Adiposity, Sex Hormones, and Repetitive Element DNA Methylation in Healthy Postmenopausal Women

INTRODUCTION: Low levels of methylation within repetitive DNA elements, such as long interspersed nuclear element-1 (LINE-1) and Alu repeats, are believed to epigenetically predispose an individual to cancer and other diseases. The extent to which lifestyle factors affect the degree of DNA methylation within these genomic regions has yet to be fully understood. Adiposity and sex hormones are established risk factors for certain types of cancer and other illnesses, particularly amongst postmenopausal women. The aim of the current investigation is to assess the impact of adiposity and sex hormones on LINE-1 and Alu methylation in healthy postmenopausal women. METHODS: A cross-sectional study was conducted using baseline data from an ancillary study of the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial. Current adiposity was measured using a dual-energy x-ray absorptiometry (DXA) scan, computed tomography (CT) scan, and balance beam scale. Historical weights were self-reported in a questionnaire. Current endogenous sex hormone concentrations were measured in fasting blood serum. Estimated lifetime number of menstrual cycles was used as a proxy for cumulative exposure to ovarian sex hormones. Repetitive element methylation was quantified in white blood cells using a pyrosequencing assay. Linear regression was used to model the relations of interest while adjusting for important confounders. RESULTS: Adiposity and serum estrogen concentrations were positively related to LINE-1 methylation but were not associated with Alu methylation. Cumulative ovarian sex hormone exposure had a “U-shaped” relation with LINE-1 regardless of folate intake and a negative relation with Alu methylation amongst low folate consumers. Androgens were not associated with repetitive element DNA methylation in this population. CONCLUSION: Adiposity and estrogens appear to play a role in maintaining high levels of repetitive element DNA methylation in healthy postmenopausal women. LINE-1 methylation may be a mechanism whereby estrogen exposure protects against cardiovascular and neurodegenerative illnesses. These results add to the growing body of literature showing how the epigenome is shaped by our lifestyle choices. Future prospective studies assessing the relation between levels of repetitive element DNA methylation in healthy individuals and subsequent disease risk are needed to better understand the clinical significance of these results.

Hormonal factors and insulin-like growth factor-1 in North American postmenopausal women

Background: Mechanisms underlying the effect of estrogen exposure on breast cancer risk remain unclear. Insulin-like growth factor-1 (IGF-1) levels have been positively associated with breast cancer and are a potential mechanism. Objectives: The objectives of this thesis are: 1) to explore whether the reproductive risk factors and the lifetime cumulative number of menstrual cycles (LCMC), as measures for long-term estrogen exposure, are associated with IGF-1 levels, and 2) to examine the effect of an aromatase inhibitor (AI) on IGF-1 levels, and the potential interaction with BMI. Methods: A cross sectional study and a randomized controlled trial nested with the MAP.3 chemoprevention trial were used to address objective 1 and 2, respectively. 567 postmenopausal women were selected. Anthropometric measurements, lifestyle factors, reproductive characteristics and serum IGF-1 concentrations were collected at baseline and one year. Objective 1. The LCMC was computed as a composite measure of the reproductive characteristics. Multivariable linear regression models were used to assess the association between IGF-1 levels and LCMC and the hormonal risk factors, while adjusting for potential covariates. Objective 2. Changes in IGF-1 were compared between the exemestane and placebo, and effect modification by BMI was tested with an interaction term. Results: Objective 1. Women aged 55 years or older at menopause had 16.26 ng/mL (95% CI: 1.76, 30.75) higher IGF-1 compared to women aged less than 50 years at menopause. Women in the highest category of menstrual cycles (≥500 cycles) had an average 19.00 ng/mL (95%CI: 5.86, 32.14) higher concentration of IGF-1 compared to women in the lowest category (<350). Exogenous hormones had no effect on postmenopausal IGF-1 levels. Objective 2. Exemestane significantly increased IGF-1 levels by 18% (95% CI: 14%-22%); while, placebo had no effect on IGF-1. The changes in IGF-1 were significantly different between the treatment arms (P<0.0001) and no significant interaction was observed between treatment and BMI on IGF-1 changes (P=0.1327). Conclusion: Objective 1. Larger number of menstrual cycles and a later age at menopause are positively associated with IGF-1. IGF-1 may be one mechanism by which prolonged estrogen exposure increases cancer risk. Objective 2. We conclude that the reduced cancer risk observed with AI therapy likely occurs in an IGF-1 independent mechanism. Further studies exploring the clinical consequences of increased IGF-1 on AI therapy are needed.