Endogenous Sex Hormones and Cardiovascular Disease Incidence in Men

  1. Johan Ärnlöv, MD, PhD;
  2. Michael J. Pencina, PhD;
  3. Shreyasee Amin, MD;
  4. Byung-Ho Nam, PhD;
  5. Emelia J. Benjamin, MD, ScM;
  6. Joanne M. Murabito, MD, ScM;
  7. Thomas J. Wang, MD;
  8. Philip E. Knapp, MD;
  9. Ralph B. D'Agostino, Sr., PhD;
  10. Shalendar Bhasin, MD; and
  11. Ramachandran S. Vasan, MD
  1. From the National Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes of Health, Bethesda, Maryland; Boston University School of Medicine, Boston University, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts; Mayo Clinic College of Medicine, Rochester, Minnesota; and Uppsala University, Uppsala, Sweden.

    Abstract

    Background: Data suggest that endogenous sex hormones (testosterone, dehydroepiandrosterone sulfate [DHEA-S], and estradiol) influence cardiovascular disease (CVD) risk factors and vascular function. Yet, prospective studies relating sex hormones to CVD incidence in men have yielded inconsistent results.

    Objective: To examine the association of circulating sex hormone levels and CVD risk in men.

    Design: Prospective cohort study.

    Setting: Community-based study in Framingham, Massachusetts.

    Participants: 2084 middle-aged white men without CVD at baseline.

    Measurements: The authors used multivariable Cox regression to relate baseline levels of testosterone, DHEA-S, and estradiol to the incidence of CVD (coronary, cerebrovascular, or peripheral vascular disease or heart failure) during 10 years of follow-up.

    Results: During follow-up, 386 men (18.5%) experienced a first CVD event. After adjustment for baseline standard CVD risk factors, higher estradiol level was associated with lower risk for CVD (hazard ratio per SD increment in log estradiol, 0.90 [95% CI, 0.82 to 0.99]; P = 0.035). The authors observed effect modification by age: Higher estradiol levels were associated with lower CVD risk in older (median age >56 years) men (hazard ratio per SD increment, 0.86 [CI, 0.78 to 0.96]; P = 0.005) but not in younger (median age ≤56 years) men (hazard ratio per SD increment, 1.11 [CI, 0.89 to 1.38]; P = 0.36). The association of higher estradiol level with lower CVD incidence remained robust in time-dependent Cox models (updating standard CVD risk factors during follow-up). Serum testosterone and DHEA-S levels were not statistically significantly associated with incident CVD.

    Limitations: Sex hormone levels were measured only at baseline, and the findings may not be generalizable to women and nonwhite people.

    Conclusions: In the community-based sample, a higher serum estradiol level was associated with lower risk for CVD events in older men. The findings are consistent with the hypothesis that endogenous estrogen has vasculoprotective influences in men.

    Article and Author Information

    • Acknowledgments: The authors acknowledge the assistance of Ms. Pamela Bacharach, who performed all the sex hormone assays, and Clark Sawin, MD, who supervised the assays. Dr. Sawin passed away in August 2004.

    • Grant Support: By a Bergmarks travel grant, a Viking Björks Hedersledamotstipendium, a Capio travel grant, and the Thuréus Foundation and through research grants (National Heart, Lung, and Blood Institute contracts N01-HC-25195, 6R01-NS 17950, K23 HL074077, and 2K24 HL04334) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

    • Potential Financial Conflicts of Interest: Consultancies: T.J. Wang (Novartis Institutes for Biomedical Research); Grants received: S. Bhasin (Solvay Pharmaceuticals).

    • Requests for Single Reprints: Ramachandran S. Vasan, MD, Boston University School of Medicine, Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702-5803; e-mail, vasan{at}bu.edu.

    • Current Author Addresses: Dr. Ärnlöv: Section of Geriatrics, Uppsala University, PO Box 609, 75215 Uppsala, Sweden.

    • Drs. Pencina and D'Agostino Sr.: Mathematics Department, Boston University, 111 Cummington Street, Boston, MA 02215.

    • Dr. Amin: Division of Rheumatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55902.

    • Drs. Nam, Benjamin, Murabito, Wang, and Vasan: Boston University School of Medicine, Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702-5803.

    • Drs. Knapp and Bhasin: Endocrinology Division, Department of Medicine, Boston University School of Medicine, 670 Albany Street, 2nd Floor, Boston, MA 02118.

    • Author Contributions: Conception and design: J. Ärnlöv, B.-H. Nam, J.M. Murabito, R.S. Vasan.

    • Analysis and interpretation of the data: J. Ärnlöv, M.J. Pencina, S. Amin, B.-H. Nam, J.M. Murabito, R.B. D'Agostino Sr., S. Bhasin, R.S. Vasan.

    • Drafting of the article: J. Ärnlöv, M.J. Pencina, B.-H. Nam, S. Bhasin, R.S. Vasan.

    • Critical revision of the article for important intellectual content: J. Ärnlöv, M.J. Pencina, S. Amin, B.-H. Nam, E.J. Benjamin, T.J. Wang, P.E. Knapp, R.B. D'Agostino Sr., S. Bhasin, R.S. Vasan.

    • Final approval of the article: J. Ärnlöv, M.J. Pencina, S. Amin, B.-H. Nam, E.J. Benjamin, J.M. Murabito, T.J. Wang, R.B. D'Agostino Sr., S. Bhasin, R.S. Vasan.

    • Statistical expertise: M.J. Pencina, B.-H. Nam, R.B. D'Agostino Sr.

    • Obtaining of funding: R.S. Vasan.

    • Administrative, technical, or logistic support: R.B. D'Agostino Sr., R.S. Vasan.

    • Collection and assembly of data: S. Amin, R.S. Vasan.

    Responses to this article

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