Hormones and Cancer

, Volume 6, Issue 2–3, pp 107–119 | Cite as

Relationship of Serum Estrogens and Metabolites with Area and Volume Mammographic Densities

  • Gretchen L. GierachEmail author
  • Deesha A. Patel
  • Roni T. Falk
  • Ruth M. Pfeiffer
  • Berta M. Geller
  • Pamela M. Vacek
  • Donald L. Weaver
  • Rachael E. Chicoine
  • John A. Shepherd
  • Amir Pasha Mahmoudzadeh
  • Jeff Wang
  • Bo Fan
  • Sally D. Herschorn
  • Xia Xu
  • Timothy Veenstra
  • Barbara Fuhrman
  • Mark E. Sherman
  • Louise A. Brinton
Original Paper


Elevated mammographic density is a breast cancer risk factor, which has a suggestive, but unproven, relationship with increased exposure to sex steroid hormones. We examined associations of serum estrogens and estrogen metabolites with area and novel volume mammographic density measures among 187 women, ages 40–65, undergoing diagnostic breast biopsies at an academic facility in Vermont. Serum parent estrogens, estrone and estradiol, and their 2-, 4-, and 16-hydroxylated metabolites were measured using liquid chromatography-tandem mass spectrometry. Area mammographic density was measured in the breast contralateral to the biopsy using thresholding software; volume mammographic density was quantified using a density phantom. Linear regression was used to estimate associations of estrogens with mammographic densities, adjusted for age and body mass index, and stratified by menopausal status and menstrual cycle phase. Weak, positive associations between estrogens, estrogen metabolites, and mammographic density were observed, primarily among postmenopausal women. Among premenopausal luteal phase women, the 16-pathway metabolite estriol was associated with percent area (p = 0.04) and volume (p = 0.05) mammographic densities and absolute area (p = 0.02) and volume (p = 0.05) densities. Among postmenopausal women, levels of total estrogens, the sum of parent estrogens, and 2-, 4- and 16-hydroxylation pathway metabolites were positively associated with area density measures (percent: p = 0.03, p = 0.04, p = 0.01, p = 0.02, p = 0.07; absolute: p = 0.02, p = 0.02, p = 0.01, p = 0.02, p = 0.03, respectively) but not volume density measures. Our data suggest that serum estrogen profiles are weak determinants of mammographic density and that analysis of different density metrics may provide complementary information about relationships of estrogen exposure to breast tissue composition.


Breast Cancer Risk Mammographic Density Menopausal Hormone Therapy Menstrual Cycle Phase Percent Mammographic Density 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Body mass index


Breast Radiology Evaluation and Study of Tissues


Estrogens and estrogen metabolites








Fletcher Allen Health Care


Liquid chromatography-tandem mass spectroscopy


Mammographic density


Area mammographic density


Volume mammographic density


National Cancer Institute


Standard deviation


Single X-ray absorptiometry











The authors are indebted to the participants in the BREAST Stamp Project for their outstanding cooperation and to the physicians, pathologists, nurses, technologists, and interviewers for their efforts in the field. The authors thank Clair Bove, Patricia Lutton, Ellen Young, Aileen Burke, Laura Linville, and Daphne Papathomas for research assistance. We also thank Janet Lawler-Heaver and Kerry Grace Morrissey from Westat for study management support and Jane Demuth at Information Management Services for data support and analysis.


This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Cancer Institute federal funds awarded under Contract No. HHSN261200800001E to SAIC-Frederick, Inc. Breast Cancer Research Stamp Funds and cooperative agreement U01CA70013 (B.M. Geller, P.M. Vacek, D.L. Weaver, R.E. Chicoine, S.D. Herschorn) and 1R21CA157254 (J.A. Shepherd, B. Fan, A.P. Mahmoudzadeh) from the National Cancer Institute funded some of the data collection and image analysis for this study. Grant number M01 RR000109 from the National Center for Research Resources funded the blood processing at the University of Vermont’s General Clinical Research Center. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Conflict of Interest

S.D. Herschorn is a stockholder in Hologic.

Supplementary material

12672_2015_216_MOESM1_ESM.doc (40 kb)
Supplementary Table 1 (DOC 40 kb)
12672_2015_216_MOESM2_ESM.doc (51 kb)
Supplementary Table 2 (DOC 51 kb)
12672_2015_216_MOESM3_ESM.doc (52 kb)
Supplementary Table 3 (DOC 51 kb)
12672_2015_216_MOESM4_ESM.doc (46 kb)
Supplementary Table 4 (DOC 45 kb)
12672_2015_216_MOESM5_ESM.doc (46 kb)
Supplementary Table 5 (DOC 46 kb)


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Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2015

Authors and Affiliations

  • Gretchen L. Gierach
    • 1
    • 10
    Email author
  • Deesha A. Patel
    • 1
  • Roni T. Falk
    • 1
  • Ruth M. Pfeiffer
    • 2
  • Berta M. Geller
    • 3
  • Pamela M. Vacek
    • 3
  • Donald L. Weaver
    • 3
  • Rachael E. Chicoine
    • 3
  • John A. Shepherd
    • 4
  • Amir Pasha Mahmoudzadeh
    • 4
  • Jeff Wang
    • 4
    • 5
  • Bo Fan
    • 4
  • Sally D. Herschorn
    • 3
  • Xia Xu
    • 6
  • Timothy Veenstra
    • 6
    • 7
  • Barbara Fuhrman
    • 8
  • Mark E. Sherman
    • 9
  • Louise A. Brinton
    • 1
  1. 1.Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  3. 3.University of VermontBurlingtonUSA
  4. 4.University of California, San FranciscoSan FranciscoUSA
  5. 5.Graduate School of MedicineHokkaido UniversitySapporoJapan
  6. 6.Laboratory of Proteomics and Analytical Technologies, Cancer Research Technology Program, Leidos Biomedical Research, Inc.Frederick National Laboratory for Cancer ResearchFrederickUSA
  7. 7.CN DiagnosticsSaint LouisUSA
  8. 8.Department of Epidemiology, Fay W. Boozman College of Public HealthUniversity of Arkansas for Medical SciencesLittle RockUSA
  9. 9.Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  10. 10.BethesdaUSA

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