title: Hormone therapy, estrogen metabolism, and risk of breast cancer in the Women's Health Initiative Hormone Therapy Trial.
abstract: BACKGROUND
  In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.
  
  
  METHODS
  In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year.
  
  
  RESULTS
  The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.
  
  
  CONCLUSIONS
  Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.
  
  
  CONCLUSIONS
  Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens.
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261, USA. mackey@edc.pitt.edu
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Mackey
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Fanelli
authors.forename: Francesmary
authors.initials: F
authors.lastname: Modugno
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: McTigue
authors.forename: Maria Mori
authors.initials: MM
authors.lastname: Brooks
authors.forename: Rowan T
authors.initials: RT
authors.lastname: Chlebowski
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Klug
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Kip
authors.forename: J David
authors.initials: JD
authors.lastname: Curb
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000378:metabolism*; D016022:Case-Control Studies; D004198:Disease Susceptibility; D004967:Estrogens / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods / Q000706:statistics & numerical data*; D006801:Humans; D008875:Middle Aged; D011372:Progestins / Q000008:administration & dosage* / Q000378:metabolism*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D004967:Estrogens; D011372:Progestins