الفهرس 
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Abstract
Over the 40 years since the breakthrough of the IVF treatment into infertility treatment field, many of infertile couples be able to have a family despite of social, traditional and medical factorsrelated to either male or female. The ovarian stimulation is a critical step in such process for the recruitment of multiple mature oocytes for further insemination.
Although,infertility is increasingly becoming overcome through the use of all sorts of Assisted Reproductive Technologies (ART), there are some challenges in confrontation to successful IVF outcome should be kept in mind. We can summarize them according to response togonadotropins stimulation into two major cases; the first is an insufficient stimulation in poor responders leading to cycle cancelation; the second isthe occurrence of life-threatening ovarian hyperstimulation syndrome (OHSS) in patients with hyper response to gonadotropins.
Genetic variability among IVF patients plays a key role for the differences in the response of the ovary to exogenous FSH stimulation and consequently the outcome of the IVF process. Single nucleotidepolymorphismsof FSHR Thr307Ala and Asn680Ser are considered molecular markers that may predict the ovarian response to gonadotropins stimulation during IVF cycles.
The aim of the current study was to evaluate the association between the follicle stimulating hormone receptor (FSHR) gene polymorphisms Ala307Thr (rs6165), Ser680Asn (rs6166) and the response to controlled ovarian hyperstimulation in a sample of Egyptian women undergoing in vitro fertilization (IVF).
The study included 96 Egyptian females from those attending Omoma Fertility Center at Tanta and Future Fertility Center at Alexandria for their first IVF treatment attempt.
All patients were subjected to the following:
1. Personal history taking.
2. Gynecologic examination.
3. Hormone Assays including basal FSH and Peak E2 level on the day of hCG administration during the IVF cycle.
4. Molecular genetics testing for FSHR Thr307Ala and Asn680Ser using PCR-RFLP.
All patients in this study were submitted to ovarian stimulation using a long agonist protocol with individually adjusted regimes and at the end of each IVF cycle, the following data were recorded:
1. Stimulation length.
2. Total exogenous FSH dose.
3. Number of retrieved oocytes
4. No. of embryo transfer
5. Occurrence of Clinical pregnancy
The ovarian response to gonadotropins of all patients were evaluated according to the number of retrieved oocytes and the peak of serum E2level as follow: Poor responders (PR) with five or less (≤5) oocytes retrieved and/or a peak serum E2 level 650 pg/ml.While they were considered as b) Good responders(GR) if they produced six or more (6≥) oocytes.
The results of the present study were as follow:
i. The age of all studied patients ranged from 20 to 40 years with mean ± SD 30.96 ± 5.25 years.
ii. The causes of infertility varied among patients between male factorswhich represented 45.8% (44/96) and tubal or unexplained infertility which represented 54.1% (52/96).
iii. Day 3 basal FSH levels of IVF patients ranged from 4.35 to 7.47 mIU/ml (mean ± SD=5.79±0.69 mIU/ml), while the values of the Estradiol (E2) hormone that had been measured on the day of hCG injection ranged from 129 to 8232 pg/ml with median 2110.5 pg/ml.
iv. The dosage of gonadotropins administration during controlled ovarian stimulation differed greatly between patients from 450 to 8775 IU of exogenous FSH with mean ± SD (2386.7 ± 1401.8). While The mean number of days of ovulation induction was (10.11 ± 3.06 days).
v. from the whole number of patients (n=96), only 59/96 women (61.5%) had become pregnant, while 37/96 women (38.5%) hadn’t.
vi. The total percentage of poor responders was 30.2% (29/96), whereas for good respondersthe percentage was 69.8% (67/96).
vii. The A/A genotype of the FSHR Asn680Ser polymorphism was observed in 28.1% of all patients, while the A/G genotype was shown in 57.3% and the G/G genotype was observed in 14.6%. The frequencies ofgenotypesof the FSHRThr307Alapolymorphism were: 31.3% for A/A; 42.7% for A/G and 26% for G/G.
viii. For the results of hormonal assays in both FSHR polymorphisms, there was a statistically significant difference between patients with different genotypes (AA, AG, and GG) and the basal FSH as well as the peak E2 level related to those patients. Firstly, regarding to Asn680Ser, the mean basal FSH was significantly higher in GG genotypes than in heterozygote AG and even higher than in AA genotype. While regarding to Thr307Ala polymorphism, the mean basal FSH was lower in patients carrying the AA and AG genotypes, but higher in patients carrying the GG genotype (P<0.001*) in both FSHR polymorphisms.
Secondly, regarding to Asn680Ser, the peak E2 level of patients with AA genotypewas similar to that of AG genotype, but statistically higher than in GG
genotype (p=0.007*).A similar resultwas observed regarding to FSHRThr307Ala polymorphism(p<0.001*).
ix. There was a statistically significant difference (p=0.005*) in the dosage of exogenous FSH consumed in relation to the different genotypes (AA, AG, and GG) among the patients for the FSHR Asn680Ser gene polymorphism and even more regarding to the FSHR Thr307Ala gene polymorphism (p<0.001*). A significant increase in the dosage was given to patients with GG genotype to achieve adequate ovarian stimulation compared with patients with AA genotype, who treated with a significantly lower dosage of exogenous FSH. Whereas, there was no statistically significant difference in the duration of ovulation induction and the (AA, AG, and GG) genotypes of both FSHR polymorphism.
x. For the FSHR Asn680Ser polymorphism, there was no statistically significant difference between patients and either: 1) The causes of infertility among patients (p=0.556); 2) No. of oocytes retrieved (P=0.059); 3) No. of embryo transfer (p=0.369);4) The clinical pregnancy rate per IVF/ICSI cycle (p=0.376).
xi. For the FSHR Thr307Ala polymorphism, there was no statistically significant difference between patients and 1) the causes of infertility among patients (p=0.671); 2) the clinical pregnancy rate per IVF/ICSI cycle (p=0.392), but there was a significant difference between the (AA, AG, and GG) genotypes and either of No. of oocytes retrieved as well as No. of embryo transfer (p<0.001*), where the mean No. of oocytes retrieved in AA and AG genotypes was (14.30 ± 7.88) and (13.20 ± 6.49) respectively higher than the mean No. of oocytes retrieved in GG genotype (6.72 ± 5.93). The same for the No. of embryo transfer per cycle, since the mean No. of embryo transfer occurred in (AA, AG, GG) genotypes was: (3.60 ± 1.48), (3.39 ± 1.30), and (2.40 ± 1.68) respectively.
xii. For the FSHR Asn680Ser polymorphism, the difference in the frequency of genotypes between the good and poor responders’ groups was a statistically significant. Since, patients with GG genotype (Ser680Ser) had a statistically significant increase within the group of poor responders to FSH stimulation. whereas the GG genotype represented (31.0%) from the poor responders’ group which was 4.1-fold higher than its frequency within the good responders’ group (7.5%), the wild genotype AA (Asn680Asn) was 2.5-fold higher in the good responders (34.3%) than in poor responders’ group (13.8%).
xiii. We observed that the GG (Ala307Ala) was significantly associated with higher frequency of poor ovarian response, it was 5.9-fold higher in the poor responders’ group (62.1%) than in the good responders’ group (10.4%). Whereas the wild genotype AA (Thr307Thr) was 2.2-fold higher in the good responders’ group (37.3%) than in the poor responders’ group (17.2%). Moreover, allele A was more common in the good responders’ group 63.4% versus 27.6% in the poor responders’ groups, while allele G was 2.0-fold higher in the poor responders’ group.