Prospective Study of Endogenous Hormones and Incidence of Venous Thromboembolism: The Atherosclerosis Risk in Communities Study

Nicholas S. Roetker; Richard F. MacLehose; Ron C. Hoogeveen; Christie M. Ballantyne; Saonli Basu; Mary Cushman; Aaron R. Folsom

doi:10.1055/s-0038-1673613

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(11): 1940-1950
DOI: 10.1055/s-0038-1673613

Stroke, Systemic or Venous Thromboembolism

Georg Thieme Verlag KG Stuttgart · New York

Prospective Study of Endogenous Hormones and Incidence of Venous Thromboembolism: The Atherosclerosis Risk in Communities Study

Authors

Nicholas S. Roetker

¹Chronic Disease Research Group, Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States

²Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States
Richard F. MacLehose

²Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States
Ron C. Hoogeveen

³Section of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, The Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas, United States
Christie M. Ballantyne

³Section of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, The Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas, United States
Saonli Basu

⁴Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States
Mary Cushman

⁵Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, United States
Aaron R. Folsom

²Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States

Abstract

Exogenous hormone treatments in women (oral contraceptives and hormone replacement therapy [HRT]) are established risk factors for venous thromboembolism (VTE), but less is known about associations between plasma levels of endogenous hormones and VTE risk. We examined the association of baseline dehydroepiandrosterone sulphate (DHEAS), testosterone and sex hormone-binding globulin (SHBG) with risk of future VTE in men and post-menopausal women in the Atherosclerosis Risk in Communities Study. Testosterone, DHEAS and SHBG were measured in plasma samples collected in 1996 to 1998. Cox proportional hazards models were used to estimate hazard ratios for incident VTE adjusting for age, race/ethnicity, body mass index, height, smoking, estimated glomerular filtration rate and C-reactive protein. All analyses were stratified by sex and by current HRT use in women. Among 3,051 non-HRT-using women, 1,414 HRT-using women and 3,925 men at risk at baseline, 184, 62 and 206 experienced incident VTE after a median follow-up of 17.6 years. Plasma hormones were not associated with incidence of VTE among men and non-HRT-using women, although lower plasma DHEAS, when modelled using quartiles or restricted cubic splines, was associated with higher risk of VTE among HRT-using women. This study does not support the existence of an important association between plasma concentrations of endogenous testosterone, DHEAS or SHBG with risk of VTE in middle-aged to older men or post-menopausal women not using HRT.

Keywords

deep vein thrombosis - pulmonary embolism - epidemiologic studies - risk factors - hormones

Full Text

References

References
1 Crous-Bou M, Harrington LB, Kabrhel C. Environmental and genetic risk factors associated with venous thromboembolism. Semin Thromb Hemost 2016; 42 (08) 808-820
2 Malan NT, von Känel R, Schutte AE. , et al. Testosterone and acute stress are associated with fibrinogen and von Willebrand factor in African men: the SABPA study. Int J Cardiol 2013; 168 (05) 4638-4642
3 Agledahl I, Brodin E, Svartberg J, Hansen JB. Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels. Thromb Haemost 2009; 101 (03) 471-477
4 Tsai AW, Cushman M, Rosamond WD. , et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113 (08) 636-642
5 Zakai NA, Lutsey PL, Folsom AR, Heckbert SR, Cushman M. Total tissue factor pathway inhibitor and venous thrombosis. The Longitudinal Investigation of Thromboembolism Etiology. Thromb Haemost 2010; 104 (02) 207-212
6 Bonithon-Kopp C, Scarabin PY, Bara L, Castanier M, Jacqueson A, Roger M. Relationship between sex hormones and haemostatic factors in healthy middle-aged men. Atherosclerosis 1988; 71 (01) 71-76
7 Haring R, Baumeister SE, Völzke H. , et al. Prospective inverse associations of sex hormone concentrations in men with biomarkers of inflammation and oxidative stress. J Androl 2012; 33 (05) 944-950
8 Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sié P. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism 1989; 38 (10) 1010-1015
9 Yang XC, Jing TY, Resnick LM, Phillips GB. Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men. Arterioscler Thromb 1993; 13 (04) 467-471
10 Sowers MR, Jannausch M, Randolph JF. , et al. Androgens are associated with hemostatic and inflammatory factors among women at the mid-life. J Clin Endocrinol Metab 2005; 90 (11) 6064-6071
11 Meltzer ME, Lisman T, de Groot PG. , et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116 (01) 113-121
12 Harrington LB, Marck BT, Wiggins KL. , et al. Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women. J Thromb Haemost 2017; 15 (01) 80-90
13 Folsom AR, Golden SH, Boland LL, Szklo M. Association of endogenous hormones with C-reactive protein, fibrinogen, and white blood count in post-menopausal women. Eur J Epidemiol 2005; 20 (12) 1015-1022
14 Williams MS, Cushman M, Ouyang P, Heckbert SR, Kalyani RR, Vaidya D. Association of serum sex hormones with hemostatic factors in women on and off hormone therapy: the Multiethnic Study of Atherosclerosis. J Womens Health (Larchmt) 2016; 25 (02) 166-172
15 Labrie F, Luu-The V, Bélanger A. , et al. Is dehydroepiandrosterone a hormone?. J Endocrinol 2005; 187 (02) 169-196
16 Ohlsson C, Vandenput L, Tivesten A. DHEA and mortality: what is the nature of the association?. J Steroid Biochem Mol Biol 2015; 145: 248-253
17 Jenkins PV, Rawley O, Smith OP, O'Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157 (06) 653-663
18 Smith NL, Chen M-H, Dehghan A. , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
19 Folsom AR, Alonso A, George KM, Roetker NS, Tang W, Cushman M. Prospective study of plasma D-dimer and incident venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study. Thromb Res 2015; 136 (04) 781-785
20 Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?. Acta Obstet Gynecol Scand 2002; 81 (06) 482-490
21 Raps M, Helmerhorst F, Fleischer K. , et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10 (06) 992-997
22 van Rooijen M, Silveira A, Hamsten A, Bremme K. Sex hormone--binding globulin--a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004; 190 (02) 332-337
23 Folsom AR, Cushman M, Tsai MY. , et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99 (08) 2720-2725
24 Svartberg J, Braekkan SK, Laughlin GA, Hansen JB. Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study. Eur J Endocrinol 2009; 160 (05) 833-838
25 Holmegard HN, Nordestgaard BG, Schnohr P, Tybjaerg-Hansen A, Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost 2014; 12 (03) 297-305
26 Stegeman BH, Helmerhorst FM, Vos HL, Rosendaal FR, Van Hylckama Vlieg A. Sex hormone-binding globulin levels are not causally related to venous thrombosis risk in women not using hormonal contraceptives. J Thromb Haemost 2012; 10 (10) 2061-2067
27 The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol 1989; 129 (04) 687-702
28 Cushman M, Tsai AW, White RH. , et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117 (01) 19-25
29 Inker LA, Schmid CH, Tighiouart H. , et al; CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012; 367 (01) 20-29
30 Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis. 2nd ed. Cham: Springer; 2015
31 van Vliet HAAM, Frolich M, Christella M. , et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod 2005; 20 (02) 563-568
32 Xu L, Schooling CM. Differential risks in men and women for first and recurrent venous thrombosis: the role of genes and environment: comment. J Thromb Haemost 2015; 13 (05) 884-886
33 Martinez C, Suissa S, Rietbrock S. , et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 2016; 355: i5968
34 Baillargeon J, Urban RJ, Morgentaler A. , et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc 2015; 90 (08) 1038-1045
35 Sharma R, Oni OA, Chen G. , et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the Veterans Administration Database. Chest 2016; 150 (03) 563-571
36 Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013; 173 (15) 1465-1466
37 Brambilla DJ, O'Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf) 2007; 67 (06) 853-862
38 Valero-Politi J, Fuentes-Arderiu X. Within- and between-subject biological variations of follitropin, lutropin, testosterone, and sex-hormone-binding globulin in men. Clin Chem 1993; 39 (08) 1723-1725
39 Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007; 92 (02) 405-413

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