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Research Article J Infertil Reprod Biol, 2016, Vol 4, No 1, pp: 1-5 Research Article Relation between aromatase gene CYP19 variation and hyperandrogenism in Polycystic Ovary Syndrome Egyptian women Rowaa A. Mostafa 1, Mohammed M. Al-Sherbeeny 1, Ibrahim A. Abdelazim 1,2*, Ahmed A. Fahmy 1, Mohamed M. Farghali 1, Mustafa A Abdel-Fatah 1, Manal Z.Mahran 3 1. Department of Obstetrics and Gynaecology, Ain-Shams University, Cairo, Egypt 2. Department of Obstetrics and Gynaecology, Ahmadi Hospital, Kuwait Oil Company (KOC), Kuwait 3. Department of Clinical Pathology, Ain-Shams University, Cairo, Egypt Abstract Background: This study designed to detect the relation between the aromatase CYP19 gene SNP50 variation and hyperandrogenism in polycystic ovary syndrome (PCOS) Egyptian women. Methods: Sixty women included in this comparative study and divided into 2 groups; 30 PCOS women with clinical hyperandrogenism included in study group and 30 healthy non-PCOS women in control group. PCOS diagnosis based on the Rotterdam criteria. Studied women underwent complete physical examination with calculation of body mass index (BMI) and assessment of hirsutism. Studied women subjected to hormonal profile and to CYP19 genotyping by collecting 5 ml whole blood on EDITA for DNA extraction and SNP 50 (rs2414096) genotype to detect the relation between the aromatase CYP19 gene SNP50 variation and hyperandrogenism in polycystic ovary syndrome Egyptian women. Results: Results showed that LH and LH/FSH ratio were significantly higher in PCOS women compared to controls. Also, serum testosterone and estradiol were significantly high in PCOS women compared to controls. CYP19 rs2424096 genotypic distribution AG alleles was significantly high in PCOS women compared to controls (11 (44%) versus 2 (8.4%); respectively) (p = 0.02). Estradiol/testosterone ratio was significantly low in AG genotypes PCOS compared to AG genotype controls (P = 0.001). Conclusion: In conclusion, CYP 19 rs2414096 polymorphism is associated with aromatase deficiency or reduced aromatase activity with subsequent hyperandrogenism in PCOS Egyptian women. Keywords: Aromatase, Gene, Hyperandrogenism, PCOS, Egyptian women 1. Introduction Polycystic ovary syndrome (PCOS) is a complex step of estrogen biosynthesis by converting disorder affects 5%-6% of women during testosterone and androstenedione to estradiol and reproductive age group (1). PCOS is typically estrone separately (8). PCOS has been observed in associated with menstrual irregularities, obesity, women with aromatase deficiency or reduced hyperandrogenism, chronic anovulation and aromatase activity caused by rare loss-of function infertility (2, 3). Ovarian androgen overproduction mutations and antral follicles taken from PCOS is the key physio-pathologic feature of PCOS (4). women exhibited no aromatase activity (9-11). Women with PCOS and precocious puberty Aromatase deficiency or reduced aromatase have increased circulating testosterone activity in the ovarian follicles and the possible concentrations and genetic variation at the androgen excess resulting might contribute to androgen receptor, suggesting that hyperandrogen- abnormal follicle development seen in PCOS ism in both precocious puberty and PCOS may be women (12-15). The CYP19 gene is located on the partly genetically determined (5, 7). Aromatase long arm of chromosome 15 at position 15q21.1 (EC 1.14.14.1) is a member of the cytochrome and encodes aromatase (P450arom) (16). P450 family of enzymes (subfamily 19), which a It is reported that several single nucleotide key steroidogenic enzyme that catalyzes the final polymorphisms (SNPs) of the CYP19 gene are *Corresponding address: Professor Ibrahim A. Abdelazim, Department of Obstetrics and Gynecology, Ain Shams University, Cairo, Egypt and Ahmadi Kuwait Oil Company (KOC) Hospital, Ahmadi, Kuwait. E-mail: [email protected] 1 J Infertil Reprod Biol, 2016, Vol 4, No 1, pp: 1-5 associated with variation in serum androgen each primer, 25µl short tandem repeat (STR), 10x concentrations among women, both within and buffer (STR 10x buffer, Promega, Madison, Wl, between racial/ethnic groups (17). Several studies USA). The PCR was performed in a PTC-100 (MJ have reported the association of the SNP rs2414096 Research Inc., Waltham, United States) in the CYP19 gene with hyperandrogenism (16- thermocycler as follows: 30 cycles consisting of 1 18). In view of the strong evidence implicating the minute of denaturation at 94°C, 1 minute of importance of CYP19 SNP rs2414096 in androgen annealing at 60 °C and 1 minute of extension at metabolic pathways, this study designed to detect 72°C. An initial denaturation step of 5 minutes at the relation between the aromatase CYP19 gene 94°C and a final extension of 10 minutes at 72°C SNP50 variation and hyperandrogenism in PCOS used. The DNA fragments separated by Egyptian women. electrophoresis on a 2% agarose gel and visualized by staining with ethidium bromide. The PCR 2. Patients and methods products of 189-bp were then digested with HSP92 Sixty women included in this comparative study, ΙΙ at 37 °C overnight. A single 189 bp band which conducted at Ain Shams University corresponds to the wild-type G homozygote; bands Maternity hospital from September 2008 to June of 189, 161, and 28 bp stand for the AG 2011 and divided into 2 groups; 30 PCOS women heterozygotes; and 161 and 28 bp for the A with clinical hyperandrogenism mainly hirsutism homozygote. included in study group and 30 healthy non-PCOS women in control group. Studied women included 3. Results in this study after informed consent and approval of Mean age, BMI and FSH were similar with no the study by local institute ethical committee. statistical difference between PCOS women and Women with endocrinal disorders (thyroid controls. LH and LH/FSH ratio were significantly dysfunction, Cushing syndrome and high in PCOS compared to controls, also, serum hyperprolactinemia) and women received oral testosterone and estradiol were significantly high in contraceptives pills, corticosteroids or ovulation PCOS women compared to controls (Table 1). inducing medications during last 6 months CYP19 rs2424096 genotypic distribution AG excluded from the study. PCOS diagnosis based on alleles was significantly high in PCOS women the Rotterdam criteria by at least 2 out of 3 of the compared to controls (p = 0.02) (Table 2). following criteria: oligo-or an-ovulation, clinical or biochemical hyperandrogenism and polycystic Table 1. Characteristics of PCOS women and controls ovaries on trans-vaginal ultrasound (TVS) (17). P value, Studied women underwent complete physical Significance PCOS Control Variables 95% examination with calculation of body mass index n=30 n= 30 (BMI) and assessment of hirsutism by modified Confidence interval Ferriman Gallway score with a score ≥ 8 is P = 0.9 (>0.05) Age (Years) considered abnormal. Studied women subjected to NS Mean ± SD 31.1 ± 4.9 28.5 ± 7.4 hormonal profile including; follicle stimulating (-0.6, 2.6, 5.8) Body Mass P = 0.6 (>0.05) hormone (FSH), luteinizing hormone (LH), Index (Kg/m 2) NS 27.6 ± 4.5 26.2 ± 4.8 testosterone and estradiol followed by TVS to Mean ± SD (-0.9, 1.4, 3.8) P = 0.9 (>0.05) detect polycystic ovaries according to criteria of FSH (IU/l) NS Mean ± SD 8.3 ± 3.5 7.7 ± 5.6 Balen and associates if present (18, 19). (-1.8, 0.6, 2.9) Studied women subjected to CYP19 genotyping P = 0.005 by collecting 5 ml whole blood on EDITA which LH (IU/l) (<0.05) S Mean ± SD 16.7 ± 2.1 3.5 ± 1.3 (12.3, 13.2, sent to Genetic Center for DNA extraction and 14.1) P = 0.008 SNP 50 (rs2414096) genotype using primer LH/FSH Ratio (<0.05) S Mean ± SD 2.01 ± 3.3 0.45 ± 2.1 Polymerase Chain Reaction (PCR) – Restriction (0.16, 1.6, 2.9) Fragment Length Polymorphism (RFLP) (20). Testosterone P = 0.03 (<0.05) (nMol/l) S Genomic DNA was isolated from human 3.2 ± 3.8 1.2 ± 2.7 Mean ± SD (0.33, 2, 3.7) leukocytes by using Chelex-100 as a medium P = 0.03 (<0.05) Estradiol S (Promega Corporation, Madison, USA). The (pMol/l) 245.5 ± 198 176.2 ± 142.3 (-18.1, 69, Mean ± SD sequences of the primers were 5´- 156.6) TCTGGAAACTTTTGGTTTGAGTG-3´ (forward FSH = Follicle stimulating hormone. LH= Luteinizing primer) and 5´-GATTTAGCTTAAGAGCCTTTT hormone. NS = Non Significant difference. CTTACA-3´ (reverse primer). PCR amplification PCOS = Polycystic ovary syndrome. S= Significant difference. was carried out in a total volume of 25 µl Student t test used for statistical analysis containing 50 ng of genomic DNA, 6.25 pmol of 2 J Infertil Reprod Biol, 2016, Vol 4, No 1, pp: 1-5 4. Discussion Table 2. Comparison between PCOS women and controls A limited number of studies have focused on regarding CYP19 mutation, alleles and genotype androgens in women’s health, particularly at the Controls P value, PCOS group genetic level (18), this why this study designed Variables = 30 Significance = 30 women detect the relation between the aromatase CYP19 Women gene SNP50 variation and the features of 0.8 (>0.05) Negative 5 (16.7%) 6 (20%) CYP19 NS hyperandrogenism in PCOS Egyptian women. mutation 1 (>0.05) Positive 25 (83.3%) 24 (80%) Sixty women included in this comparative study NS 11 0.6 (>0.05) and divided into 2 groups; 30 PCOS women with AA 9 (36%) (45.8%) NS clinical hyperandrogenism included in study group 0.02 (<0.05) Genotype AG 11 (44%) 2 (8.4%) and 30 healthy non-PCOS women in control group. S 11 0.18 (>0.05) PCOS diagnosis based on the Rotterdam criteria GG 5 (20%) (45.8%) NS (19). Studied women underwent complete physical Chi-Square test (x 2) used for statistical analysis. NS= Non examination with calculation BMI and assessment Significant difference. S = Significant difference . of hirsutism. Studied women subjected to hormonal profile and to CYP19 genotyping by collecting 5 Mean age, BMI and FSH were similar with no ml whole blood on EDITA for DNA extraction and significant difference between AG genotypes SNP 50 (rs2414096) genotype using primer PCR – Restriction Fragment Length Polymorphism PCOS and AG genotype controls.
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