Estradiol Level as a Risk Factor for Cardiovascular Endpoints in Men: A Systematic Review

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Cardiovascular disease is a major cause of higher mortality of middle-aged and elderly males in comparison to women. Sex hormones action on cardiovascular system is the most likely explanation of this differences. Nevertheless, estradiol and cardiovascular disease relationship is still unclear. The authors conducted a systematic review to identify the association of endogenous estradiol with cardiovascular endpoints in men. Articles were identified by a MedLine search (1961 — July 2023) and citation tracking. No evidence synthesis was conducted. 24 eligible articles were found. In 10 studies no association of sex hormones and endpoints was found. In 7 studies there was an association of testosterone and endpoints, but no significant results for estradiol. 7 studies have reported significant association of estradiol and cardiovascular endpoints. Inconsistency in evidence is significantly influenced by differences between studies in patient age, follow-up, researched endpoints and quality of estradiol essay. Over 40% of published studies, that researched the association of estradiol and death, found such a link. However, existing body of literature is largely heterogenous and doesn’t provide definite evidence for a pronounced net effect of estradiol on cardiovascular health in general men population. The present systematic review hints, that endogenous estradiol could be linked with cardiovascular risks in white men of young and middle age.

Full Text

Restricted Access

About the authors

Iana A. Orlova

Lomonosov Moscow State University

Email: YAOrlova@mc.msu.ru
ORCID iD: 0000-0002-8160-5612
SPIN-code: 3153-8373

MD, PhD, Professor

Russian Federation, Moscow

Egor D. Sorokin

Lomonosov Moscow State University

Author for correspondence.
Email: srknegor@gmail.com
ORCID iD: 0009-0002-5730-4286
Russian Federation, Moscow

Zukhra Sh. Pavlova

Lomonosov Moscow State University

Email: zukhra73@gmail.com
ORCID iD: 0000-0001-7954-0437
SPIN-code: 9329-7628

MD, PhD

Russian Federation, Moscow

Alina G. Plisyuk

Lomonosov Moscow State University

Email: apl.cardio@yandex.ru
ORCID iD: 0000-0003-2015-4712
SPIN-code: 3541-2077

MD, PhD, Associate Professor

Russian Federation, Moscow

Armais A. Kamalov

Lomonosov Moscow State University

Email: AAKamalov@mc.msu.ru
ORCID iD: 0000-0003-4251-7545
SPIN-code: 6609-5468

MD, PhD, Professor, Academician of the RAS

Russian Federation, Moscow

References

  1. Федеральная служба государственной статистики. Женщины и мужчины России 2022: стат. сборник. — М., 2022. — 208 с. [Federalnaya sluzhba gosudarstvennoj statistiki. ZHenshchiny i muzhchiny Rossii 2022: Statisticheskij sbornik. Moscow; 2022. 208 p. (In Russ.)]
  2. Tsilidis KK, Rohrmann S, Mcglynn KA, et al. Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology. 2013;1(6):919–928. doi: https://doi.org/10.1111/J.2047-2927.2013.00129.x
  3. Ellis JA, Infantino T, Harrap SB. Sex-dependent association of blood pressure with oestrogen receptor genes ERalpha and ERbeta. J Hypertens. 2004;22(6):1127–1131. doi: https://doi.org/10.1097/00004872-200406000-00013
  4. Stachenfeld NS, Keefe DL. Estrogen effects on osmotic regulation of AVP and fluid balance. Am J Physiol Endocrinol Metab. 2002;283(4):Е711–721. doi: https://doi.org/10.1152/ajpendo.00192.2002
  5. The Coronary Drug Project: Findings Leading to Discontinuation of the 2,5-mg/day Estrogen Group. JAMA. 1973;226(6):652–657. doi: https://doi.org/10.1001/JAMA.1973.03230060030009
  6. Blackard CE, Doe RP, Mellinger GT, Byar DP. Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer. 1970;26(2):249–256. doi: https://doi.org/10.1002/1097-0142(197008)26:2<249::aid-cncr2820260202>3.0.co;2-7
  7. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: https://doi.org/10.1136/BMJ.n71
  8. Haffner SM, Moss SE, Klein BE, et al. Sex Hormones and DHEA-SO4 in Relation to Ischemic Heart Disease Mortality in Diabetic subjects: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care. 1996;19(10):1045–1050. doi: https://doi.org/10.2337/diacare.19.10.1045
  9. Lerchbaum E, Pilz S, Grammer TB, et al. High estradiol levels are associated with increased mortality in older men referred to coronary angiography. Exp Clin Endocrinol Diabetes. 2011;119(8):490–496. doi: https://doi.org/10.1055/S-0031-1284370
  10. Raparelli V, Nocella C, Proietti M, et al. Testosterone-to-estradiol ratio and platelet thromboxane release in ischemic heart disease: the EVA project. J Endocrinol Invest. 2022;45(7):1367–1377. doi: https://doi.org/10.1007/S40618-022-01771-0
  11. Cai J, Li J, Chen S, et al. Early post-haemorrhagic stroke testosterone and oestradiol levels and long-term risk of death. Brain Inj. 2017;31(3):401–405. doi: https://doi.org/10.1080/02699052.2016.1265668
  12. Van Koeverden ID, De Bakker M, Haitjema S, et al. Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis. Cardiovasc Res. 2019;115(2):453–462. doi: https://doi.org/10.1093/cvr/cvy188
  13. Jankowska EA, Rozentryt P, Ponikowska B, et al. Circulating Estradiol and Mortality in Men with Systolic Chronic Heart Failure. JAMA. 2009;301(18):1892–1901. doi: https://doi.org/10.1001/jama.2009.639
  14. Khaw KT, Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol. 1992;2(5):675–682. doi: https://doi.org/10.1016/1047-2797(92)90012-f
  15. Haring R, Travison TG, Bhasin S, et al. Relation between Sex Hormone Concentrations, Peripheral Arterial Disease, and Change in Ankle-Brachial Index: Findings from the Framingham Heart Study. J Clin Endocrinol Metab. 2011;96(12):3724–3732. doi: https://doi.org/10.1210/jc.2011-1068
  16. Holmegard HN, Nordestgaard BG, Schnohr P, et al. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost. 2014;12(3):297–305. doi: https://doi.org/10.1111/jth.12484
  17. Magnani JW, Moser CB, Murabito JM, et al. Association of sex hormones, aging, and atrial fibrillation in men the framingham heart study. Circ Arrhythm Electrophysiol. 2014;7(2):307–312. doi: https://doi.org/10.1161/CIRCEP.113.001322
  18. Chasland LC, Knuiman MW, Divitini ML, et al. Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men. Clin Endocrinol (Oxf). 2017;87(5):466–474. doi: https://doi.org/10.1111/cen.13407
  19. Chan YX, Knuiman MW, Hung J, et al. Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17–97 years. Clin Endocrinol (Oxf). 2016;85(4):575–582. doi: https://doi.org/10.1111/cen.13089
  20. Chasland LC, Knuiman MW, Divitini ML, et al. Higher circulating androgens and higher physical activity levels are associated with less central adiposity and lower risk of cardiovascular death in older men. Clin Endocrinol (Oxf). 2019;90(2):375–383. doi: https://doi.org/10.1111/cen.13905
  21. Yeap BB, Alfonso H, Paul Chubb SA, et al. In Older Men an Optimal Plasma Testosterone Is Associated with Reduced All-Cause Mortality and Higher Dihydrotestosterone with Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality. J Clin Endocrinol Metab. 2014;99(1):E9–E18. doi: https://doi.org/10.1210/jc.2013-3272
  22. Yeap BB, Alfonso H, Chubb SAP, et al. In Older Men, Higher Plasma Testosterone or Dihydrotestosterone Is an Independent Predictor for Reduced Incidence of Stroke but Not Myocardial Infarction. J Clin Endocrinol Metab. 2014;99(12):4565–4573. doi: https://doi.org/10.1210/jc.2014-2664
  23. Heller RF, Miller NE, Wheeler MJ, et al. Coronary heart disease in “low risk” men. Atherosclerosis. 1983;49(2):187–193. doi: https://doi.org/10.1016/0021-9150(83)90196-x
  24. Cauley JA, Gutai JP, Kuller LH, et al. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol. 1987;60(10):771–777. doi: https://doi.org/10.1016/0002-9149(87)91021-6
  25. Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation. 1988;78(3):539–545. doi: https://doi.org/10.1161/01.cir.78.3.539
  26. Eldrup E, Winkel P, Lindholm J, et al. Coronary risk factors, development of mycocardial infarction, and plasma oestrogens: a prospective casecontrol study in men. J Intern Med. 1989;225(6):367–372. doi: https://doi.org/10.1111/j.1365-2796.1989.tb00098.x
  27. Contoreggi CS, Blackman MR, Andres R, et al. Plasma Levels of Estradiol, Testosterone, and DHEAS Do Not Predict Risk of Coronary Artery Disease in Men. J Androl. 1990;11(5):460–470. doi: https://doi.org/10.1002/j.1939-4640.1990.tb00178.x
  28. Yarnell JWG, Beswick AD, Sweetnam PM, et al. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb. 1993;13(4):517–520. doi: https://doi.org/10.1161/01.atv.13.4.517
  29. Mikulec KH, Holloway L, Krasnow RE, et al. Relationship of Endogenous Sex Hormones to Coronary Heart Disease: A Twin Study. J Clin Endocrinol Metab. 2004;89(3):1240–1245. doi: https://doi.org/10.1210/jc.2003-031333
  30. Nilsson SE, Fransson E, Brismar K. Relationship between serum progesterone concentrations and cardiovascular disease, diabetes, and mortality in elderly Swedish men and women: An 8-Year prospective study. Gend Med. 2009;6(3):433–443. doi: https://doi.org/10.1016/j.genm.2009.09.011
  31. Glisic M, Mujaj B, Rueda-Ochoa OL, et al. Associations of Endogenous Estradiol and Testosterone Levels with Plaque Composition and Risk of Stroke in Subjects with Carotid Atherosclerosis. Circ Res. 2018;122(1):97–105. doi: https://doi.org/10.1161/CIRCRESAHA.117.311681
  32. Laughlin GA, Barrett-Connor E, Bergstrom J. Low Serum Testosterone and Mortality in Older Men. J Clin Endocrinol Metab. 2008;93(1):68–75. doi: https://doi.org/10.1210/jc.2007-1792
  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(3):435–442. doi: https://doi.org/10.1530/eje-09-0284
  34. 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(1):232–236. doi: https://doi.org/10.1016/j.atherosclerosis.2009.10.037
  35. Haring R, Teng Z, Xanthakis V, et al. Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study. Clin Endocrinol (Oxf). 2013;78(4):629–634. doi: https://doi.org/10.1111/cen.12013
  36. Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas. 2013;75(3):282–288. doi: https://doi.org/10.1016/j.maturitas.2013.04.012
  37. Holmegard HN, Nordestgaard BG, Jensen GB, et al. Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses. J Clin Endocrinol Metab. 2016;101(1):69–78. doi: https://doi.org/10.1210/jc.2015-2687
  38. Ärnlöv J, Pencina MJ, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med. 2006;145(3):176–184. doi: https://doi.org/10.7326/0003-4819-145-3-200608010-00005
  39. Abbott RD, Launer LJ, Rodriguez BL, et al. Serum estradiol and risk of stroke in elderly men. Neurology. 2007;68(8):563–568. doi: https://doi.org/10.1212/01.wnl.0000254473.88647.ca
  40. Szulc P, Claustrat B, Delmas PD. Serum concentrations of 17β-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men – the MINOS study. Clin Endocrinol (Oxf). 2009;71(4):594–602. doi: https://doi.org/10.1111/j.1365-2265.2009.03530.x
  41. Tivesten Å, Vandenput L, Labrie F, et al. Low Serum Testosterone and Estradiol Predict Mortality in Elderly Men. J Clin Endocrinol Metab. 2009;94(7):2482–2488. doi: https://doi.org/10.1210/jc.2008-2650
  42. Menke A, Guallar E, Rohrmann S, et al. Sex Steroid Hormone Concentrations and Risk of Death in US Men. Am J Epidemiol. 2010;171(5):583–592. doi: https://doi.org/10.1093/aje/kwp415
  43. Holmboe SA, Vradi E, Jensen TK, et al. The Association of Reproductive Hormone Levels and All-Cause, Cancer, and Cardiovascular Disease Mortality in Men. J Clin Endocrinol Metab. 2015;100(12):4472–4480. doi: https://doi.org/10.1210/jc.2015-2460
  44. Appiah D, Luitel S, Nwabuo CC, et al. Low endogenous estradiol levels are associated with elevated risk of cardiovascular disease mortality in young and middle-aged men in the United States. Atherosclerosis. 2022;361:34–40. doi: https://doi.org/10.1016/j.atherosclerosis.2022.09.006
  45. Vandenplas G, De Bacquer D, Calders P, et al. Endogenous oestradiol and cardiovascular disease in healthy men: a systematic review and meta-analysis of prospective studies. Heart. 2012;98(20):1478–1482. doi: https://doi.org/10.1136/heartjnl-2011-301587
  46. Bräuner EV, Uldbjerg C, Lim YH, et al. Is male gynaecomastia associated with an increased risk of death? A nationwide register-based cohort study. BMJ Open. 2024;14(2):e076608. doi: https://doi.org/10.1136/bmjopen-2023-076608
  47. Uldbjerg CS, Lim YH, Bräuner EV, et al. Increased Morbidity in Males Diagnosed With Gynecomastia: A Nationwide Register-based Cohort Study. J Clin Endocrinol Metab. 2023;108(7):e380–e387. doi: https://doi.org/10.1210/clinem/dgad048
  48. Chadid S, Barber JR, Rohrmann S, et al. Age-Specific Serum Total and Free Estradiol Concentrations in Healthy Men in US Nationally Representative Samples. J Endocr Soc. 2019;3(10):1825. doi: https://doi.org/10.1210/js.2019-00178
  49. EEST — Overview: Estradiol, Serum. Available from: https://www.mayocliniclabs.com/test-catalog/overview/81816#Clinical-and-Interpretive (accessed: 21.01.2024).
  50. Fernandez CJ, Chacko EC, Pappachan JM. Male Obesity-related Secondary Hypogonadism — Pathophysiology, Clinical Implications and Management. Eur Endocrinol. 2019;15(2):83. doi: https://doi.org/10.17925/EE.2019.15.2.83
  51. Rohrmann S, Nelson WG, Rifai N, et al. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. J Clin Endocrinol Metab. 2007;92(7):2519–2525. doi: https://doi.org/10.1210/jc.2007-0028
  52. Fiers T, Casetta B, Bernaert B, et al. Development of a highly sensitive method for the quantification of estrone and estradiol in serum by liquid chromatography tandem mass spectrometry without derivatization. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;893–894:57–62. doi: https://doi.org/10.1016/j.jchromb.2012.02.034
  53. Shackleton C. Clinical steroid mass spectrometry: a 45-year history culminating in HPLC-MS/MS becoming an essential tool for patient diagnosis. J Steroid Biochem Mol Biol. 2010;121(3–5):481–490. doi: https://doi.org/10.1016/j.jsbmb.2010.02.017
  54. Cerda-Kipper AS, Montiel BE, Hosseini S. Radioimmunoassays and Enzyme-Linked Immunosorbent Assay. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. doi: https://doi.org/10.1016/B978-0-12-409547-2.14510-X
  55. Ohlsson C, Nilsson ME, Tivesten Å, et al. Comparisons of immunoassay and mass spectrometry measurements of serum estradiol levels and their influence on clinical association studies in men. J Clin Endocrinol Metab. 2013;98(6):E1097–1102. doi: https://doi.org/10.1210/jc.2012-3861
  56. Figtree GA, Ngo DTM, Bubb KJ. Testosterone to estradiol ratio and plaque inflammation: mechanistic insights and biomarker potential? Cardiovasc Res. 2019;115(2):255–257. doi: https://doi.org/10.1093/cvr/cvy260

Supplementary files

Supplementary Files
Action
1. JATS XML
2. Fig. 1. Schematic diagram of the systematic review

Download (297KB)

Copyright (c) 2024 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies