Background of study: Experimental research supports the hypothesis that fetal exposure to androgen excess may programme in utero the development of PCOS in adult life. Potential mechanisms for prenatal androgenization could be a reduced binding capacity of androgens by SHBG or reduced aromatization of androgens by aromatase. The aim of this study was to examine whether the SHBG(TAAAA)n polymorphism, known to be associated with SHBG levels and the CYP19(TTTA)n polymorphism, known to affect aromatase activity, may play a synergistic role in the development of PCOS.
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 was determined on 35th 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 611 repeats and 6 CYP19(TTTA)n alleles with 712 repeats. Women were subdivided in 4 groups: women with short SHBG (≤8TAAAA repeats) and CYP19 alleles (≤9TTTA repeats), women with short SHBGlong CYP19 alleles, women with long SHBGshort CYP19 alleles and women with long SHBG and CYP19 alleles. Women with PCOS had at greater frequency long SHBGshort CYP19 alleles compared to controls (57.3% vs 42.4%, P=0.07). Among patients, those with long SHBGshort 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 to other genotypes. This association was independent of age, BMI and insulin resistance indexes.
Conclusion: The SHBG and CYP19 genes may have a synergistic role in the developmental programming of PCOS by affecting androgen bioavailability and aromatization, respectively. Women with long SHBG(TAAAA)n and short CYP19(TTTA)n alleles may be exposed to excess androgens even during intrauterine life and this may programme the development of PCOS in adult life.
03 - 07 May 2008
European Society of Endocrinology