Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer

Abstract

Hormone therapy (HT) and body mass index (BMI) have been associated with postmenopausal breast cancer. Because estrogen metabolism may affect breast cancer risk and can be altered by weight and HT, it might play a role in the HT-BMI-breast cancer associations. We undertook a nested case-control study within the Observational Study of the Women's Health Initiative. Baseline levels of 2-and 16a-hydroxy estrone (2-OHE1 and 16a-OHE1) were measured in 200 women who developed breast cancer during follow-up and 200 healthy controls matched to cases by ethnicity, enrollment date, clinic site, type of HT and years since menopause. Wilcoxon nonparametric tests were used to compare estrogen metabolite levels between cases and controls. Conditional logistic regression was used to assess the relationship between BMI, estrogen metabolites and breast cancer risk. 16a-OHE1 levels were modestly but significantly higher in HT users among cases (median 356 pg/ml vs. 315 pg/ml) and controls (354 pg/ml vs. 298 pg/ml). 2-OHE1 levels were substantially and significantly higher in HT users among cases (369 pg/ml vs. 125 pg/ml) and controls (347 pg/ml vs. 134 pg/ml). For non-HT users only, greater BMI and higher 16a-OHE1 levels were individually and jointly associated with increased breast cancer risk (OR for women with high BMI and high 16a-OHE1 compared to those with low BMI and low 16a-OHE1 5 3.51, 95% CI 5 1.34-9.16). No associations between BMI, estrogen metabolism and breast cancer risk were found for HT users. Estrogen metabolism differs according to both BMI and HT use, potentially explaining the interaction between BMI and HT in relation to breast cancer risk. ' 2005 Wiley-Liss, Inc.Key words: breast neoplasms; hormone therapy; estrogen metabolism; body mass index; obesity The Women's Health Initiative (WHI) clinical trial recently confirmed observational study findings 1,2 that progestin-containing hormone therapy (HT) formulations are associated with an increased risk of postmenopausal breast cancer.3 Elevated circulating estrogen levels may underlie this association, as substantial data, including markers of long-term estrogen exposure, 4 implicate estrogen in the etiology of postmenopausal breast cancer. However, for a given dose of estrogen, estrogen-only HT formulations appear to impart less risk than combined estrogen and progestin therapies. 1,3,[5][6][7][8] In particular, the WHI clinical trial reported no increase in risk associated with an estrogen-only formulation, 8 but a 24% increase in risk among women assigned to a combination estrogen-progestin formulation compared to placebo.3 Interestingly, this increase is less than expected, given the magnitude of the increase in circulating estrogens resulting from oral estrogen preparations 9,10 and among studies that associate higher blood levels of estrogen with increased breast cancer risk. 11,12Body size has also been implicated in postmenopausal breast cancer.13,14 For example, risk increases by 3% for each kilogram per meter square increase in body mass index (BMI)...

Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status

“…the higher estradiol levels observed in normal-weight hormone therapy users may be due to the lower volume of distribution 37 or differential metabolism of exogenous estrogens. 38 in the liver, estradiol is converted to estrone and subsequently to either 2-hydroxy estrone (OHe1) or 16α-OHe1 in target cells. Higher levels of 16α-OHe1-but not 2-OHe1-have been associated with increased breast cancer risk.…”

Ovarian function and obesity—Interrelationship, impact on women's reproductive lifespan and treatment options

“…Obesity not only increases breast cancer risk (Modugno et al, 2006) but also enhances the risk of thrombo-embolic complications such as deep vein thrombosis or pulmonary Page 13 of 21 A c c e p t e d M a n u s c r i p t embolism. Therefore, it is advocated that the use of HRT in obese women should be given in lowest effective doses and preferably through parenteral route (i.e.…”

Effect of Flaxseed Consumption on Urinary Levels of Estrogen Metabolites in Postmenopausal Women

“…Several (8)(9)(10)(11) but not all (12) retrospective case-control studies have reported a lower 2/16α-OHE1 ratio in postmenopausal breast cancer cases than control study subjects. Results from prospective studies have been inconclusive (13)(14)(15)(16)(17)(18). Eliassen and colleagues (18) recently suggested that future studies should include a broader panel of estrogen metabolites to fully evaluate the role of the estrogen metabolism pathway in breast cancer risk.…”