, 14:97 | Cite as

Serum metabolomic profiles associated with postmenopausal hormone use

  • Victoria L. StevensEmail author
  • Ying Wang
  • Brian D. Carter
  • Mia M. Gaudet
  • Susan M. Gapstur
Original Article



Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin.


Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was done to identify metabolites associated with each type of hormone treatment.


Untargeted metabolomics analysis was done on serum from 1336 women enrolled in the Cancer Prevention II Nutrition Cohort. Levels of 781 named metabolites were compared between 667 nonusers with 332 estrogen-only and with 337 estrogen plus progestin users using linear regression. Metabolite levels were also compared between estrogen-only and estrogen plus progestin users.


Compared to nonusers, 276 metabolites were statistically significantly (P < 6.40 × 10− 5) associated with estrogen-only use and 222 were associated with estrogen plus progestin use. The metabolites associated with both types of hormones included numerous lipids, acyl carnitines, and amino acids as well as the thyroid hormone thyroxine and the oncometabolite fumarate. The 65 metabolites that differed significantly between estrogen-only and estrogen plus progestin users included 19 steroids and 12 lipids that contained the bioactive fatty acid arachidonic acid.


These findings suggest that postmenopausal hormone use influences metabolic pathways linked to a variety of cellular processes, including the regulation of metabolism and stress responses, energy production, and inflammation. The differential association of numerous lipids which influence cellular signaling suggests that differences in signal transduction may contribute to the disparate risks for some diseases between estrogen-only and estrogen plus progestin users.


Hormone replacement therapy Estrogen Progestin Postmenopausal 



The authors express sincere appreciation to all Cancer Prevention Study II participants and to each member of the study and biospecimen management group. We also thank Dr. Steven Moore (National Cancer Institute) for assistance in obtaining partial financial support for this project.


The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society—Cancer Action Network.

Author contributions

Conception and design: V.L. Stevens; Acquisition of the data: V.L. Stevens, Y. Wang, B.D. Carter; Analysis and interpretation of the data: V.L. Stevens, Y. Wang, B.D. Carter; Writing and review of the manuscript: V.L. Stevens, Y. Wang, M.M. Gaudet, S.M. Gapstur.


The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II cohort. The metabolomic analyses were supported, in part, through the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval

All aspects of the CPS-II Nutrition Cohort were approved by the Emory University Institutional Review Board (IRB00045780).

Informed consent

Informed consent was obtained from all individual participants included in this study.

Supplementary material

11306_2018_1393_MOESM1_ESM.xlsx (36 kb)
Supplementary material 1 (XLSX 35 KB)
11306_2018_1393_MOESM2_ESM.xlsx (40 kb)
Supplementary material 2 (XLSX 39 KB)


  1. Calle, E. E., Rodriguez, C., Jacobs, E. J., Almon, M. L., Chao, A., McCullough, M. L., et al. (2002). The American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer, 94, 2490–2501.CrossRefPubMedGoogle Scholar
  2. Chlebowski, R. T., & Anderson, G. L. (2014). Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity. Steroids, 90, 53–59.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Cho, C. E., & Caudill, M. A. (2017). Trimethylamine-N-oxide: Friend, foe, or simply caught in the cross-fire? Trends in Endocrinology Metabolism, 28, 121–130.CrossRefPubMedGoogle Scholar
  4. Clarke, R., Daly, L., Robinson, K., Naughten, E., Cahalane, S., Fowler, B., et al. (1991). Hyperhomocysteinemia: An independent risk factor for vascular disease. New England Journal of Medicine, 324, 1149–1155.CrossRefPubMedGoogle Scholar
  5. Collins, R. R. J., Patel, K., Putnam, W. C., Kapur, P., & Rakheja, D. (2017). Oncometabolites: A new paradigm for oncology, metabolism, and the clinical laboratory. Clinical chemistry, 63, 1812–1820.CrossRefPubMedGoogle Scholar
  6. Cushman, M., Legault, C., Barrett-Connor, E., Stefanick, M. L., Kessler, C., Judd, H. L., et al. (1999). Effect of postmenopausal hormones on inflammation-sensitive proteins: The postmenopausal estrogen/progestin interventions (PEPI) study. Circulation, 100, 717–722.CrossRefPubMedGoogle Scholar
  7. Day, C. R., & Kempson, S. A. (2016). Betaine chemistry, roles, and potential use in liver disease. Biochimica et Biophysica Acta (BBA), 1860, 1098–1106.CrossRefGoogle Scholar
  8. Evans, A. M., DeHaven, C. D., Barrett, T., Mitchell, M., & Milgram, E. (2009). Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Analytical chemistry, 81, 6656–6667.CrossRefPubMedGoogle Scholar
  9. Grodstein, F., Manson, J. E., Colditz, G. A., Willett, W. C., Speizer, F. E., & Stampfer, M. J. (2000). A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Annals of Internal Medicine, 133, 933–941.CrossRefPubMedGoogle Scholar
  10. Hartiala, J. A., Tang, W. H., Wang, Z., Crow, A. L., Stewart, A. F., Roberts, R., et al. (2016). Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nature Communications, 7, 10558.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Houben, A. J., & Moolenaar, W. H. (2011). Autotaxin and LPA receptor signaling in cancer. Cancer and Metastasis Reviews, 30, 557–565.CrossRefPubMedGoogle Scholar
  12. Johnson, D. C., Martin, H., & Tsai-Morris, C. H. (1984). The in vitro and in vivo effect of estradiol upon the 17 alpha-hydroxylase and C17,20-lyase activity in the ovaries of immature hypophysectomized rats. Molecular and Cellular Endocrinology, 35, 199–204.CrossRefPubMedGoogle Scholar
  13. Katayama, H., Paczesny, S., Prentice, R., Aragaki, A., Faca, V. M., Pitteri, S. J., et al. (2009). Application of serum proteomics to the Women’s Health Initiative conjugated equine estrogens trial reveals a multitude of effects relevant to clinical findings. Genome Medicine, 1, 47.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lakryc, E. M., Machado, R. B., Soares, J. M. Jr., Fernandes, C. E., 3rd and Baracat, E. C. (2015) What is the influence of hormone therapy on homocysteine and CRP levels in postmenopausal women? Clinics (Sao Paulo) 70, 107–113.CrossRefGoogle Scholar
  15. Lobo, R. A. (2016). Hormone-replacement therapy: Current thinking. Nature Reviews Endocrinology, 13(4), 220.CrossRefPubMedGoogle Scholar
  16. Luan, H., Meng, N., Liu, P., Feng, Q., Lin, S., Fu, J., et al. (2014). Pregnancy-induced metabolic phenotype variations in maternal plasma. Journal of Proteome Research, 13, 1527–1536.CrossRefPubMedGoogle Scholar
  17. Lustgarten, M. S., & Fielding, R. A. (2017). Metabolites associated with circulating interleukin-6 in older adults. Journals of Gerontology Series A, 72, 1277–1283.Google Scholar
  18. Manson, J. E., Chlebowski, R. T., Stefanick, M. L., Aragaki, A. K., Rossouw, J. E., & Prentice, R. L., et al. (2013). Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA, 310, 1353–1368.CrossRefPubMedGoogle Scholar
  19. Mazer, N. A. (2004). Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women. Thyroid, 14 Suppl(1), S27–S34.CrossRefPubMedGoogle Scholar
  20. Parizek, A., Hill, M., Duskova, M., Vitek, L., Velikova, M., & Kancheva, R., et al. (2016). A comprehensive evaluation of steroid metabolism in women with intrahepatic cholestasis of pregnancy. PLoS ONE, 11, e0159203.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Pitteri, S. J., Hanash, S. M., Aragaki, A., Amon, L. M., Chen, L., & Buson, B., et al. (2009). Postmenopausal estrogen and progestin effects on the serum proteome. Genome Medicine, 1, 121.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ratner, S., & Ofri, D. (2001). Menopause and hormone-replacement therapy: Part 2. Hormone-replacement therapy regimens. The Western Journal of Medicine, 175, 32–34.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Ridker, P. M., Hennekens, C. H., Rifai, N., Buring, J. E., & Manson, J. E. (1999). Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation, 100, 713–716.CrossRefPubMedGoogle Scholar
  24. Rijpkema, A. H., van der Sanden, A. A., & Ruijs, A. H. (1990). Effects of post-menopausal oestrogen-progestogen replacement therapy on serum lipids and lipoproteins: A review. Maturitas, 12, 259–285.CrossRefPubMedGoogle Scholar
  25. Rossouw, J. E., Cushman, M., Greenland, P., Lloyd-Jones, D. M., Bray, P., & Kooperberg, C., et al. (2008). Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women’s health initiative trials of hormone therapy. Archives of Internal Medicine, 168, 2245–2253.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Rozenberg, S., Vandromme, J., & Antoine, C. (2013). Postmenopausal hormone therapy: Risks and benefits. Nature Reviews Endocrinology, 9, 216–227.CrossRefPubMedGoogle Scholar
  27. Ruoppolo, M., Campesi, I., Scolamiero, E., Pecce, R., Caterino, M., & Cherchi, S., et al. (2014). Serum metabolomic profiles suggest influence of sex and oral contraceptive use. American Journal of Translational Research, 6, 614–624.PubMedPubMedCentralGoogle Scholar
  28. Sciacovelli, M., Goncalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S., & Gaude, E., et al. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 537, 544–547.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Stefanick, M. L. (2005). Estrogens and progestins: Background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. The American journal of medicine, 118 Suppl 12B, 64–73.CrossRefPubMedGoogle Scholar
  30. Tazuke, S., Khaw, K. T., & Barrett-Connor, E. (1992). Exogenous estrogen and endogenous sex hormones. Medicine (Baltimore), 71, 44–51.CrossRefGoogle Scholar
  31. Villa, P., Moruzzi, M. C., Lassandro, A. P., Lanzone, A., & Mancuso, S. (2010). Metabolic Impact of Estrogen Replacement Therapy. Journal of Reproductive Medicine and Endocrinology, 7, 119–124.Google Scholar
  32. Villa, P., Suriano, R., Ricciardi, L., Tagliaferri, V., De Cicco, S., & De Franciscis, P., et al. (2011). Low-dose estrogen and drospirenone combination: Effects on glycoinsulinemic metabolism and other cardiovascular risk factors in healthy postmenopausal women. Fertility and Sterility, 95, 158–163.CrossRefPubMedGoogle Scholar
  33. Wood, C. E., Cline, J. M., Anthony, M. S., Register, T. C., & Kaplan, J. R. (2004). Adrenocortical effects of oral estrogens and soy isoflavones in female monkeys. The Journal of Clinical Endocrinology & Metabolism, 89, 2319–2325.CrossRefGoogle Scholar
  34. Zang, H., Moritz, T., Norstedt, G., Hirschberg, A. L., & Tollet-Egnell, P. (2012). Effects of oestrogen and testosterone therapy on serum metabolites in postmenopausal women. Clinical Endocrinology, 77, 288–295.CrossRefPubMedGoogle Scholar
  35. Zeisel, S. H. (2013). Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis. Clinical Chemistry and Laboratory Medicine, 51, 467–475.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Behavioral and Epidemiology Research GroupAmerican Cancer SocietyAtlantaUSA

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