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The synergistic effect of sex hormone-binding globulin and aromatase genes on polycystic ovary syndrome phenotype.

¹ , Department of Endocrinology and ² Laboratory of Human Reproductive Genetics, University of Ioannina, Ioannina 45110, Greece and ³ Laboratory of Biochemistry, University Hospital of Ioannina, Ioannina 45110, Greece

(Correspondence should be addressed to A Tsatsoulis; Email: atsatsou{at}uoi.gr)

Objective: Experimental evidence suggests that fetal exposure to androgen excess may program the development of polycystic ovary syndrome (PCOS) in utero. The aim of this study was to examine whether the sex hormone binding globulin (SHBG)(TAAAA)n and the cytochrome P450, family 19 (CYP19)(TTTA)n polymorphisms, known to influence sex hormone-binding globulin (SHBG) levels and aromatase activity respectively, play a synergistic role in the development of PCOS.

Design and methods: We studied 180 women with PCOS and 160 healthy women of reproductive age. The body mass index (BMI) was recorded and the hormonal profile determined from the third to fifth day of menstrual cycle. DNA was extracted from blood leucocytes and the SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms were genotyped.

Results: Genotype analysis revealed 6 SHBG(TAAAA)n alleles with 6–11 repeats and 6 CYP19(TTTA)n alleles with 7–12 repeats. Women were subdivided into four groups: those with short SHBG (8 TAAAA repeats) and CYP19 alleles (9 TTTA repeats), those with short SHBG–long CYP19 alleles, those with long SHBG–short CYP19 alleles, and those with long SHBG and CYP19 alleles. Women with PCOS tended to have at greater frequency, long SHBG–short CYP19 alleles compared with controls (57.3 vs 42.4%, P=0.07). Importantly, PCOS women with long SHBG–short CYP19 alleles had the lowest SHBG levels (P=0.02) and the highest total testosterone (P=0.008), free androgen index (P=0.002), DHEAS (P=0.02), and testosterone/estradiol ratio (P=0.03), compared with those with other genotypes. This association was independent of age, BMI, and insulin resistance indexes.

Conclusion: We speculate that the SHBG and CYP19 genes may have a synergistic role in the developmental programming of PCOS, by affecting androgen bioavailability and aromatization respectively.