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


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 (< or = 8 TAAAA repeats) and CYP19 alleles (< or = 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.


CONCLUSIONS
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.
Xita
Nectaria
N
Department of Endocrinology, University of Ioannina, Ioannina 45110, Greece.
Georgiou
Ioannis
I
Lazaros
Leandros
L
Psofaki
Vasiliki
V
Kolios
George
G
Tsatsoulis
Agathocles
A
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000728:Androgens / Q000097:blood; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D015992:Body Mass Index; D004958:Estradiol / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012738:Sex Hormone-Binding Globulin / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D000728:Androgens; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D004958:Estradiol; D001141:Aromatase