Exogenous Estrogen as Mediator of Racial Differences in Bioactive Insulin-Like Growth Factor-I Levels Among Postmenopausal Women

Racial disparities in cancer risk and prognosis for African American (AA) people are well documented, especially for breast, colorectal, and prostate cancer (1). Several epidemiological and clinical studies have suggested that higher insulin-like growth factor-I (IGF-I) levels are associated with higher cancer risk and worse cancer survival (2,3). Previous studies also showed that the circulating concentrations of bioavailable IGF-I are higher in AA than in whites (4,5), and this variation is plausibly related to racial differences in cancer risk and prognosis. Given its association with the growth hormone-IGF axis (6), obesity has been postulated to be a driver of IGF-I production (7,8). However, the inconstant findings such as the null (9), nonlinear (10), and positive (7) associations of obesity, and the negative (8,11) relationship of visceral obesity with IGF-I imply that obesity or central adiposity is not the only major influence on IGF-I levels. In postmenopausal women, IGF-I levels and endogenous sex hormones, especially estrogen, may influence one another (2,7,12). Endogenous estrogen levels decrease as women age (13). Among postmenopausal women, excess exogenous estrogen has been postulated to interact with circulating IGF-I proteins to affect cancer risk (7). Previous observational studies reported both positive (2,7) and null (12,14) relationships between estrogen (both estrone and estradiol) and IGF-I levels among postmenopausal women; more recently, studies reported an inverse relationship between estrogen and IGF-I levels among postmenopausal women (7,13,15,16), suggesting that estrogen suppresses hepatic IGF-I production (17–19). Rates of exogenous estrogen use among postmenopausal white women may be higher than those among postmenopausal AA women, and this could account for differences in circulating bioactive IGF-I levels between white and AA women. Most studies evaluating interactions of exogenous estrogen use with IGF-I levels in different racial groups conducted subset analyses of one racial group or the other. Such an approach has reduced statistical power with which to evaluate the main association, especially after accounting for multiple other covariates in models, due to a decreased sample size from dividing the sample by race. To address this methodological challenge, in the present study, we examined the mediation effect of exogenous estrogen use in relationship with racial differences of IGF-I levels using two complementary statistical methods: (a) a Baron–Kenny approach (20) and (b) a quantitative estimation of a mediation effect (20,21) paired with a bootstrapping approach to test its significance (22). To our knowledge, no studies to date directly test for the effect of exogenous estrogen use on the relationship between race and circulating IGF-I concentrations as proposed here. The purpose of this cross-sectional study was to assess the role of exogenous estrogen use as a mediator of the relationship between race and plasma concentrations of bioactive IGF-I among postmenopausal women and to determine whether exogenous estrogen’s role in the race–IGF-I relationship differs by statistically selected medical characteristics. We hypothesized that AA women have higher IGF-I levels and lower exogenous estrogen use than white women and compared with nonusers, exogenous estrogen users have lower IGF-I levels.