Λουτράδης Δημήτριος, Καθηγητής, Ιατρική, ΕΚΠΑ
Δρακάκης Πέτρος, Αναπλ. Καθηγητής, Ιατρική, ΕΚΠΑ
Ντόμαλη Αικατερίνη, Επίκ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
The ever increasing number of infertile couples, without any pathological findings in the reproductive system, in the modern society of the Westernized world, in combination with the lack of distinct markers and parameters that define the successful outcome of stimulation treatments, lead the research interest towards the study of genetic markers that seem to play a pivotal role in the reproductive system. One of those is the Follicle Stimulating Hormone Receptor (FSHR) gene that actively contributes towards follicle maturation and estrogen production, hence controlling female and male fertility. A number of studies have defined the importance of several polymorphisms in the FSHR gene and have associated the derived genotypes with phenotypes that relate to reduced or unsuccessful stimulation protocols. The majority of these studies have investigated the impact of Ser680Asn polymorphism individually or in combination with the Thr307Ala polymorphism, with which it is at a linkage disequilibrium (LD), and some of them have associated the polymorphisms with reduced oocyte or follicle sensitivity to FSH and increased risk of hypo– or hyper-responsiveness, while others with increased follicle or oocyte number and higher implantation or pregnancy rates. On the other hand, -29 promoter polymorphism (A>G) in FSHR is a less studied polymorphism that seems to lead to reduced FSHR expression levels, whereas a limited number of studies have investigated its impact in combination with other polymorphisms.
Therefore, the aim of this study was to analyze two different polymorphisms, Ser680Asn and -29 (A>G) promoter polymorphism, of the FSHR gene, individually but also in combination, in a sample of Greek women undergoing IVF or ICSI, in order to elucidate their role in the outcome of controlled oocyte stimulation (COS) protocols and in pregnancy rates, as well as to determine their value as infertility markers.
The genotyping for the two polymorphisms was performed in 141 women undergoing an infertility therapy (IVF or ICSI) and in 94 controls, by real time polymerase chain reaction (RT-PCR). Each polymorphism was analyzed separately and in combination, concerning the the genotype distribution in the infertility group and also concerning the clinical (age, infertility duration, number of trials), biochemical (FSH, LH and AMH) and other parameters that determine COS outcome (estradiol, days of stimulation, number and quality of COC, fertility rates etc.) as well as the qualitative parameters concerning infertility cause, endometrial quality and pregnancy rates. Furthermore, the impact of genotype on poor response to the protocol was also determined.
The study of each locus revealed a positive correlation of the SerSer genotype with higher LH levels, as assayed on the 3rd day of stimulation, and decreased endometrial thickness, whereas the most frequent heterozygote genotype (SerAsn) in the study group undergoing COS exhibited type II endometrial quality. On the other hand, the A allele for the -29 polymorphism correlated to increased number and quality of cumulus oocyte complexes (COCs). The worst theoretically combined genotype of the two polymorphisms AsnAsn AA exhibited the lowest LH levels (2.62 ± 0.68 mIU/L), was not found in the good COS responders and women underwent stimulation due to male infertility.
The present study supports the clinical value of the functional clarification of multiple genetic loci that are involved in the outcome of COS in Greece as well as in other European countries, verifying the efforts of other research groups that are attempting to elucidate the significance of FSHR in the biological processes of reproduction. Further investigations in a greater number of combined genetic loci in large cohorts of infertile women as well as men will contribute to the fine planning and successful implementation of controlled ovarian stimulation protocols.
Receptor FSHR, Gene FSHR, Polymorphism, IVF, ICSI, RT-PCR, Ser680Asn