Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

INTRODUCTION: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. METHODS: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. RESULTS: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). CONCLUSION: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.