Masculinising testosterone treatment and effects on preclinical cardiovascular disease, muscle strength and power, aggression, physical fitness and respiratory function in transgender men: protocol for a 10-year, prospective, observational cohort study in Denmark at the Body Identity Clinic (BIC)

Louise Lehmann Christensen, Dorte Glintborg, Tine Taulbjerg Kristensen, Axel Diederichsen, Guy T'Sjoen, Jan Frystyk, Marianne Skovsager Andersen, Louise Lehmann Christensen, Dorte Glintborg, Tine Taulbjerg Kristensen, Axel Diederichsen, Guy T'Sjoen, Jan Frystyk, Marianne Skovsager Andersen

Abstract

Introduction: The number of individuals with gender dysphoria seeking gender-affirming treatment is increasing. The short-term and long-term effects of masculinising treatment with testosterone are debated as serum testosterone increases up to 20-fold compared with cisgender women. We will investigate short-term and long-term effects of masculinising testosterone treatment on preclinical and clinical coronary disease, muscle strength and power, oxygen consumption (VO2) max, cardiac and respiratory function and quality of life including aggression in transgender men.

Methods and analyses: Prospective, single-centre, observational cohort study at the Body Identity Clinic (BIC), Odense University Hospital, Denmark. Investigations are performed at inclusion and following 1, 3, 5 and 10 years of testosterone therapy. Non-calcified coronary plaque volume and calcium score are estimated by coronary CT angiography. CT is only performed at inclusion and following 1 and 10 years. Upper body muscle strength and power are measured by a 'low row' weight stack resisted exercise machine. Evaluation of aggression and quality of life is assessed by questionnaires, VO2 max is estimated by maximal testing on bike ergometer, and cardiac and respiratory functions are measured by echocardiography and spirometry, respectively. Markers of cardiovascular risk and inflammation and also cortisol and cortisone are assessed in blood, diurnal urine and/or hair samples. Our cohort (BIC), including dropouts, will be an embedded subcohort in a future national registry study in all individuals with gender dysphoria and controls. Data are available on International Statistical Classification of Diseases and Related Health Problems 10th version diagnostic codes, prescriptions, socioeconomics and causes of death.

Ethics and dissemination: The Regional Committee on Health Research Ethics for Southern Denmark (S-20190108) and the Danish Data Protection Agency (19/27572) approved the study. Signed informed consent will be obtained from all participants. All findings will be published in peer-reviewed journals or at scientific conferences.

Trial registration number: NCT04254354.

Keywords: coronary heart disease; general endocrinology; sex steroids & HRT.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study outline.
Figure 2
Figure 2
The figure displays a coronary CT angiography. A semiautomatic programme detects non-calcified coronary plaque. LAD, left anterior descending artery; LCX, left circumflex artery; LMCA, left maincoronary artery; OM, obtuse marginal branch 1; RCA, right coronary artery.

References

    1. Kuyper L, Wijsen C. Gender identities and gender dysphoria in the Netherlands. Arch Sex Behav 2014;43:377–85. 10.1007/s10508-013-0140-y
    1. Van Caenegem E, Wierckx K, Elaut E, et al. . Prevalence of gender Nonconformity in Flanders, Belgium. Arch Sex Behav 2015;44:1281–7. 10.1007/s10508-014-0452-6
    1. Frederiksen L, Højlund K, Hougaard DM, et al. . Testosterone therapy decreases subcutaneous fat and adiponectin in aging men. Eur J Endocrinol 2012;166:469–76. 10.1530/EJE-11-0565
    1. Magnussen LV, Andersen PE, Diaz A, et al. . MR spectroscopy of hepatic fat and adiponectin and leptin levels during testosterone therapy in type 2 diabetes: a randomized, double-blinded, placebo-controlled trial. Eur J Endocrinol 2017;177:157–68. 10.1530/EJE-17-0071
    1. Magnussen LV, Hvid LG, Hermann AP, et al. . Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial. Andrology 2017;5:946–53. 10.1111/andr.12396
    1. Nielsen TL, Hagen C, Wraae K, et al. . Visceral and subcutaneous adipose tissue assessed by magnetic resonance imaging in relation to circulating androgens, sex hormone-binding globulin, and luteinizing hormone in young men. J Clin Endocrinol Metab 2007;92:2696–705. 10.1210/jc.2006-1847
    1. Rubin JB, Borden WB. Coronary heart disease in young adults. Curr Atheroscler Rep 2012;14:140–9. 10.1007/s11883-012-0226-3
    1. Otaki Y, Gransar H, Cheng VY, et al. . Gender differences in the prevalence, severity, and composition of coronary artery disease in the young: a study of 1635 individuals undergoing coronary CT angiography from the prospective, multinational confirm registry. Eur Heart J Cardiovasc Imaging 2015;16:490–9. 10.1093/ehjci/jeu281
    1. Dey D, Gaur S, Ovrehus KA, et al. . Integrated prediction of lesion-specific ischaemia from quantitative coronary CT angiography using machine learning: a multicentre study. Eur Radiol 2018;28:2655–64. 10.1007/s00330-017-5223-z
    1. Snyder PJ, Bhasin S, Cunningham GR, et al. . Lessons from the testosterone trials. Endocr Rev 2018;39:369–86. 10.1210/er.2017-00234
    1. Shaikh K, Ellenberg SS, Nakanishi R, et al. . Biomarkers and noncalcified coronary artery plaque progression in older men treated with testosterone. J Clin Endocrinol Metab 2020;105:2142–9. 10.1210/clinem/dgz242
    1. 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;102:3914–23. 10.1210/jc.2017-01643
    1. Emi Y, Adachi M, Sasaki A, et al. . Increased arterial stiffness in female-to-male transsexuals treated with androgen. J Obstet Gynaecol Res 2008;34:890–7. 10.1111/j.1447-0756.2008.00857.x
    1. 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;11:1999–2011. 10.1111/jsm.12571
    1. Alzahrani T, Nguyen T, Ryan A, et al. . Cardiovascular disease risk factors and myocardial infarction in the transgender population. Circ Cardiovasc Qual Outcomes 2019;12:e005597. 10.1161/CIRCOUTCOMES.119.005597
    1. Wierckx K, Mueller S, Weyers S, et al. . Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med 2012;9:2641–51. 10.1111/j.1743-6109.2012.02876.x
    1. Bhasin S, Woodhouse L, Casaburi R, et al. . Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001;281:E1172–81. 10.1152/ajpendo.2001.281.6.E1172
    1. Frederiksen L, Højlund K, Hougaard DM, et al. . Testosterone therapy increased muscle mass and lipid oxidation in aging men. Age 2012;34:145–56. 10.1007/s11357-011-9213-9
    1. T'Sjoen G, Arcelus J, Gooren L, et al. . Endocrinology of transgender medicine. Endocr Rev 2019;40:97–117. 10.1210/er.2018-00011
    1. Wiik A, Lundberg TR, Rullman E, et al. . Muscle strength, size, and composition following 12 months of Gender-affirming treatment in transgender individuals. J Clin Endocrinol Metab 2020;105:e805–13. 10.1210/clinem/dgz247
    1. Kadi F, Bonnerud P, Eriksson A, et al. . The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids. Histochem Cell Biol 2000;113:25–9. 10.1007/s004180050003
    1. Van Caenegem E, Wierckx K, Taes Y, et al. . Bone mass, bone geometry, and body composition in female-to-male transsexual persons after long-term cross-sex hormonal therapy. J Clin Endocrinol Metab 2012;97:2503–11. 10.1210/jc.2012-1187
    1. Coleman E, Bockting W, Botzer M, et al. . Standards of care for the health of transsexual, transgender, and Gender-Nonconforming people, version 7. Int J Transgend 2012;13:165–232. 10.1080/15532739.2011.700873
    1. Defreyne J, Kreukels B, T'Sjoen G, et al. . No correlation between serum testosterone levels and state-level anger intensity in transgender people: results from the European network for the investigation of gender incongruence. Horm Behav 2019;110:29–39. 10.1016/j.yhbeh.2019.02.016
    1. Defreyne J, T'Sjoen G, Bouman WP, et al. . Prospective evaluation of self-reported aggression in transgender persons. J Sex Med 2018;15:768–76. 10.1016/j.jsxm.2018.03.079
    1. Campbell A. Sex differences in direct aggression: what are the psychological mediators? Aggress Violent Behav 2006;11:237–64. 10.1016/j.avb.2005.09.002
    1. Kristensen T, Christensen LL, Frystyk J. Effects of testosterone therapy on constructs related to aggression in transgender men: a systematic review, 2020. 10.1016/j.yhbeh.2020.104912
    1. Buss AH, Perry M. The aggression questionnaire. J Pers Soc Psychol 1992;63:452–9. 10.1037/0022-3514.63.3.452
    1. Kodama S, Saito K, Tanaka S, et al. . Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009;301:2024–35. 10.1001/jama.2009.681
    1. Chen L, Kuang J, Pei J-H, et al. . Predictors of cardiorespiratory fitness in female and male adults with different body mass index: National health and nutrition examination survey 1999-2004 dataset. Ann Med 2017;49:83–92. 10.1080/07853890.2016.1252056
    1. Myers J, Kaminsky LA, Lima R, et al. . A reference equation for normal standards for VO2 max: analysis from the fitness registry and the importance of exercise National database (FRIEND registry). Prog Cardiovasc Dis 2017;60:21–9. 10.1016/j.pcad.2017.03.002
    1. Hirschberg AL, Elings Knutsson J, Helge T, et al. . Effects of moderately increased testosterone concentration on physical performance in young women: a double blind, randomised, placebo controlled study. Br J Sports Med 2020;54:599–604. 10.1136/bjsports-2018-100525
    1. Shah R, Newcomb DC. Sex bias in asthma prevalence and pathogenesis. Front Immunol 2018;9:2997. 10.3389/fimmu.2018.02997
    1. Haynes JM, Stumbo RW. The impact of using Non-Birth sex on the interpretation of spirometry data in subjects with air-flow obstruction. Respir Care 2018;63:215–8. 10.4187/respcare.05586
    1. Hughes LJ, Peiffer JJ, Scott BR. Reliability and validity of using the push band v2.0 to measure repetition velocity in Free-Weight and Smith machine exercises. J Strength Cond Res 201910.1519/JSC.0000000000003436
    1. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72. 10.1210/jcem.84.10.6079
    1. 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. 10.1093/clinchem/18.6.499
    1. Frystyk J, Tarnow L, Hansen TK, et al. . Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia 2005;48:1911–8. 10.1007/s00125-005-1850-z
    1. D'Anna-Hernandez KL, Ross RG, Natvig CL, et al. . Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity throughout pregnancy: comparison to salivary cortisol. Physiol Behav 2011;104:348–53. 10.1016/j.physbeh.2011.02.041
    1. Stalder T, Kirschbaum C. Analysis of cortisol in hair--state of the art and future directions. Brain Behav Immun 2012;26:1019–29. 10.1016/j.bbi.2012.02.002
    1. Gao W, Stalder T, Foley P, et al. . Quantitative analysis of steroid hormones in human hair using a column-switching LC-APCI-MS/MS assay. J Chromatogr B Analyt Technol Biomed Life Sci 2013;928:1–8. 10.1016/j.jchromb.2013.03.008
    1. Seo D-I, Kim E, Fahs CA, et al. . Reliability of the one-repetition maximum test based on muscle group and gender. J Sports Sci Med 2012;11:221–5.
    1. Harris PA, Taylor R, Minor BL, et al. . The REDCap Consortium: building an international community of software platform partners. J Biomed Inform 2019;95:103208. 10.1016/j.jbi.2019.103208
    1. Harris PA, Taylor R, Thielke R, et al. . Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 10.1016/j.jbi.2008.08.010
    1. Altman DG. Practical statistics for medical research: Chapmann and Hall/CRC. 458, 1991.
    1. Rubin KH, Glintborg D, Nybo M, et al. . Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2017;102:3848–57. 10.1210/jc.2017-01354
    1. Nielsen TL, Wraae K, Brixen K, et al. . Prevalence of overweight, obesity and physical inactivity in 20- to 29-year-old, Danish men. Relation to sociodemography, physical dysfunction and low socioeconomic status: the Odense androgen study. Int J Obes 2006;30:805–15. 10.1038/sj.ijo.0803197
    1. NTL CLL, Hermann P, Glintborg D. Body composition and testosterone determined VO2max in 780 young men - results from the Odense Androgen Study. European Conference of Endocrinology Lisboa, 2017.
    1. Nielsen TL, Hagen C, Wraae K, et al. . The impact of the CAG repeat polymorphism of the androgen receptor gene on muscle and adipose tissues in 20-29-year-old Danish men: Odense androgen study. Eur J Endocrinol 2010;162:795–804. 10.1530/EJE-09-0763

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