has been shown that common genetic variations, called single-nucleotidepolymorphisms (SNPs), affect the reproductive ability of both men and women, and also the outcome of the IVFtreatment. 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 conflictingresults have been produced from previous studies, no firm conclusions can be drawn. Therefore, the aims of thisthesis were to investigate the impact of the FSHR SNPs T307A and N680S on male reproductive function in acohort of homogenous Swedish men (n=313) from the general population, study the connection between theFSHR 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 FSHRgenotypes of the men and FSHR/LHCGR genotypes of the women were associated with clinical parameters, andin the case of the women also associated with outcomes after IVF. The activity of the different receptor variantswere investigated in vitro in granulosa cells from women undergoing IVF and in monkey kidney cells, by means ofthe level of the produced downstream signaling molecule cAMP, measured by ELISA, in response to FSHtreatment. Swedish men from the general population that were homozygous for the FSHR T307/N680 genotypedisplayed a lower serum FSH concentration, as well as higher estradiol, sex hormone-binding globulin andtestosterone concentrations, and also higher sperm counts and larger testicles. Women undergoing IVF gotpregnant to a higher extent (four-fold in IVF cycle 1 and two-fold in IVF cycle 2 and 3) if they were homozygous forthe combination of FSHR S680/LHCGR S312. In vitro results indicated that the FSHR S680/LHCGR N312 variantwas superior in terms of cAMP production. In conclusion, the results from this thesis show favourable reproductivehormonal status and sperm parameters of men with the FSHR T307/N680 genotype, while women homozygousfor the FSHR S680/LHCGR S312 combination more often got pregnant after IVF. In vitro results corroborated theobserved higher pregnancy rate for women with the FSHR S680/LHCGR S312 genotype, in terms of a highercAMP level in response to FSH treatment for this receptor combination. A gender difference may explain why thesame pattern was not observed in men, since several differences in the hormonal regulation between the femaleand male reproductive system exist. In general, this knowledge may be utilized in the development ofindividualized treatments of infertile men and women.
KW - FSHR
KW - LHCGR
KW - single-nucleotide polymorphism (SNP)
KW - in vitro fertilization (IVF)
KW - reproduction
KW - Infertility
KW - male fertility
KW - female fertility
M3 - Doctoral Thesis (compilation)
SN - 978-91-7619-413-3
PB - Lund University: Faculty of Medicine
CY - Lund
ER -