Abstract 4237: Estrogen metabolism in menopausal hormone users: Does it differ between estrogen plus progestin and estrogen alone users in the Women’s Health Initiative Observational Study
Authors: Falk Roni T. , Anderson Garnet L. , Barnabei Vanessa M. , Brinton Louise A. , Cauley Jane A. , Chen Chu , Chlebowski Rowan T. , Coburn Sally B. , Manson JoAnn E. , Pfeiffer Ruth M. , Reding Kerryn W. , Rohan Thomas E. , Sarto Gloria E. , Wentzensen Nicolas , Trabert Britton 
Published: July 2017

Abstract
Background: The Women’s Health Initiative (WHI) provided divergent results regarding the effects of menopausal hormone therapy (MHT) on breast cancer risk, with women in the conjugated equine estrogen plus medroxyprogesterone (CEE+MPA) arm at elevated risk, and women in the CEE alone arm at reduced risk. Although direct progestin-mediated effects may largely explain the elevated risk, we hypothesize that in addition, these MHT treatments may differentially influence patterns of estrogen metabolism, with CEE alone preferentially inducing metabolism along the 2-hydroxylation pathway, a pattern previously linked to reduced breast cancer risk.
Study methods/population: Women in a case-control study of estrogen metabolites (EM) and ovarian and endometrial cancer from the WHI Observational Study were identified for this analysis. Unlike the WHI trial, no medication restrictions were applied. At enrollment, serum, anthropometric measures, and self-administered questionnaires which ascertained reproductive history, lifestyle factors and health behaviors including MHT use, were obtained. 615 women reported current use of estrogen plus progestin formulations (E+P), of whom 343 used CEE+MPA; 266 used estrogens alone (E alone), with 148 using CEE. Fifteen EM were measured by liquid chromatography/mass spectrometry and analyses were conducted separately for each EM. EM differences between E alone and E+P users were assessed using inverse probability weighted linear regression. Primary analyses included women using any MHT formulation; secondary analyses were restricted to CEE users.
Results: Compared to users of E+P, concentrations of all EM were higher in E alone users, and significantly so for unconjugated estrone, estradiol, 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol. Relative to total EM, concentrations of 2- and 4-pathway EM did not differ by MHT group (for E alone and E+P users, 2-pathway EM were ~14% of the total EM; 4-pathway EM were &lt;2% of the total), but E+P users had a significantly higher proportion of 16-pathway EM compared to E alone users (32% vs. 30%, p=0.025). Similar patterns were observed in analyses comparing users of CEE alone to CEE+MPA, albeit not significant.
Conclusion: Our data suggest that women using E alone may preferentially metabolize estrogens along the 2- and 4-hydroxylation pathways, whereas in E+P users, more extensive metabolism occurs along the 16-pathway. However, we did not observe these effects in the smaller groups of women using CEE alone or CEE+MPA, the MHT formulations administered in the treatment arms of the WHI trial. Our findings in E alone users are consistent with epidemiologic investigations demonstrating reduced breast cancer risk in postmenopausal women with more extensive 2-pathway estrogen metabolism, and may provide a clue to the breast cancer risk reduction observed in these women.
Citation Format: Roni T. Falk, Garnet L. Anderson, Vanessa M. Barnabei, Louise A. Brinton, Jane A. Cauley, Chu Chen, Rowan T. Chlebowski, Sally B. Coburn, JoAnn E. Manson, Ruth M. Pfeiffer, Kerryn W. Reding, Thomas E. Rohan, Gloria E. Sarto, Nicolas Wentzensen, Britton Trabert. Estrogen metabolism in menopausal hormone users: Does it differ between estrogen plus progestin and estrogen alone users in the Women’s Health Initiative Observational Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4237. doi:10.1158/1538-7445.AM2017-4237