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Endogenous Sex Hormones and Cardiovascular Disease Incidence in Men

Johan Ärnlöv, MD, PhD; Michael J. Pencina, PhD; Shreyasee Amin, MD; Byung-Ho Nam, PhD; Emelia J. Benjamin, MD, ScM; Joanne M. Murabito, MD, ScM; Thomas J. Wang, MD; Philip E. Knapp, MD; Ralph B. D'Agostino Sr., PhD; Shalendar Bhasin, MD; and Ramachandran S. Vasan, MD
[+] Article and Author Information

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.


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@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.


Ann Intern Med. 2006;145(3):176-184. doi:10.7326/0003-4819-145-3-200608010-00005
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Figure.
Multivariable-adjusted association of serum levels of estradiol and cardiovascular disease risk.

The solid line shows the hazard ratio estimated as a function of penalized regression splines of estradiol to the baseline hazard. Dashed lines are 95% confidence limits for the hazard ratio. Dotted lines represent quartile limits of serum estradiol levels. Hazard ratios greater than 1.0 indicate increased hazard compared with the baseline hazard, and hazard ratios less than 1.0 indicate decreased hazard compared with the baseline hazard. To convert estradiol levels from pg/mL to pmol/L, multiply value by 3.671.

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REGULATION OF BIGLYCAN EXPRESSION BY SEX HORMONES UNIFIES THE CLINICAL TENETS OF ATHEROSCLEROSIS
Posted on August 4, 2006
Melvin K. Leow
Tan Tock Seng Hospital
Conflict of Interest: None Declared

Dear Sir:

After decades of controversies that shed more heat than light over the conflicting effects of endogenous and exogenous sex hormones on cardiovascular disease (CVD), two large studies have finally advanced our current thinking. The first is the Women¡¦s Health Initiative (WHI) Study that showed an overall greater risk-to-benefit ratio of exogenous estrogen in postmenopausal females (1). The second is this seminary Framingham study by Arnlov J et al. (2) that showed the reduced CVD event rates in older men with higher estrogen levels, thereby suggesting a vasculoprotective effect of endogenous estrogens. The authors are to be congratulated for the well conceived study design adequately powered to address this question.

In contrast, no vasculoprotective effect of testosterone or dehydroepiandrosterone sulfate (DHEA-S) was found, and that endogenous estrogen does not confer similar protection in younger men. Whenever large scale, prospective epidemiological studies have successfully ¡§filtered out the signal from the noise¡¨ and borne striking or counterintuitive data, real biological phenomena probably exist that merit further translational research. In this instance, Arnlov et al. have highlighted plausible mechanisms for the estrogens-CVD risk linkage including traditional (blood pressure, lipids, glycemia) and non-traditional risk factors (homocysteine, hemostatic factors, inflammation, endothelial function). However, it remains mysterious how estrogen operates on such factors at the molecular level. Notably, they quoted from literature that genetic variation in estrogen receptor-ƒÑ has been associated with higher CVD events, and that androgen and estrogen receptor expression in coronary arteries has been reported to influence coronary atherosclerosis in men.

To lend greater scientific credence to their findings, we should draw our attention to the increasing role of extracellular matrix proteoglycans called biglycan, in atherogenesis. Biglycan tends to bind low density lipoprotein (LDL) in the subendothelium and is proinflammatory (3). In addition, biglycan modulate structural integrity and biophysical properties of the vessel wall by decreasing arterial compliance while increasing its stiffness. DNA microarray technology has unraveled reduction of biglycan expression by estradiol and phytoestrogens (4), though regulation of biglycan expression by other exogenous estrogens is still unknown. Testosterone, however, upregulate vascular proteoglycan expression, and increases their binding to LDL (5). These compelling novel molecular findings on biglycan-sex hormone-lipid interactions seem to unify most of the macroscopic tenets of atherosclerosis and agree well with clinical observations.

Yours sincerely,

Melvin Khee-Shing Leow, MD, FACE, FACP

References

1. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women¡¦s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333.

2. Arnlov J, Pencina MJ, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 2006; 145: 176- 184.

3. Figueroa JE, Vijayagopal P. Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties. Atherosclerosis 2002; 162: 261-268.

4. Rodrigo MC, Martin DS, Eyster KM. Estrogen decreases biglycan mRNA expression in resistance blood vessels. Am J Physiol Regul Integr Comp Physiol 2003; 285: R754-761.

5. Hashimura K, Sudhir K, Nigro J, et al. Androgens stimulate human vascular smooth muscle proteoglycan biosynthesis and increase lipoprotein binding. Endocrinology 2005; 146: 2085-90.

Conflict of Interest:

None declared

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