Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI)

Published:March 18, 2021DOI:



      Cardiovascular (CV) implications of long-term gender affirming hormonal treatment (GAHT) in transgender individuals still remain largely unknown.


      To evaluate changes in the 30-year Framingham cardiovascular disease (CVD) risk in a large cohort of transgender individuals after the start of GAHT.


      In a multicenter prospective study, a consecutive series of 309 participants (165 transmen and 144 transwomen) was evaluated during a 2-year follow-up. Prospectively, after the start of GAHT a physical examination was performed and blood samples were drawn. CVD risk was calculated for each person, according to the Framingham 30-year CVD risk estimate.

      Main Outcome Measure

      Changes in CV risk factors and 30-year Framingham CVD risk during GAHT.

      Clinical Implications

      In transmen testosterone-induced lipid profile alterations may have a clinical relevance on the individual long-term CVD risk.

      Strengths & Limitations

      The strength of the present study is the possibility to predict long-term CV outcomes in transgender individuals receiving GAHT based on a short observation; whereas the main limitation is that CVD risk prospective changes mainly represent the expression of risk factors changes during GAHT.


      In transwomen a significant decrease in triglycerides, total cholesterol and LDL-cholesterol was observed during the 2-year follow-up (P < .05), whereas unfavorable lipid changes – such as increased total cholesterol, triglycerides, and LDL cholesterol levels and decreased HDL cholesterol levels (P < .05)- occurred after the start of GAHT in transmen. These changes in risk factors led to an increase in the risk of general and hard CVD events based on lipid profile over time in transmen (P = .001 and P = .005, respectively). No significant changes in general and hard CVD risk based on lipid profile were observed in transwomen over time.


      Our findings confirmed the unfavorable lipid changes in transmen after the start of GAHT even during a longer follow-up, empathizing the potential clinical impact of these modifications on individual long-term CVD risk.
      Cocchetti C, Castellini G, Iacuaniello D, et al. Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI). J Sex Med 2021;18:821–829.

      Key Words

      To read this article in full you will need to make a payment
      ISSM Member Login
      Login with your ISSM username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pekka Jousilahti
        • Erkki Vartiainen
        • Jaakko Tuomilehto
        • et al.
        Sex, age, cardiovascular risk factors, and coronary heart disease.
        Circulation. 1999; 99: 1165-1172
        • Leening MJG
        • Ferket BS
        • Steyerberg EW
        • et al.
        Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study.
        BMJ. 2014; 349: g5992
        • Mueller A
        • Haeberle L
        • Zollver H
        • et al.
        Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals.
        J Sex Med. 2010; 7: 3190-3198
        • Klaver M
        • De Blok CJM
        • Wiepjes CM
        • et al.
        Changes in regional body fat, lean body mass and body shape in trans persons using cross-sex hormonal therapy: results from a multicenter prospective study.
        Eur J Endocrinol. 2018; 178: 163-171
        • van Velzen DM
        • Paldino A
        • Klaver M
        • et al.
        Cardiometabolic effects of testosterone in transmen and estrogen plus cyproterone acetate in transwomen.
        J Clin Endocrinol Metab. 2019; 104: 1937-1947
        • Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women
        The postmenopausal estrogen/progestin interventions (PEPI) trial. The writing roup for the PEPI trial.
        JAMA. 1995; 273: 199-208
        • Godsland IF
        Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000.
        Fertil Steril. 2001; 75: 898-915
        • dos Santos RL
        • da Silva FB
        • Ribeiro RF
        • et al.
        Sex hormones in the cardiovascular system.
        Horm Mol Biol Clin Invest. 2014; 18: 89-103
        • English Katherine M
        • Steeds Richard P
        • Jones T
        • et al.
        Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina.
        Circulation. 2000; 102: 1906-1911
        • Zhang K-S
        • Zhao M-J
        • An Q
        • et al.
        Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2 DM: a meta-analysis of randomized controlled trials.
        Andrology. 2018; 6: 37-46
        • Finkle WD
        • Greenland S
        • Ridgeway GK
        • et al.
        Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
        PLoS One. 2014; 9: e85805
        • Grodstein F
        • Stampfer MJ
        • Manson JE
        • et al.
        Postmenopausal estrogen and progestin use and the risk of cardiovascular disease.
        N Engl J Med. 1996; 335: 453-461
        • Bush TL
        • Cowan LD
        • Barrett-Connor E
        • et al.
        Estrogen use and all-cause mortality. Preliminary results from the lipid research clinics program follow-up study.
        JAMA. 1983; 249: 903-906
        • Rossouw JE
        • Anderson GL
        • Prentice RL
        • et al.
        Writing group for the women's health initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Corona G
        • Rastrelli G
        • Di Pasquale G
        • et al.
        Testosterone and cardiovascular risk: Meta-analysis of interventional studies.
        J Sex Med. 2018; 15: 820-838
        • Streed CG
        • Harfouch O
        • Marvel F
        • et al.
        Cardiovascular disease among transgender adults receiving hormone therapy: a narrative review.
        Ann Intern Med. 2017; 167: 256-267
        • Gooren LJ
        • Wierckx K
        • Giltay EJ
        Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern.
        Eur J Endocrinol. 2014; 170: 809-819
        • 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: 471-478
        • Giltay EJ
        • Toorians A
        • Sarabdjitsingh AR
        • et al.
        Established risk factors for coronary heart disease are unrelated to androgen-induced baldness in female-to-male transsexuals.
        J Endocrinol. 2004; 180: 107-112
        • Elamin MB
        • Garcia MZ
        • Murad MH
        • et al.
        Effect of sex steroid use on cardiovascular risk in transsexual individuals: a systematic review and meta-analyses.
        Clin Endocrinol (Oxf). 2010; 72: 1-10
        • Chandra P
        • Basra SS
        • Chen TC
        • et al.
        Alterations in lipids and adipocyte hormones in female-to-male transsexuals.
        Int J Endocrinol. 2010; 2010: 945053
        • 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: 3914-3923
        • 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: 205-213
        • Nota NM
        • Wiepjes CM
        • De Block CJM
        • et al.
        Occurrence of acute cardiovascular events in transgender individuals receiving hormone therapy.
        Circulation. 2019; 139: 1461-1462
        • Dekker MJHJ
        • Wierckx K
        • Van Caenegem E
        • et al.
        A European network for the investigation of gender incongruence: endocrine part.
        J Sex Med. 2016; 13: 994-999
        • Kreukels BPC
        • Haraldsen IR
        • De Cuypere G
        • et al.
        A European network for the investigation of gender incongruence: the ENIGI initiative.
        Eur Psychiatry. 2012; 27: 445-450
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th Edition. American Psychiatric Association, Washington, DC2013 (DSM-5)
        • 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: 3869-3903
        • Friedewald WT
        • Levy RI
        • Fredrickson DS
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Pencina MJ
        • D'Agostino Sr, RB
        • Larson MG
        • et al.
        Predicting the thirty-year risk of cardiovascular disease: the Framingham Heart Study.
        Circulation. 2009; 119: 3078
        • Velho I
        • Fighera TM
        • Ziegelmann PK
        • et al.
        Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review.
        Andrology. 2017; 5: 881-888
        • Ott J
        • Aust S
        • Promberger R
        • et al.
        Cross-sex hormone therapy alters the serum lipid profile: a retrospective cohort study in 169 transsexuals.
        J Sex Med. 2011; 8: 2361-2369
        • Damewood MD
        • Bellantoni JJ
        • Bachorik PS
        • et al.
        Exogenous estrogen effect on lipid/lipoprotein cholesterol in transsexual males.
        J Endocrinol Invest. 1989; 12: 449-454
        • Jones BA
        • Haycraft E
        • Bouman WP
        • et al.
        The levels and predictors of physical activity engagement within the treatment-seeking transgender population: a matched control study.
        J Phys Activity Health. 2018; 15: 99-107
        • Sidhwani S
        • Scoccia B
        • Sunghay S
        • et al.
        Polycystic ovary syndrome is associated with atherogenic changes in lipoprotein particle number and size independent of body weight.
        Clin Endocrinol (Oxf). 2011; 75: 76-82
        • Shadid S
        • Abosi-Appeadu K
        • De Maertelaere A-S
        • et al.
        Effects of gender-affirming hormone therapy on insulin sensitivity and Incretin responses in transgender people.
        Diabetes Care. 2020; 43: 411-417
        • Lee JJ
        • Pedley A
        • Hoffmann U
        • et al.
        Association of changes in abdominal fat quantity and quality with incident cardiovascular disease risk factors.
        J Am Coll Cardiol. 2016; 68: 1509-1521
        • Langer C
        • Gansz B
        • Goepfert C
        • et al.
        Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages.
        Biochem Biophys Res Commun. 2002; 296: 1051-1057
        • Haffner SM
        • Kushwaha RS
        • Foster DM
        • et al.
        Studies on the metabolic mechanism of reduced high density lipoproteins during anabolic steroid therapy.
        Metab Clin Exp. 1983; 32: 413-420
        • Walsh BW
        • Schiff I
        • Rosner B
        • et al.
        Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins.
        N Engl J Med. 1991; 325: 1196-1204
        • Wolfe BM
        • Huff MW
        Effects of low dosage progestin-only administration upon plasma triglycerides and lipoprotein metabolism in postmenopausal women.
        J Clin Invest. 1993; 92: 456-461
        • Vita R
        • Settineri S
        • Liotta M
        • et al.
        Changes in hormonal and metabolic parameters in transgender subjects on cross-sex hormone therapy: a cohort study.
        Maturitas. 2018; 107: 92-96
        • Fernandez JD
        • Tannock LR
        Metabolic effects of hormone therapy in transgender patients.
        Endocr Pract. 2016; 22: 383-388
        • Suppakitjanusant P
        • Ji Y
        • Stevenson MO
        • et al.
        Effects of gender affirming hormone therapy on body mass index in transgender individuals: a longitudinal cohort study.
        J Clin Transl Endocrinol. 2020; 21100230
        • Fisher AD
        • Castellini G
        • Ristori J
        • et al.
        Cross-sex hormone treatment and psychobiological changes in transsexual persons: two-year follow-up data.
        J Clin Endocrinol Metab. 2016; 101: 4260-4269
        • Defreyne J
        • Van de Bruaene LDL
        • Rietzschel E
        • et al.
        Effects of gender-affirming hormones on lipid, metabolic, and cardiac surrogate blood markers in transgender persons.
        Clin Chem. 2019; 65: 119-134
        • Van Kesteren PJ
        • Asscheman H
        • Megens JA
        • et al.
        Mortality and morbidity in transsexual subjects treated with cross-sex hormones.
        Clin Endocrinol (Oxf). 1997; 47: 337-342