Is pharmacogenomics our future? Metformin, ovulation and polymorphism of the STK11 gene in polycystic ovary syndrome.

Evaluation of: Legro RS, Barnhart HX, Schlaff WD et al.: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J. Clin. Endocrinol. Metab. 93(3), 792-800 (2008). The current study by Legro et al. is a substudy of the recent multicenter, double-blinded, prospective study Pregnancy in Polycystic Ovary Syndrome. Legro et al. randomly assigned 626 infertile women with polycystic ovary syndrome to receive 50 mg clomiphene citrate plus placebo (n = 209), 2 g extended-release metformin plus placebo (n = 208), or a combination of metformin and clomiphene (n = 209) for up to six cycles. Of 626 patients in the original study, 312 women participated in the pharmacogenetic substudy; 98 received metformin XR (2 g/day), 102 clomiphene and 112 combined clomiphene-metformin XR treatment. This study was designed "to identify predictive genetic polymorphism and other determinants of ovulatory response" in prospective fashion. Candidate genes tested included estrogen receptor 1 (ESR1), CYP genes (CYP2C9 and CYP2D6) and STK11. STK11, formerly known as LKB1, is a serine-threonine kinase gene expressed in the liver, which phosphorylates and activates AMP-activated protein kinase. It was shown to be a site of metformin action. The C allele of a SNP in the STK11 gene was associated with a significantly decreased chance of ovulation in polycystic ovary syndrome women treated with metformin. In analysis of ovulation per cycle, the adjusted odds ratio for CC versus GG (wild-type normal) was 0.30 (95% CI: 0.14-0.66) and the odds ratio for CG versus GG was 0.30 (95% CI: 0.14-0.66). This elegant study is of great importance because despite treatment, many women with polycystic ovary syndrome fail to ovulate, 24.9% in the clomiphene group, 44.7% in the metformin group and 16.7% in the clomiphene-metformin group.