Epidemiological studies of transgender women suggest that these individuals experience higher rates of venous thromboembolism than their cisgender peers. Several factors likely increase this risk, including medication use, comorbidities, and social determinants of health. Estrogen-based gender-affirming hormone therapy is critical for helping patients address unwanted secondary sexual characteristics and induce physical changes in accordance with their gender identity. However, the use of estrogen-based gender-affirming hormone therapy may increase the risk of venous thromboembolism. This review article summarizes the current evidence describing venous thromboembolism risk among patients using various forms of estrogen, including transgender and cisgender individuals. The article also discusses strategies for managing venous thromboembolism in patients using estrogen-based gender-affirming hormone therapy and methods to reduce venous thromboembolism risk.
Health Care for Transgender and Gender Diverse Individuals: ACOG Committee Opinion, Number 823. Obstet Gynecol2021; 137: e75–e88.
5.
HembreeWCCohen-KettenisPTGoorenL, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab2017; 102: 3869–3903.
CaceresBAStreedCGCorlissHL, et al. Assessing and addressing cardiovascular health in LGBTQ adults: A Scientific Statement from the American Heart Association. Circulation2020; 142: e321–e332.
10.
StreedCGHarfouchOMarvelF, et al. Cardiovascular disease among transgender adults receiving hormone therapy: A narrative review. Ann Intern Med2017; 167: 256–267.
11.
ErlangsenAJacobsenALRanningA, et al. Transgender identity and suicide attempts and mortality in Denmark. JAMA2023; 329: 2145–2153.
12.
CaceresBABrodyALuscombeRE, et al. A systematic review of cardiovascular disease in sexual minorities. Am J Public Health2017; 107: e13–e21.
13.
CaceresBAJackmanKBEdmondsonD, et al. Assessing gender identity differences in cardiovascular disease in US adults: An analysis of data from the 2014–2017 BRFSS. J Behav Med2020; 43: 329–338.
14.
DenbyKJChoLToljanK, et al. Assessment of cardiovascular risk in transgender patients presenting for gender-affirming care. Am J Med2021; 134: 1002–1008.
15.
ColemanERadixAEBoumanWP, et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgend Health2022; 23: S1–S259.
16.
ArnoldJDSarkodieEPColemanME, et al. Incidence of venous thromboembolism in transgender women receiving oral estradiol. J Sex Med2016; 13: 1773–1777.
17.
PriceTMBlauerKLHansenM, et al. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol. Obstet Gynecol1997; 89: 340–345.
18.
HeidenreichPABozkurtBAguilarD, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation2022; 145: e895–e1032.
19.
WheltonPCareyRAronowW, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension2018; 71: e13–e115.
Abou-IsmailMYCitla SridharDNayakL.Estrogen and thrombosis: A bench to bedside review. Thromb Res2020; 192: 40–51.
22.
PostMThomassenCvan der MoorenM, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis. Arterioscler Thromb Vasc Biol2003; 23: 1116–1121.
23.
OgerEAlhenec-GelasMLacutK, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women. Arterioscler Thromb Vasc Biol2003; 23: 1671–1676.
24.
GoldsteinZKhanMReismanT, et al. Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy. J Blood Med2019; 10: 209–216.
25.
KopperNWGudemanJThompsonDJ.Transdermal hormone therapy in postmenopausal women: A review of metabolic effects and drug delivery technologies. Drug Des Devel Ther2009; 2: 193–202.
26.
DollEGunsolusIThorgersonA, et al. Pharmacokinetics of sublingual versus oral estradiol in transgender women. Endocr Pract2022; 28: 237–242.
27.
CanonicoMPlu-BureauGLoweGDO, et al. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: Systematic review and meta-analysis. BMJ2008; 336: 1227–1231.
28.
MohammedKAbu DabrhAMBenkhadraK, et al. Oral vs transdermal estrogen therapy and vascular events: A systematic review and meta-analysis. J Clin Endocrinol Metab2015; 100: 4012–4020.
29.
OttJKaufmannUBentzE-K, et al. Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy. Fertil Steril2010; 93: 1267–1272.
30.
CrandallCJHoveyKMAndrewsCA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause2018; 25: 11–20.
31.
MansonJEHsiaJJohnsonKC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med2003; 349: 523–534.
32.
RenouxCDell’AnielloSSuissaS.Hormone replacement therapy and the risk of venous thromboembolism: A population-based study. J Thromb Haemost2010; 8: 979–986.
33.
BoardmanHMHartleyLEisingaA, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev2015; 2015: CD002229.
34.
NelsonHDWalkerMZakherB, et al. Menopausal hormone therapy for the primary prevention of chronic conditions: A systematic review to update the U.S. Preventive Services Task Force recommendations. Ann Intern Med2012; 157: 104–113.
35.
DefreyneJVan De BruaeneLDLRietzschelE, et al. Effects of gender-affirming hormones on lipid, metabolic, and cardiac surrogate blood markers in transgender persons. Clin Chem2019; 65: 119–134.
36.
HulleySFurbergCBarrett-ConnorE, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA2002; 288: 58–66.
37.
CushmanMKullerLHPrenticeR, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA2004; 292: 1573–1580.
38.
MillerJChanBKSNelsonHD.Postmenopausal estrogen replacement and risk for venous thromboembolism: A systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med2002; 136: 680–690.
39.
AndersonGLLimacherMAssafAR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. ACC Curr J Rev2004; 13: 19.
40.
AsschemanHGoorenLJGEklundPLE. Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism1989; 38: 869–873.
41.
Van KesterenPJMAsschemanHMegensJAJ, et al. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf)1997; 47: 337–342.
42.
SealLJFranklinSRichardsC, et al. Predictive markers for mammoplasty and a comparison of side effect profiles in transwomen taking various hormonal regimens. J Clin Endocrinol Metab2012; 97: 4422–4428.
43.
WierckxKMuellerSWeyersS, et al. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med2012; 9: 2641–2651.
44.
WierckxKElautEDeclercqE, et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: A case–control study. Eur J Endocrinol2013; 169: 471–478.
45.
TotaroMPalazziSCastelliniC, et al. Risk of venous thromboembolism in transgender people undergoing hormone feminizing therapy: A prevalence meta-analysis and meta-regression study. Front Endocrinol2021; 12: 741866.
46.
GetahunDNashRFlandersWD, et al. Cross-sex hormones and acute cardiovascular events in transgender persons. Ann Intern Med2018; 169: 205–213.
47.
BeckmanMGHooperWCCritchleySE, et al. Venous thromboembolism. Am J Prev Med2010; 38: S495–S501.
48.
BenjaminEBlahaMChiuveS, et al. Heart disease and stroke statistics—2017 Update: A report from the American Heart Association. Circulation2017; 135: e146–e603.
49.
GoldhaberSZ.Risk factors for venous thromboembolism. J Am Coll Cardiol2010; 56: 1–7.
SerhalMBarnesGD.Venous thromboembolism: A clinician update. Vasc Med2019; 24: 122–131.
52.
Crous-BouMHarringtonLKabrhelC.Environmental and genetic risk factors associated with venous thromboembolism. Semin Thromb Hemost2016; 42: 808–820.
53.
StreedCGBeachLBCaceresBA, et al. Assessing and addressing cardiovascular health in people who are transgender and gender diverse: A scientific statement from the American Heart Association. Circulation2021; 144: e136–e148.
54.
ConnorsJMMiddeldorpS.Transgender patients and the role of the coagulation clinician. J Thromb Haemost2019; 17: 1790–1797.
55.
ShatzelJJConnellyKJDeLougheryTG.Thrombotic issues in transgender medicine: A review. Am J Hematol2017; 92: 204–208.
56.
BouckEGGrinsztejnEMcnamaraM, et al. Thromboembolic risk with gender-affirming hormone therapy: Potential role of global coagulation and fibrinolysis assays. Res Pract Thromb Haemost2023; 7: 102197.
57.
SpyropoulosACAndersonFAFitzGeraldG, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest2011; 140: 706–714.
BarbarSNoventaFRossettoV, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: The Padua Prediction Score. J Thromb Haemost2010; 8: 2450–2457.
60.
PandorATonkinsMGoodacreS, et al. Risk assessment models for venous thromboembolism in hospitalised adult patients: A systematic review. BMJ Open2021; 11: e045672.
61.
Arrington-SandersRConnellNTCoonD, et al. Assessing and addressing the risk of venous thromboembolism across the spectrum of gender affirming care: A review. Endocr Pract2023; 29: 272–278.
62.
AsschemanHT’SjoenGLemaireA, et al. Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: A review. Andrologia2014; 46: 791–795.
63.
LaVasseurCNeukamSKartikaT, et al. Hormonal therapies and venous thrombosis: Considerations for prevention and management. Res Pract Thromb Haemost2022; 6: e12763.
64.
ShiffmanMA.Estrogen and thromboembolic disorders: Should patients stop hormones prior to cosmetic surgery?J Womens Health (Larchmt)2003; 12: 853–855.
65.
CastanheiraLFrescoPMacedoAF.Guidelines for the management of chronic medication in the perioperative period: Systematic review and formal consensus. J Clin Pharm Ther2011; 36: 446–467.
66.
HerndonJGuptaNDavidge-PittsC, et al. Genital surgery outcomes using an individualized algorithm for hormone management in transfeminine individuals. J Clin Endocrinol Metab2024; 109: 2774–2783.
67.
KozatoAFoxGWCYongPC, et al. No venous thromboembolism increase among transgender female patients remaining on estrogen for gender-affirming surgery. J Clin Endocrinol Metab2021; 106: 1586–1590.
68.
ChanWDrummondAKellyM.Deep vein thrombosis in a transgender woman. Can Med Assoc J2017; 189: E502–E504.
69.
OrtelTLNeumannIAgenoW, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv2020; 4: 4693–4738.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
