The associations between estrogens, the UGT2B17 gene deletion, and health-related quality of life in postmenopausal women in the MAP.3 chemoprevention trial
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Background: Natural depletions of estrogens during menopause are likely associated with symptoms and declines in health-related quality of life (HRQL). For women taking exemestane in the Mammary Prevention 3 (MAP.3) trial, symptoms may have been exacerbated, as exemestane works to further suppress estrogen levels to prevent breast cancer. Women with the UGT2B17 gene deletion have limited ability to metabolize and eliminate steroid molecules and are therefore hypothesized to have elevated estrogen levels prior to randomization (baseline) and be at increased risk of worsened HRQL during treatment. Objectives: This thesis project aimed to investigate the effects of natural estrogen levels and exemestane-induced estrogen suppression on HRQL in postmenopausal women. UGT2B17 genotype was assessed regarding its role in natural estrogen levels and effect modification between estrogen suppression and worsened HRQL during exemestane treatment. Methods: Estrone (E1), estradiol (E2), and UGT2B17 genotype were characterized for a subsample of MAP.3 participants. HRQL was assessed from Menopause-Specific Quality of Life Questionnaire (MENQOL) responses at baseline and follow-up visits. Multiple logistic and log-binomial regression models were used to estimate the association between estrogen levels and HRQL at baseline and exemestane-induced estrogen suppression and worsened HRQL one year after randomization, respectively. The association between UGT2B17 genotype and natural log-transformed estrogen levels was tested with multiple linear regression. Results: At baseline, overall vasomotor, physical, and sexual HRQL were not associated with E1, while E2 was significantly associated with sexual HRQL (p<0.05). Increasing E1 and E2 suppression during exemestane treatment was associated with increased risk of worsened vasomotor and sexual HRQL (p<0.01). E1 suppression was also associated with worsened physical HRQL (p<0.01). UGT2B17 genotype was not associated with natural estrogen levels and did not modify the effects of estrogen suppression on HRQL decline. Conclusions: Natural estrogen levels may continue to play a role in HRQL of older postmenopausal women. Increasing estrogen suppression by exemestane is associated with increased risk of experiencing worsened HRQL. Future studies should determine if baseline estrogen levels can predict worsened HRQL during treatment with the goal of increased adherence of exemestane in the chemoprevention setting.