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Cancer Causes & Control

, Volume 30, Issue 11, pp 1201–1211 | Cite as

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women’s Health Initiative Observational Study

  • Britton TrabertEmail author
  • Sally B. Coburn
  • Roni T. Falk
  • JoAnn E. Manson
  • Louise A. Brinton
  • Margery L. Gass
  • Lewis H. Kuller
  • Thomas E. Rohan
  • Ruth M. Pfeiffer
  • Lihong Qi
  • Marcia L. Stefanick
  • Nicolas Wentzensen
  • Garnet L. Anderson
  • Xia Xu
Original Paper
  • 206 Downloads

Abstract

Purpose

Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users.

Methods

We conducted a nested case–control study among postmenopausal women using MHT at baseline in the Women’s Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype.

Results

Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17–7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT).

Conclusions

These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.

Keywords

Endogenous estrogens Estrogen metabolites Ovarian cancer Endometrial cancer Nested case–control study Current hormone therapy users 

Notes

Acknowledgments

The authors would like to also acknowledge the following short list of WHI investigators: Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. For a list of all the investigators who have contributed to WHI science, please visit: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf

Funding

This work was supported in part by the Intramural Research Program of the National Cancer Institute (Grant No. ZIA CP010126-24). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through Contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

Compliance with ethical standards

Conflicts of interest

All authors declare they have no conflicts of interest.

References

  1. 1.
    Trabert B et al (2012) Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study. Br J Cancer 107(7):1181–1187CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Collaborative Group on Epidemiological Studies of Ovarian et al (2015) Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 385(9980):1835–1842.CrossRefGoogle Scholar
  3. 3.
    Trabert B et al (2013) Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk? Int J Cancer 132(2):417–426CrossRefPubMedGoogle Scholar
  4. 4.
    Trabert B et al (2016) Circulating estrogens and postmenopausal ovarian cancer risk in the Women’s Health Initiative Observational Study. Cancer Epidemiol Biomark Prev 25(4):648–656CrossRefGoogle Scholar
  5. 5.
    Brinton LA et al (2016) Serum estrogens and estrogen metabolites and endometrial cancer risk among postmenopausal women. Cancer Epidemiol Biomark Prev 25(7):1081–1089CrossRefGoogle Scholar
  6. 6.
    Schock H et al (2014) Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer. Endocr Relat Cancer 21(6):831–844CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dallal CM et al (2016) Estrogen metabolism and risk of postmenopausal endometrial and ovarian cancer: the B~FIT cohort. Horm Cancer 7(1):49–64CrossRefPubMedGoogle Scholar
  8. 8.
    Zeleniuch-Jacquotte A et al (2001) Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer 84(7):975–981CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lukanova A et al (2004) Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 108(3):425–432CrossRefPubMedGoogle Scholar
  10. 10.
    Helzlsouer KJ et al (1995) Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 274(24):1926–1930CrossRefPubMedGoogle Scholar
  11. 11.
    Lukanova A et al (2003) Circulating levels of sex steroid hormones and risk of ovarian cancer. Int J Cancer 104(5):636–642CrossRefPubMedGoogle Scholar
  12. 12.
    Falk RT et al (2019) 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 144(4):730–740CrossRefPubMedGoogle Scholar
  13. 13.
    Anderson G et al (1998) Design of the women’s health initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 19(1):61–109.Google Scholar
  14. 14.
    Langer RD et al (2003) The Women’s Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 13(9 Suppl):S107–S121CrossRefPubMedGoogle Scholar
  15. 15.
    Xu X et al (2007) Quantitative measurement of endogenous estrogens and estrogen metabolites in human serum by liquid chromatography-tandem mass spectrometry. Anal Chem 79(20):7813–7821CrossRefPubMedGoogle Scholar
  16. 16.
    Loud JT et al (2014) Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers. Breast Cancer Res Treat 143(3):517–529CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gates MA et al (2010) Risk factors for epithelial ovarian cancer by histologic subtype. Am J Epidemiol 171(1):45–53CrossRefPubMedGoogle Scholar
  18. 18.
    Yang HP et al (2012) Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study. Int J Cancer 131(4):938–948CrossRefPubMedGoogle Scholar
  19. 19.
    Fortner RT et al (2015) Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: Results from the EPIC cohort. Int J Cancer 137(5):1196–1208CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pearce CL et al (2013) Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer. Cancer Epidemiol Biomark Prev 22(5):880–890CrossRefGoogle Scholar
  21. 21.
    Pearce CL et al (2012) Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 13(4):385–394CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chang SC et al (2007) Lifetime weight history and endometrial cancer risk by type of menopausal hormone use in the NIH-AARP diet and health study. Cancer Epidemiol Biomark Prev 16(4):723–730CrossRefGoogle Scholar
  23. 23.
    Karageorgi S et al (2010) Reproductive factors and postmenopausal hormone use in relation to endometrial cancer risk in the Nurses’ Health Study cohort 1976–2004. Int J Cancer 126(1):208–216CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Allen NE et al (2008) Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 15(2):485–497CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Newbold RR, Liehr JG (2000) Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. Cancer Res 60(2):235–237PubMedGoogle Scholar
  26. 26.
    Wentzensen N et al (2016) Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium. J Clin Oncol 34(24):2888–2898CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply  2019

Authors and Affiliations

  • Britton Trabert
    • 1
    Email author
  • Sally B. Coburn
    • 1
  • Roni T. Falk
    • 1
  • JoAnn E. Manson
    • 2
  • Louise A. Brinton
    • 1
  • Margery L. Gass
    • 3
  • Lewis H. Kuller
    • 4
  • Thomas E. Rohan
    • 4
    • 5
  • Ruth M. Pfeiffer
    • 1
  • Lihong Qi
    • 6
  • Marcia L. Stefanick
    • 7
  • Nicolas Wentzensen
    • 1
  • Garnet L. Anderson
    • 8
  • Xia Xu
    • 9
  1. 1.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  2. 2.Department of Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Women’s Health Institute, Cleveland ClinicClevelandUSA
  4. 4.Department of EpidemiologyUniversity of PittsburghPittsburghUSA
  5. 5.Department of Epidemiology and Population HealthAlbert Einstein College of MedicineBronxUSA
  6. 6.Public Health Sciences, School of MedicineUC DavisSacramentoUSA
  7. 7.Department of MedicineStanford University School of MedicineStanfordUSA
  8. 8.Division of Public Health Sciences, Cancer Prevention ProgramFred Hutchinson Cancer Research CenterSeattleUSA
  9. 9.Frederick National Laboratory for Cancer Research, Cancer Research Technology ProgramLeidos Biomedical Research, Inc.FrederickUSA

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