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Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?


ABSTRACT: The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.

SUBMITTER: Falk RT 

PROVIDER: S-EPMC6746113 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

Falk Roni T RT   Manson JoAnn E JE   Barnabei Vanessa M VM   Anderson Garnet L GL   Brinton Louise A LA   Rohan Thomas E TE   Cauley Jane A JA   Chen Chu C   Coburn Sally B SB   Pfeiffer Ruth M RM   Reding Kerryn W KW   Sarto Gloria E GE   Wentzensen Nicolas N   Chlebowski Rowan T RT   Xu Xia X   Trabert Britton B  

International journal of cancer 20181101 4


The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used  ...[more]

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