High Estradiol Levels are Associated with Increased Mortality in Older Men Referred to Coronary Angiography

Abstract

Objective:

There is evidence showing an important role of estrogens in men’s health. We aimed to evaluate whether estradiol levels are associated with overall mortality and specific fatal events.

Design, Setting, and Participants:

We measured estradiol levels in 2 078 men who were routinely referred for coronary angiography (1997–2000).

Measurements:

The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes including cancer according to estradiol levels.

Results:

Multivariable HRs (with 95% confidence intervals) for all-cause, non-cardiovascular, and cancer mortality were 1.43 (1.08–1.91), 2.11 (1.34–3.34), and 2.27 (1.00–5.19), respectively, in the fourth estradiol quartile as compared to the first. There was no significant association of estradiol levels with cardiovascular mortality. In multivariate adjusted analyses, higher estradiol levels in men were significantly associated with prevalent strokes, peripheral vascular disease, and carotid artery stenosis compared to lower estradiol levels.

Conclusion:

High levels of estradiol are associated with all-cause and non-cardiovascular mortality in a large cohort of older men referred to coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms.

Key words

estradiol - mortality

• References

• 1 Abbott RD, Launer LJ, Rodriguez BL et al. Serum estradiol and risk of stroke in elderly men. Neurology 2007; 68: 563-568
• 2 Akishita M, Hashimoto M, Ohike Y et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis 2010; 210: 232-236
• 3 Araujo AB, Kupelian V, Page ST et al. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 2007; 167: 1252-1260
• 4 Arnlöv J, Pencina MJ, Amin S et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 2006; 145: 176-184
• 5 Barrett-Conner E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men: A prospective population based study. Circulation 1988; 78: 539-545
• 6 Cavasin MA, Sankey SS, Yu AL et al. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 2003; 284: H1560-H1569
• 7 Christeff N, Benassayag C, Carli-Vielle C et al. Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem 1988; 29: 435-440
• 8 Corrada MM, Kawas CH, Mozaffar F et al. Association of body mass index and weight change with all-cause mortality in the elderly. Am J Epidemiol 2006; 163: 938-949
• 9 Daniels NA, Nielson CM, Hoffman AR et al. Osteoporotic Fractures In Men (MrOS) Study Group. Sex Hormones and the Risk of Incident Prostate Cancer. Urology 2010; in press
• 10 Ding EL, Song Y, Malik VS et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006; 295: 1288-1299
• 11 Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab 1999; 84: 4677-4694
• 12 Irie F, Strozyk D, Peila R et al. Brain lesions on MRI and endogenous sex hormones in elderly men. Neurobiol Aging 2006; 27: 1137-1141
• 13 Jankowska EA, Rozentryt P, Ponikowska B et al. Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA 2009; 301: 1892-1901
• 14 Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005; 26: 833-876
• 15 Khaw KT, Dowsett M, Folkerd E et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007; 116: 2694-2701
• 16 Kovacs EJ, Messingham KA, Gregory MS. Estrogen regulation of immune responses after injury. Mol Cell Endocrinol 2002; 193: 129-135
• 17 Lakshman KM, Kaplan B, Travison TG et al. The Effects of Injected Testosterone Dose and Age on the Conversion of Testosterone to Estradiol and Dihydrotestosterone in Young and Older Men. J Clin Endocrinol Metab. 2010 in press
• 18 Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68-75
• 19 May AK, Dossett LA, Norris PR et al. Estradiol is associated with mortality in critically ill trauma and surgical patients. Crit Care Med 2008; 36: 62-68
• 20 Muller M, van der Schouw YT, Thijssen JH et al. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003; 88: 5076-5086
• 21 Phillips GB, Castelli WP, Abbott RD et al. Association of hyperestrogenemia and coronary heart disease in men in the Framingham cohort. Am J Med 1983; 74: 863-869
• 22 Phillips GB. Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity. Metabolism 1993; 42: 116-120
• 23 Shores MM, Matsumoto AM, Sloan KL et al. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006; 166: 1660-1665
• 24 Smith EP, Boyd J, Frank GR et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 2004; 331: 1056-1061
• 25 Spratt DI, Morton JR, Kramer RS et al. Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization. Am J Phys Endocrinol Metab 2006; 291: E631-E638
• 26 Sudhir K, Komesaroff PA. Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab 1999; 84: 3411-3415
• 27 Szulc P, Garnero P, Claustrat B et al. Increased bone resorption in moderate smokers with low body weight: the Minos study. J Clin Endocrinol Metab 2002; 87: 666-674
• 28 Szulc P, Claustrat B, Delmas PD. Serum concentrations of 17beta-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men–the MINOS study. Clin Endocrinol (Oxf) 2009; 71: 594-602
• 29 Tivesten A, Hulthe J, Wallenfeldt K et al. Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men. J Clin Endocrinol Metab 2006; 91: 4433-4437
• 30 Tivesten A, Vandenput L, Labrie F et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009; 94: 2482-2488
• 31 T’Sjoen GG, De Vos S, Goemaere S et al. Sex steroid level, androgen receptor polymorphism, and depressive symptoms in healthy elderly men. J Am Geriatr Soc 2005; 53: 636-642
• 32 Vandenput L, Mellström D, Karlsson MK et al. Serum estradiol is associated with lean mass in elderly Swedish men. Eur J Endocrinol 2010; 162: 737-745
• 33 Vikan T, Schirmer H, Njølstad I et al. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol 2009; 161: 435-442
• 34 Wehr E, Pilz S, Boehm BO et al. Sex steroids and mortality in men referred for coronary angiography. Clin Endocrinol 2010; 73: 613-621
• 35 Winkelmann BR, März W, Boehm BO et al. LURIC Study Group. (LUdwigshafen RIsk and Cardiovascular Health). Rationale and design of the LURIC study – a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001; 2: S1-S73