Sex Differences in Sex Hormones, Carotid Atherosclerosis, and Stroke

HomeCirculation ResearchVol. 122, No. 1Sex Differences in Sex Hormones, Carotid Atherosclerosis, and Stroke Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessEditorialPDF/EPUBSex Differences in Sex Hormones, Carotid Atherosclerosis, and Stroke Kathryn Rexrode Kathryn RexrodeKathryn Rexrode From the Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, Boston, MA. Search for more papers by this author Originally published5 Jan 2018https://doi.org/10.1161/CIRCRESAHA.117.312336Circulation Research. 2018;122:17–19There are notable sex differences in cardiovascular disease. Although the cumulative incidence of cardiovascular disease in women lags behind that of men by ≈7 to 10 years, strokes comprise a larger proportion of cardiovascular events in women than in men.1 In terms of clinical impact, aspirin used for primary prevention is associated with a significance reduction in stroke women but not myocardial infarction in men.2 Differences in endogenous sex hormones have been hypothesized to underlie these substantial sex differences, but clinical data are limited on the relationship between endogenous levels and cardiovascular disease occurrence.Article, see p 97In this issue, Glisic et al3 examine the relationship of endogenous sex hormone levels and carotid plaque composition, as well as incident stroke, in >2100 older men and women in the Rotterdam Study. Notably, presence of carotid atherosclerosis (carotid intimal–medial thickness of >2.0 mm on carotid screening) was more common among men than women in the study. Among those with established atherosclerosis, the prevalence of calcified plaques was similar in men and women, whereas women were less likely to have a lipid core (36.9% of women; 49.5% of men) and less likely to have intraplaque hemorrhage than men (29.0% of women; 40.0% of men).Endogenous hormones, specifically estradiol and testosterone, were correlated with carotid plaque composition. Higher estradiol levels were associated with increased odds of a lipid core in carotid plaque in both men and women. Women with detectable estradiol levels had a 58% increased odds of having intraplaque hemorrhage compared with women with low estradiol, whereas higher total testosterone levels were associated with decreased odds. No relationship was observed for total testosterone and carotid plaque composition features in men.3Endogenous hormones were also related to incident stroke in women. Among women with carotid plaque, those with detectable total estradiol levels had a nearly 2-fold increased risk of stroke during a median follow-up of 10 years. However, when women without evidence of carotid atherosclerosis at baseline were examined, the association was substantially attenuated; those with detectable estradiol had a nonsignificant 29% increased odds of stroke. No association between total estradiol and risk of stroke was noted in men, and no associations were observed for total testosterone with incident stroke in either men or women.3 Notable strengths of the study include a well-characterized, cohort-based, population study; use of magnetic resonance imaging for analysis of carotid plaque composition; and exclusion of exogenous hormone therapy users. Although testosterone levels were measured via chromatography–tandem mass spectroscopy, the gold standard, estradiol was measured by immunoassay, which has particularly low sensitivity in postmenopausal women and prevented the investigators from examining estradiol as a continuous variable in women. Additionally, relatively few incident stroke events were observed within sex strata.Detailed examination of sex hormones and cardiovascular disease may shed light on sex differences. Postmenopausal women have markedly lower estradiol and testosterone levels than men of roughly the same age.3,4 After the cessation of estrogen production by the ovaries, estrogen biosynthesis takes place in peripheral tissues, especially adipose, through aromatase conversion of androgens in postmenopausal women. Although absolute levels of both estradiol and testosterone are lower in postmenopausal women than men, the estradiol to testosterone ratio is >6-fold higher in women than in men.There are relatively few prospective studies of endogenous sex hormones and stroke in women. No association between estradiol levels and risk of cardiovascular disease, including stroke, was found in the Women’s Health Study.5 In the Copenhagen City Heart Study, there was no association between estradiol or testosterone levels and incidence ischemic stroke in women during almost 30-year follow-up and >500 events.4 Lee et al found that higher free estradiol index, but not estradiol, was associated with increased risk of stroke in older women, but this was not independent of standard cardiovascular risk factors.6 Higher estradiol levels were associated with a nonsignificant 34% increase in stroke among women aged >65 years in the Three City Cohort Study.7 In a meta-analysis of the prior 3 studies of stroke in women without evidence of pre-existing cardiovascular disease,4,6,7 being in the highest 10th percentile of estradiol levels was associated with a nonsignificant increased risk of ischemic stroke (hazard ratio, 1.15; 95% confidence interval, 0.91–1.45).4 In addition to the association with atherosclerotic features, higher endogenous estrogens may also contributed to thrombotic risk through association with lower levels of the natural anticoagulant protein S antigen.8 Glisic et al3 add to this body of evidence by showing that higher estradiol levels are associated with high-risk carotid plaque features, as well as a 2-fold increased risk of stroke in women with established carotid atherosclerosis.Testosterone levels have been related to carotid atherosclerosis but not stroke in women. Two cross-sectional population-based studies have shown lower prevalence of carotid atherosclerosis in postmenopausal women with higher testosterone levels.9,10 In the present study, higher testosterone levels were associated with reduced odds of intraplaque hemorrhage in women, but no association was noted for incident stroke.3 Similarly, in a meta-analysis of the 2 prior studies of testosterone levels and risk of ischemic stroke, no association between testosterone levels and stroke in women was observed.4The timing hypothesis postulates differential effect and risk associated with estrogen exposure in women based on underlying subclinical atherosclerosis or time since menopause. The work by Glisic et al3 further strengthens these biological underpinnings, finding a nearly 2-fold increased risk of stroke for detectable estradiol levels among women with established carotid atherosclerosis, but a weaker, nonsignificant association for women without. This is consistent with biological studies showing that exogenous estrogen treatment in apolipoprotein E–deficient mice inhibited the development of early atherosclerosis including initiation of fatty plaques but did not inhibit intraplaque hemorrhage or progression of established lesions.11 Time since menopause having a differential impact based on cardiovascular disease is generally less supported for stroke than for coronary heart disease. For exogenous estrogen use, Grodstein et al12 found no evidence of differences in the increased risk of stroke associated with postmenopausal hormone therapy based on time since menopause or age at initiation. Similarly, in the Women’s Health Initiative, initiation of hormone therapy within 10 years of menopause was associated with a 77% significantly increased risk of stroke, even though a reduced risk of coronary heart disease was observed in this group.13In men, testosterone levels decrease with age, and lower testosterone levels have been associated with several cardiovascular risk factors.14 However, in cross-sectional analyses in the Atherosclerosis Risk in Communities Study, plasma testosterone levels were not associated with mean carotid intimal–medial thickness in men,14 consistent with the lack of association for testosterone and carotid plaque features in the current study.3 In contrast, several studies have observed an inverse relationship between testosterone levels and stroke in men. Among men aged ≥70 years, higher testosterone levels were associated with reduced risk of stroke.15 In the Copenhagen City Heart Study, low testosterone levels were associated with a 34% increased risk of ischemic stroke, which seemed to be partially mediated by obesity and hypertension.4 In a meta-analysis of 4 studies examining sex hormones and ischemic stroke in men,4 lower testosterone levels (<10th percentile) were associated with increased risk of ischemic stroke (hazard ratio, 1.43; 95% confidence interval, 1.21–1.70), whereas no association was observed for estradiol levels.3 In the current study, in contrast, no association of testosterone levels with incident stroke was observed for men with or without established carotid atherosclerosis.3 Further research is needed to evaluate whether low testosterone levels are a risk marker or a true effector of risk.Sex differences in the association of endogenous hormones and carotid atherosclerosis and stroke may not be surprising, but further research is needed to understand how hormones differentially affect men and women. What are the intermediate biological mechanisms? How might risk be effectively reduced? How are endogenous hormones related to platelet function and thrombotic tendency? Further studies examining whether higher estradiol levels at baseline lead to changes in carotid plaque composition over time would add to our biological understanding. Moreover, the increased risk of stroke among women higher with established carotid atherosclerosis and higher estradiol levels, but not among those without carotid atherosclerosis, adds to the hypothesis that higher estrogen levels may have a role in preventing atherosclerosis but may aggravate progression among those with established disease, at least in women. There has been a paucity of studies of endogenous hormones and cardiovascular disease, particularly in women. A better understanding of how sex hormones influence the progression of atherosclerosis in men and women will advance our biological understanding and lead to better preventive strategies of both sexes.AcknowledgmentsDr Rexrode is supported by HL088521 and other grants from the National Institutes of Health.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Kathryn Rexrode, MD, MPH, Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, OBC3, Boston, MA 02115. E-mail [email protected]References1. Leening MJ, Ferket BS, Steyerberg EW, Kavousi M, Deckers JW, Nieboer D, Heeringa J, Portegies ML, Hofman A, Ikram MA, Hunink MG, Franco OH, Stricker BH, Witteman JC, Roos-Hesselink JW. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study.BMJ. 2014; 349:g5992.CrossrefMedlineGoogle Scholar2. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.JAMA. 2006; 295:306–313. doi: 10.1001/jama.295.3.306.CrossrefMedlineGoogle Scholar3. Glisic M, Mujaj B, Rueda-Ochoa OL, Asllanaj E, Laven JSE, Kavousi M, Ikram MK, Vernooij MW, Ikram MA, Franco OH, Bos D, Muka T. Associations of endogenous estradiol and testosterone levels with plaque composition and risk of stroke in subjects with carotid atherosclerosis.Circ Res. 2018; 122:97–105. doi: 10.1161/CIRCRESAHA.117.311681.LinkGoogle Scholar4. Holmegard HN, Nordestgaard BG, Jensen GB, Tybjærg-Hansen A, Benn M. 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Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297:1465–1477. doi: 10.1001/jama.297.13.1465.CrossrefMedlineGoogle Scholar14. Srinath R, Hill Golden S, Carson KA, Dobs A. Endogenous testosterone and its relationship to preclinical and clinical measures of cardiovascular disease in the atherosclerosis risk in communities study.J Clin Endocrinol Metab. 2015; 100:1602–1608. doi: 10.1210/jc.2014-3934.CrossrefMedlineGoogle Scholar15. Yeap BB, Alfonso H, Chubb SA, Hankey GJ, Handelsman DJ, Golledge J, Almeida OP, Flicker L, Norman PE. 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; 99:4565–4573. doi: 10.1210/jc.2014-2664.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Garg K, Patel T, Kanwal A, Villines T, Aggarwal N, Nasir K, Blumenthal R, Blaha M, Douglas P, Shaw L and Sharma G (2022) The evolving role of coronary computed tomography in understanding sex differences in coronary atherosclerosis, Journal of Cardiovascular Computed Tomography, 10.1016/j.jcct.2021.09.004, 16:2, (138-149), Online publication date: 1-Mar-2022. Krishnamurthy Y and Bhatt A (2021) Congenital Heart Disease Sex Differences in Cardiac Diseases, 10.1016/B978-0-12-819369-3.00006-X, (383-399), . 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Fan L, Yang Q, Zhang X, Lin Q, Guo D, Liu J, Tu J, Wang J, Li Y and Ning X (2021) Sex -Specific Differences in the Association Between Metabolic Syndrome and Carotid Intima-Media Thickness Among a Low-Income Population in China: A Cross-Sectional Study, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 10.2147/DMSO.S313702, Volume 14, (3263-3272) Lucà F, Abrignani M, Parrini I, Di Fusco S, Giubilato S, Rao C, Piccioni L, Cipolletta L, Passaretti B, Giallauria F, Leone A, Francese G, Riccio C, Gelsomino S, Colivicchi F and Gulizia M (2022) Update on Management of Cardiovascular Diseases in Women, Journal of Clinical Medicine, 10.3390/jcm11051176, 11:5, (1176) Huang D, Wang X, Zhu Y, Gong J, Liang J, Song Y, Zhang Y, Liu L and Wei C (2021) Bazi Bushen Capsule Alleviates Post-Menopausal Atherosclerosis via GPER1-Dependent Anti-Inflammatory and Anti-Apoptotic Effects, Frontiers in Pharmacology, 10.3389/fphar.2021.658998, 12 January 5, 2018Vol 122, Issue 1 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.312336PMID: 29301839 Originally publishedJanuary 5, 2018 KeywordsestradiolstrokeEditorialsatherosclerosistestosteronePDF download Advertisement SubjectsBiomarkersMagnetic Resonance Imaging (MRI)UltrasoundWomen, Sex, and Gender