Oxidative stress promotes hyperandrogenism by reducing sex hormone-binding globulin in polycystic ovary syndrome

Background: Decreased sex hormone-binding globulin (SHBG) levels were associated with polycystic ovary syndrome (PCOS). SHBG polymorphisms associated with reduced SHBG production were tested for their association with PCOS, but with inconclusive results. We tested whether altered SHBG levels and SHBG variants were associated with PCOS. Methods: The study subjects included 242 women with PCOS and 238 control women. SHBG genotyping was done by real-time PCR. Results: Higher minor allele frequency of rs13894, rs858521 and rs727428 was seen in PCOS cases, and significant differences in rs858521 and rs727428 genotypes distribution were seen between PCOS cases and controls. Multivariate regression analysis confirmed the association of only rs727428 with PCOS. Though it was not statistically significant, serum SHBG levels were reduced according to rs727428 genotypes in PCOS cases than in controls. Carriage of rs727428 minor allele was associated with significant increases in free/bioactive testosterone in PCOS cases. Seven-locus (rs9898876-rs13894-rs858521-rs1799941-rs6257-rs6259-rs727428) haploview analysis showed increased frequency of GCCGTGA, GTCGTGA and GTCATGG, and reduced frequency of GTCGTGG haplotypes in PCOS cases than in controls, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. Conclusion: Specific SHBG variants affecting serum SHBG levels and SHBG haplotypes are associated with PCOS, suggesting the role for SHBG as PCOS candidate gene.

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Increased urinary free cortisol and decreased serum corticosteroid-binding globulin in polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/acta.0.1250028 ◽

1991 ◽

Vol 125 (1) ◽

pp. 28-32 ◽

Cited By ~ 18

Author(s):

Cecilia Invitti ◽

Francesca Pecori Giraldi ◽

Antonella Dubini ◽

Martina De Martin ◽

Francesco Cavagnini

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Free Testosterone ◽

Urinary Free Cortisol ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Ovary Syndrome ◽

Free Cortisol ◽

Corticosteroid Binding Globulin

Abstract. The adrenal participation in the pathogenesis of polycystic ovary syndrome is still under debate. In order to reappraise androgen and glucocorticoid secretion in this disease, we measured serum androstenedione, dehydroepiandrosterone-sulphate, total and free testosterone, sex hormone-binding globulin, LH, FSH, PRL, cortisol, corticosteroid-binding globulin, and urinary free cortisol in 45 women with polycystic ovary syndrome and 27 controls, subdivided in obese and normal-weight subjects. Androstenedione, total and free testosterone were significantly increased, whereas sex hormone-binding globulin tended to be reduced in patients with polycystic ovary syndrome compared with controls, reaching a significant difference between obese patients and matched controls. Free testosterone and sex hormone-binding globulin were significantly increased and reduced, respectively, in obese compared with normal-weight patients. Urinary free cortisol and serum corticosteroid-binding globulin were significantly increased (p<0.001) and decreased (p<0.005), respectively. Urinary free cortisol exceeded the upper limit of the normal range in 50% of our patients. No appreciable differences were found in PRL and cortisol levels. Besides confirming a hyperandrogenic state, our findings point to an overactivity of the hypothalamic-pituitary-adrenal axis with subsequent diminution of corticosteroid-binding globulin in polycystic ovary syndrome. They also indicate that urinary free cortisol is not a reliable index in differentiating polycystic ovary syndrome from Cushing's disease.

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

Acta Endocrinologica ◽

10.1530/eje-07-0905 ◽

2008 ◽

Vol 158 (6) ◽

pp. 861-865 ◽

Cited By ~ 29

Author(s):

Nectaria Xita ◽

Ioannis Georgiou ◽

Leandros Lazaros ◽

Vasiliki Psofaki ◽

George Kolios ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Sex Hormone ◽

The Body ◽

Reproductive Age ◽

Sex Hormone Binding Globulin ◽

Total Testosterone ◽

Aromatase Activity ◽

Hormone Binding ◽

Ovary Syndrome

ObjectiveExperimental 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 methodsWe 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.ResultsGenotype 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.ConclusionWe 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.

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