Thromb Haemost 2024; 124(05): 387-398
DOI: 10.1055/a-2188-8898
Review Article

Venous Thromboembolism and Estrogen-Containing Gender-Affirming Hormone Therapy

1   Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia
Mollie Moloney
2   Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia
Huyen A. Tran
1   Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia
2   Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia
James D. McFadyen
1   Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia
2   Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia
3   Atherothrombosis and Vascular Biology Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
› Author Affiliations
Funding J.D.M. is supported by a Heart Foundation Future Leader Fellowship.


Gender-affirming therapy involves the use of hormones to develop the physical characteristics of the identified gender and suppressing endogenous sex hormone production. Venous thromboembolism (VTE) is a known risk of exogenous estrogen therapy, and while evidence of VTE risk among transgender women using modern gender-affirming hormone therapy (GAHT) is still emerging, it is thought to affect up to 5% of transgender women. Historically, GAHT was associated with a high risk of VTE; however, modern preparations are less thrombogenic mainly due to significantly lower doses used as well as different preparations. This review presents the available literature regarding the following four topics: (1) risk of VTE among transgender women receiving estradiol GAHT, (2) how the route of administration of estradiol affects the VTE risk, (3) perioperative management of GAHT, (4) VTE risk among adolescents on GAHT. There is a need for large, longitudinal studies of transgender women using GAHT to further characterize VTE risk and how this is affected by factors such as patient age, duration of GAHT use, tobacco use, body mass index, and comorbidities. Future studies in these areas could inform the development of clinical guidelines to improve the care of transgender people.

Authors' Contribution

M.M. performed the literature review and wrote the manuscript; C.D. performed the literature review and wrote the manuscript. J.D.M. wrote and reviewed the manuscript. H.T. wrote and reviewed the manuscript.

Publication History

Received: 14 June 2023

Accepted: 09 October 2023

Accepted Manuscript online:
10 October 2023

Article published online:
02 November 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Human Rights Campaign. Sexual orientation and gender identity definitions. Accessed April 3, 2023 at:
  • 2 World Health Organisation (WHO). Gender and health. Accessed April 3, 2023 at:
  • 3 American Psychological Association (APA). Answers to your questions about transgender people, gender identity and gender expression 2014. Accessed April 19, 2023 at:
  • 4 Connors JM, Middeldorp S. Transgender patients and the role of the coagulation clinician. J Thromb Haemost 2019; 17 (11) 1790-1797
  • 5 Goodman M, Adams N, Corneil T, Kreukels B, Motmans J, Coleman E. Size and distribution of transgender and gender nonconforming populations: a narrative review. Endocrinol Metab Clin North Am 2019; 48 (02) 303-321
  • 6 Collin L, Reisner SL, Tangpricha V, Goodman M. Prevalence of transgender depends on the “case” definition: a systematic review. J Sex Med 2016; 13 (04) 613-626
  • 7 Coleman E, Radix AE, Bouman WP. et al. Standards of care for the health of transgender and gender diverse people, Version 8. Int J Transgender Health 2022; 23 (Suppl. 01) S1-S259
  • 8 Maraka S, Singh Ospina N, Rodriguez-Gutierrez R. et al. sex steroids and cardiovascular outcomes in transgender individuals: a systematic review and meta-analysis. J Clin Endocrinol Metab 2017; 102 (11) 3914-3923
  • 9 Harrison RL, McKee PA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood 1984; 63 (03) 657-664
  • 10 Middeldorp S, Meijers JC, van den Ende AE. et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000; 84 (01) 4-8
  • 11 Cosman F, Baz-Hecht M, Cushman M. et al. Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116 (01) 1-13
  • 12 van Rooijen M, Hansson LO, Frostegård J, Silveira A, Hamsten A, Bremme K. Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response. J Thromb Haemost 2006; 4 (01) 77-82
  • 13 Rosing J, Tans G, Nicolaes GA. et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97 (01) 233-238
  • 14 Norris LA, Bonnar J. Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives. Thromb Haemost 1994; 72 (06) 926-930
  • 15 Scheres LJJ, Selier NLD, Nota NM, van Diemen JJK, Cannegieter SC, den Heijer M. Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen. J Thromb Haemost 2021; 19 (04) 1029-1037
  • 16 Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 2010; 126 (05) 373-378
  • 17 Goldstein Z, Khan M, Reisman T, Safer JD. Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy. J Blood Med 2019; 10: 209-216
  • 18 de Bastos M, Stegeman BH, Rosendaal FR. et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014; (03) CD010813
  • 19 Hembree WC, Cohen-Kettenis PT, Gooren L. et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2017; 102 (11) 3869-3903
  • 20 Gooren LJ, Giltay EJ, Bunck MC. Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. J Clin Endocrinol Metab 2008; 93 (01) 19-25
  • 21 Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G. SSC of the ISTH. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10 (04) 698-702
  • 22 Martinelli I, Lensing AW, Middeldorp S. et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016; 127 (11) 1417-1425
  • 23 Baker KE, Wilson LM, Sharma R, Dukhanin V, McArthur K, Robinson KA. Hormone therapy, mental health, and quality of life among transgender people: a systematic review. J Endocr Soc 2021; 5 (04) bvab011
  • 24 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (06) 585-593
  • 25 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
  • 26 Stegeman BH, de Bastos M, Rosendaal FR. et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013; 347: f5298
  • 27 LaVasseur C, Neukam S, Kartika T, Samuelson Bannow B, Shatzel J, DeLoughery TG. Hormonal therapies and venous thrombosis: considerations for prevention and management. Res Pract Thromb Haemost 2022; 6 (06) e12763
  • 28 Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int J Gynaecol Obstet 2018; 141 (03) 287-294
  • 29 Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019; 364: k4810
  • 30 Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89 (03) 493-498
  • 31 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118 (09) 978-980
  • 32 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323 (7305) 131-134
  • 33 Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; 2004 (04) CD002978
  • 34 Thorogood M, Villard-Mackintosh L. Combined oral contraceptives: risks and benefits. Br Med Bull 1993; 49 (01) 124-139
  • 35 Mullins ES, Geer R, Metcalf M. et al. Thrombosis risk in transgender adolescents receiving gender-affirming hormone therapy. Pediatrics 2021; 147 (04) e2020023549
  • 36 Helgason S, Damber MG, von Schoultz B, Stigbrand T. Estrogenic potency of oral replacement therapy estimated by the induction of pregnancy zone protein. Acta Obstet Gynecol Scand 1982; 61 (01) 75-79
  • 37 Totaro M, Palazzi S, Castellini C. et al. Risk of venous thromboembolism in transgender people undergoing hormone feminizing therapy: a prevalence meta-analysis and meta-regression study. Front Endocrinol (Lausanne) 2021; 12: 741866
  • 38 Khan J, Schmidt RL, Spittal MJ, Goldstein Z, Smock KJ, Greene DN. Venous thrombotic risk in transgender women undergoing estrogen therapy: a systematic review and metaanalysis. Clin Chem 2019; 65 (01) 57-66
  • 39 Haupt C, Henke M, Kutschmar A. et al. Antiandrogen or estradiol treatment or both during hormone therapy in transitioning transgender women. Cochrane Database Syst Rev 2020; 11 (11) CD013138
  • 40 Kotamarti VS, Greige N, Heiman AJ, Patel A, Ricci JA. Risk for venous thromboembolism in transgender patients undergoing cross-sex hormone treatment: a systematic review. J Sex Med 2021; 18 (07) 1280-1291
  • 41 van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47 (03) 337-342
  • 42 Asscheman H, Gooren LJ, Eklund PL. Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism 1989; 38 (09) 869-873
  • 43 Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes 2005; 113 (10) 586-592
  • 44 Arnold JD, Sarkodie EP, Coleman ME, Goldstein DA. Incidence of venous thromboembolism in transgender women receiving oral estradiol. J Sex Med 2016; 13 (11) 1773-1777
  • 45 Prior JC, Vigna YM, Watson D. Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Arch Sex Behav 1989; 18 (01) 49-57
  • 46 Ott J, Kaufmann U, Bentz EK, Huber JC, Tempfer CB. Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy. Fertil Steril 2010; 93 (04) 1267-1272
  • 47 Wierckx K, Van Caenegem E, Schreiner T. et al. Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European network for the investigation of gender incongruence. J Sex Med 2014; 11 (08) 1999-2011
  • 48 Wierckx K, Elaut E, Declercq E. 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 Endocrinol 2013; 169 (04) 471-478
  • 49 Meyer G, Mayer M, Mondorf A, Flügel AK, Herrmann E, Bojunga J. Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. Eur J Endocrinol 2020; 182 (02) 149-156
  • 50 Lim HY, Leemaqz SY, Torkamani N. et al. Global coagulation assays in transgender women on oral and transdermal estradiol therapy. J Clin Endocrinol Metab 2020; 105 (07) dgaa262
  • 51 Sobel TH, Shen W. Transdermal estrogen therapy in menopausal women at increased risk for thrombotic events: a scoping review. Menopause 2022; 29 (04) 483-490
  • 52 Spitzer WO. Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation. J Obstet Gynaecol Can 2003; 25 (12) 1011-1018
  • 53 Nightingale AL, Lawrenson RA, Simpson EL, Williams TJ, MacRae KD, Farmer RD. The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000; 5 (04) 265-274
  • 54 Wierckx K, Mueller S, Weyers S. et al. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med 2012; 9 (10) 2641-2651
  • 55 Kerrebrouck M, Vantilborgh A, Collet S, T'Sjoen G. Thrombophilia and hormonal therapy in transgender persons: a literature review and case series. Int J Transgender Health 2022; 23 (04) 377-391
  • 56 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Thromb Haemost 2005; 94 (01) 17-25
  • 57 de Moreuil C, Le Mao R, Le Moigne E. et al. Long-term recurrence risk after a first venous thromboembolism in men and women under 50 years old: a French prospective cohort. Eur J Intern Med 2021; 84: 24-31
  • 58 Getahun D, Nash R, Flanders WD. et al. Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study. Ann Intern Med 2018; 169 (04) 205-213
  • 59 Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008; 336 (7655) 1227-1231
  • 60 Hontscharuk R, Alba B, Manno C. et al. Perioperative transgender hormone management: avoiding venous thromboembolism and other complications. Plast Reconstr Surg 2021; 147 (04) 1008-1017
  • 61 Lawrence AA. Patient-reported complications and functional outcomes of male-to-female sex reassignment surgery. Arch Sex Behav 2006; 35 (06) 717-727
  • 62 Murphy Jr RX, Alderman A, Gutowski K. et al. Evidence-based practices for thromboembolism prevention: summary of the ASPS Venous Thromboembolism Task Force Report. Plast Reconstr Surg 2012; 130 (01) 168e-175e
  • 63 Boskey ER, Taghinia AH, Ganor O. Association of surgical risk with exogenous hormone use in transgender patients: a systematic review. JAMA Surg 2019; 154 (02) 159-169
  • 64 Cronin M, Dengler N, Krauss ES. et al. Completion of the updated caprini risk assessment model (2013 Version). Clin Appl Thromb Hemost 2019; 25: 1076029619838052
  • 65 Pannucci CJ, MacDonald JK, Ariyan S. et al. Benefits and risks of prophylaxis for deep venous thrombosis and pulmonary embolus in plastic surgery: a systematic review and meta-analysis of controlled trials and consensus conference. Plast Reconstr Surg 2016; 137 (02) 709-730
  • 66 Badreddine J, Lee MH, Mishra K. et al. Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2022; 26 (07) 2511-2517
  • 67 Nolan IT, Haley C, Morrison SD, Pannucci CJ, Satterwhite T. Estrogen continuation and venous thromboembolism in penile inversion vaginoplasty. J Sex Med 2021; 18 (01) 193-200
  • 68 Kozato A, Fox GWC, Yong PC. et al. No venous thromboembolism increase among transgender female patients remaining on estrogen for gender-affirming surgery. J Clin Endocrinol Metab 2021; 106 (04) e1586-e1590
  • 69 Zhang Q, Goodman M, Adams N. et al. Epidemiological considerations in transgender health: a systematic review with focus on higher quality data. Int J Transgender Health 2020; 21 (02) 125-137
  • 70 Schlatterer K, Yassouridis A, von Werder K, Poland D, Kemper J, Stalla GK. A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients. Arch Sex Behav 1998; 27 (05) 475-492
  • 71 Abou-Ismail MY, Citla Sridhar D, Nayak L. Estrogen and thrombosis: a bench to bedside review. Thromb Res 2020; 192: 40-51