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

Int J Cancer. 2019 Feb 15;144(4):730-740. doi: 10.1002/ijc.31851. Epub 2018 Nov 1.


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.

Keywords: conjugated equine estrogens; conjugated equine estrogens plus medroxyprogesterone acetate; estrogen alone; estrogen metabolism; estrogen plus progestin; women's health initiative observational study.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Drug Therapy, Combination
  • Estrogen Replacement Therapy / methods*
  • Estrogens / administration & dosage*
  • Estrogens / metabolism
  • Estrogens, Conjugated (USP) / administration & dosage
  • Female
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Middle Aged
  • Postmenopause*
  • Progestins / administration & dosage*
  • Risk Factors
  • Treatment Outcome


  • Estrogens
  • Estrogens, Conjugated (USP)
  • Progestins
  • Medroxyprogesterone Acetate