Abstract: Infertility is a common health problem associated with various medical, emotional, and social implications. It affects one in four couples in developing countries and one in six couples worldwide at least once during their reproductive lifetime. Intracytoplasmic sperm injection (ICSI) is the most common technique of assisted reproduction, accounting for approximately three-quarters of all infertility treatments worldwide. Despite the availability of new ovarian reserve markers and improvements in the methodologies that support personalization of In vitro fertilization (IVF) treatment protocols, an accurate definition of the modalities for applying personalized therapy to optimize efficacy and daily clinical management is still required. Genetic differences between patients are most likely the main factor responsible for different responses to the drugs. The gonadotrophin hormones, follicle-stimulating hormone (FSH) and luteinising hormone (LH), control folliculogenesis, and naturally occurring polymorphisms in genes encoding these hormones and their receptors may affect the ovarian response. However, a definite association between genetic polymorphisms and ovarian responses to gonadotrophins still needs to be determined. The purpose of this study was to detect the association between five single nucleotide polymorphisms of the following four genes follicle-stimulating hormone receptor (FSHR), anti-Mullerian hormone (AMH), luteinizing hormone/choriogonadotropin receptor (LHCGR), estrogen receptor (ESR1), and the degree of the ovarian response to gonadotrophin in Egyptian Patients undergoing IVF/ICSI therapy. The study population was Egyptian Women undergoing ICSI treatment. Two hundred and eighty women have participated in the study with mean aged 20 -35 years old. The clinical part of the study was performed in the IVF unit Sohag, Egypt starting with patient recruitment and selection. Preparatory phase and investigations before ICSI then Controlled ovarian stimulation (COS) by Long Gonadotrophin releasing hormone (GnRH) agonist protocol, patient follow-up, and samples collection. The patients were classified according to ovarian response into three groups: normal responders (retrieved oocytes=4-15) (n= 80), poor responders (retrieved oocyte 15) (n= 108). Approximately 5.0 ml of blood samples were collected from all participants in EDTA tubes and stored at -80°C until the genetic analysis to be performed in assisted reproductionand Genetics Unit, Saarland University, Germany. Genomic DNA was extracted from the blood samples, and the PCR and DNA sequencing were performed to compare the variation in the DNA sequencing between the different study groups. The quantitative PCR (qPCR) was performed to evaluate the expression level of the following genes: FSHR, AMH, LHCGR, ESR1, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a reference gene among the study groups. Data analysis was performed by SPSS software. The Kruskal–Wallis (H-test) and Mann-Whitney (U-test) were applied to compare the median quantitative variables between the study groups. The Spearman rank correlation was used to evaluate the association between genetic polymorphisms (rs4073366, rs6166, rs6165, rs2234693; rs17854573) and the different investigated parameters including clinical parameters e.g., age, Body mass index (BMI), hormonal parameters e.g., AMH level, FSH Level and ICSI cycle parameters e.g., dose of gonadotrophin, number of collected oocytes, number of fertilised oocytes and number of transferred embryos. Regarding the qPCR data, the comparative analysis was used to calculate the expression level of tested genes in the cases “poor/high responder” versus controls “normal responder”. The results were considered statistically significant when P-value ≤ 0.05. The data analysis of DNA sequencing showed a significant difference in the frequency of the following genotypes FSHR (rs6166), AMH (rs17854573), and ESR1 (rs2234693) in the poor responders compared to normal responders (P ≤ 0.001, P = 0.010, and P ≤ 0.001) respectively. No significant difference has been found in the frequency of LHCGR (rs4073366) and FSHR (rs6165) genotypes in patients with poor ovarian response compared to others with a normal ovarian response (P = 0.312 and P = 0.192). Besides, no significant difference has been found in the frequency of the FSHR (rs6166), FSHR (rs6165), ESR1 (rs2234693), AMH (rs17854573) or LHCGR (rs4073366) genotypes in high responders compared to normal responders (P = 0.074, P = 0.353, P = 0.060, P = 0.060 and P = 0.091 respectively). Moreover, a significant difference has been found between the poor responders and the normal responders in the total dose of gonadotropin, the number of stimulation days, the number of collected oocytes, the number of injected oocytes, the number of fertilized oocytes, and the number of embryo transfer.On the other hand, the analysis of qPCR results revealed a variation between the study groups (poor, normal, and high response) in the expression levels of FSHR (rs6166), FSHR (rs6165), AMH, LHCGR, and ESR1 gene (P ≤ 0.0001). In conclusion, The results of this study suggest that polymorphisms in the genes for key reproductive hormones (AMH, FSHR, and ESR1) in combination with the patient’s clinical characteristics and hormonal biomarkers could be used to predict the ovarian response to gonadotrophins, to personalize and adjust the dose of gonadotrophins before starting the stimulation protocol, to improve efficacy and to avoid possible complications such as cycle cancellation and OHSS; and, finally, to improve the pregnancy rate in patients undergoing ICSI treatment.