Urinary concentrations of estrogens and estrogen metabolites and smoking in caucasian women

Cancer Epidemiol Biomarkers Prev. 2013 Jan;22(1):58-68. doi: 10.1158/1055-9965.EPI-12-0909. Epub 2012 Oct 25.


Background: Smoking has been hypothesized to decrease biosynthesis of parent estrogens (estradiol and estrone) and increase their metabolism by 2-hydroxylation. However, comprehensive studies of smoking and estrogen metabolism by 2-, 4-, or 16-hydroxylation are sparse.

Methods: Fifteen urinary estrogens and estrogen metabolites (jointly called EM) were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in luteal phase urine samples collected during 1996 to 1999 from 603 premenopausal women in the Nurses' Health Study II (NHSII; 35 current, 140 former, and 428 never smokers). We calculated geometric means and percentage differences of individual EM (pmol/mg creatinine), metabolic pathway groups, and pathway ratios, by smoking status and cigarettes per day (CPD).

Results: Total EM and parent estrogens were nonsignificantly lower in current compared with never smokers, with estradiol significant (P(multivariate) = 0.02). We observed nonsignificantly lower 16-pathway EM (P = 0.08) and higher 4-pathway EM (P = 0.25) and similar 2-pathway EM in current versus never smokers. EM measures among former smokers were similar to never smokers. Increasing CPD was significantly associated with lower 16-pathway EM (P-trend = 0.04) and higher 4-pathway EM (P-trend = 0.05). Increasing CPD was significantly positively associated with the ratios of 2- and 4-pathway to parent estrogens (P-trend = 0.01 and 0.002), 2- and 4-pathway to 16-pathway (P-trend = 0.02 and 0.003), and catechols to methylated catechols (P-trend = 0.02).

Conclusions: As hypothesized, we observed lower urinary levels of total EM and parent estrogens in active smokers. Our results also suggest smoking is associated with altered estrogen metabolism, specifically increased 2- and 4-hydroxylation, decreased 16-hydroxylation, and decreased catechol methylation.

Impact: Our study suggests how smoking might influence estrogen-related cancers and conditions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Case-Control Studies
  • Chromatography, Liquid
  • Confidence Intervals
  • Estrogens / metabolism
  • Estrogens / urine*
  • Estrone / metabolism
  • Estrone / urine*
  • European Continental Ancestry Group / statistics & numerical data
  • Female
  • Humans
  • Luteal Phase / urine*
  • Middle Aged
  • Premenopause / urine
  • Reference Values
  • Retrospective Studies
  • Risk Assessment
  • Smoking / ethnology*
  • Smoking / urine*
  • Tandem Mass Spectrometry


  • Estrogens
  • Estrone