تأثير تعدد الأشكال الجينية لسيتوكروم P4503A4 على الأستجابه السريرية للكلوميفين سترات في عينة من النساء العراقيات المصابات بمتلازمة تكيس المبايض

Impact of Genetic Polymorphism of Cytochrome P4503A4 on the Clomiphene Citrate Clinical Response in a Sample of Iraqi Women with Polycystic Ovary Syndrome

Abstract
Polycystic ovary syndrome (PCOS) is a common hormonal disorder affecting women of reproductive age. Clomiphene Citrate is often prescribed to induce ovulation in these patients. The cytochrome P450 enzymes, particularly CYP3A4, play a crucial role in the metabolism of many drugs. Genetic variations in this enzyme can lead to differences in drug metabolism. Among the most common coding variants are CYP3A4*18 (rs28371759) and CYP3A4*22 (rs35599367), which are particularly relevant to the metabolism of Clomiphene Citrate.
Aims of the study
The study aimed to detect CYP3A4*22 G>A (rs35599367) and CYP3A4*18 (rs28371759) genetic polymorphisms among Iraqi women with polycystic ovarian syndrome and to investigate the influence of these gene variants on the efficacy of clomiphene citrate.
Patients and methods
This cohort study was conducted at the Obstetrics and Gynecology Teaching Hospital in Karbala Governorate between December 2023 and June 2024. A total of 80 Iraqi women diagnosed with PCOS, aged 20–40 years, who were receiving Clomiphene Citrate (50 mg orally, twice daily) for at least two cycles, were included. Blood samples were collected for genotyping and for measuring reproductive hormone levels, including estradiol, Anti-Mullerian Hormone, Luteinizing Hormone, Follicle-Stimulating Hormone, and prolactin. Plasma concentrations of Zuclomiphene and its metabolites were also analyzed by using Liquid chromatography-tandem mass spectrometry. The Tetra-Amplification Refractory Mutation System (T-ARMS-PCR) was used to detect CYP3A4*22 G>A (rs35599367), while Restriction Fragment Length Polymorphism PCR (RFLP-PCR) was employed to detect CYP3A4*18 T>C (rs28371759) genetic polymorphism.
Results
The findings revealed variations in the genetic distribution of CYP3A4*22 G>A (rs35599367) and CYP3A4*18 T>C (rs28371759). For rs35599367 G>A, the wild-type homozygous (GG) genotype was the most common (67.5%), followed by the heterozygous (GA) genotype (25%), and the mutant homozygous (AA) genotype (7.5%).
For rs28371759 C>T, the wild-type homozygous (TT) genotype was the most frequent (83.8%), while the heterozygous (TC) and mutant homozygous (CC) genotypes were less common, with frequencies of 11.25% and 5.0%, respectively.
Significant differences were observed across CYP3A4*18 genotypes in FSH (P = 0.03), estrogen (P = 0.008), zuclomiphene levels (P = 0.044), and the metabolite/prodrug ratio (P = 0.002). Similarly, significant differences were found across CYP3A4*22 genotypes in LH (P = 0.026), endometrial thickness (P = 0.048), and the metabolite/prodrug ratio (P = 0.000003).
Conclusion
The present study concluded that there is a correlation between genetic variations in the CYP3A4*22 and CYP3A4*18 genes and the variability in response to clomiphene therapy among the study participants with polycystic ovary syndrome (PCOS). This variability is attributed to changes in certain hormone levels and ultrasound findings among different genotypes. Genetic patterns of CYP3A4*22 (rs35599367) and CYP3A4*18 (rs28371759) also affected the metabolic ratio of clomiphene.