تأثير التعدد الجيني لـ CYP450 2D6 على الاستجابة السريرية لسيترات الكلوميفين في النساء العراقيات اللاتي يعانين من متلازمة تكيس المبايض

Impact of Genetic Polymorphism of Cytochrome P450 2D6 on Clomiphene Citrate Clinical Response in Iraqi Women with PCOS

Abstract
Clomiphene citrate, a selective estrogen receptor modulator (SERM), is commonly prescribed as a first-line agent to induce ovulation in women with infertility secondary to polycystic ovary syndrome (PCOS). It is predominantly metabolized in the liver by cytochrome P450 2D6 (CYP2D6), an enzyme characterized by substantial genetic polymorphism. Variations in the CYP2D6 gene may alter the bioactivation of clomiphene, thereby impacting its pharmacokinetics and therapeutic outcomes.
Aims
This study aimed to determine the frequencies of two common CYP2D6 genetic variants—rs3892097 and rs1065852 —and to assess the impact of these single-nucleotide polymorphisms (SNPs) on the metabolic processing and clinical efficacy of clomiphene in women diagnosed with polycystic ovary syndrome (PCOS). Additionally, the study aimed to quantify the plasma concentrations of clomiphene and its active metabolite.
Patients and Methods
A cohort study of 80 women with clinically diagnosed PCOS was recruited from the Gynecology and Obstetrics Hospital in Kerbala. Participants received 100 mg of clomiphene citrate daily for five consecutive days, beginning on day two of their menstrual cycle. Blood samples were collected at cycle day 2 before treatment and cycle day 12 after treatment for CYP2D6 genotyping, hormonal profiling (including LH, FSH, and estradiol), and quantification of clomiphene and its active metabolites via plasma analysis. As well as transvaginal ultrasound assessments were conducted during the same cycle days by specialist doctors to evaluate ovarian follicular development and endometrial thickness.
Results
The study analyzed two CYP2D6 polymorphisms among women with PCOS-associated infertility. The genotype frequencies for CYP2D6*4 (GG, AG, AA) were 66.3%, 30.0%, and 3.8%, respectively, and for CYP2D6*10 (CC, CT, TT) were 66.3%, 27.5%, and 6.3% respectively. Individuals harboring the CYP2D6*4 and CYP2D6*10 variants were associated with significantly lower plasma concentration of the active metabolite of clomiphene and high levels of parent drug, indicating impaired metabolic activity. However, no significant differences (P > 0.05) were observed in hormonal profiles or ultrasound parameters among different genotypes.
Conclusion
CYP2D6*4 and CYP2D6*10 polymorphisms significantly affected the metabolic conversion of clomiphene to the active metabolite. However, they were not associated with differences in hormonal levels or ultrasound parameters. These findings suggest that while CYP2D6 genotyping may be useful for understanding individual pharmacokinetic profiles, its predictive value for clomiphene treatment outcomes in PCOS remains limited.