AS134 - Serum Estrogen Hormone Metabolites, Hormone Replacement Therapy, and the Risk of Breast Cancer

This page provides study documentation for AS134. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Francesmary Modugno, PhD, MPH, Department of Epidemiology, University of Pittsburgh


There is substantial evidence linking both exogenous and endogenous estrogens to breast cancer risk. Hormone replacement therapy (HRT), the most common source of exogenous estrogens, has also been associated with increased risk.  However, not all women using HRT will develop breast cancer, suggesting genetic and/or other factors that modify the risk associated with HRT.  In particular, our preliminary data suggests that body mass index (BMI) and HRT interact to determine how estrogen is metabolized and therefore affect a woman’s risk of breast cancer.  We have found that in women with low BMI, estrogen is usually metabolized to 2-OH estrone, the less genotoxic estrogen metabolite.  However, our data indicate that HRT use causes a shift from the 2-OH metabolite to the 16-OH metabolite. The 16-OH metabolite is more genotoxic and has been associated with breast cancer risk. In women with a high BMI, HRT does not appear to alter estrogen metabolism as much.  Hence, among HRT users, production of the 16-OH metabolite is inversely associated with BMI; this is exactly the opposite of the association found among non-HRT users.  This suggests that the increase in risk associated with HRT use among thin women may be mediated by estrogen metabolism. 

The objective of this proposal is to prospectively evaluate the extent to which BMI and estrogen metabolism are related to breast cancer associated with HRT use. We will specifically test the following hypotheses: Among postmenopausal women using HRT:

a). the risk of breast cancer is higher for women with higher serum 16-OH levels

b). lower BMI is associated with higher serum 16-OH levels

c). therefore:  the risk of breast cancer increases with decreasing BMI

We will also test the relationship between serum 2-OH levels, the 2:16-OH ratio, BMI and breast cancer risk.


Some of the publications related to this ancillary study are:

Ms209 - Modugno F, Kip KE, Cochrane B, Kuller L, Klug TL, Rohan TE, Chlebowski RT, Lasser N, Stefanick ML. Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer. 2006 Mar 1;118(5):1292-301

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.