There is a paucity of data on the safety and efficacy of long-term testosterone (T)-based gender-affirming hormone therapy (GAHT) on anthropometric parameters, body composition, and glycolipid metabolism in assigned female at birth (AFAB) persons. The purpose of this study was to provide an updated meta-analysis on this topic.
Methods:
We searched PubMed, Scopus, and Cochrane Library for relevant studies. Pre-/post-therapy changes in body mass index (BMI), waist-to-hip ratio (WHR), body composition, lipid glycemic/insulinemic profiles were combined as mean differences (MD) with 95% confidence interval (CI), using random-effect models.
Results:
Thirty-nine studies (N=1949) were analyzed. At pooled estimates, GAHT was associated with significant decrease in fat mass (MD: −1.29 kg; 95% CI: −2.52 to −0.05; p=0.04) and increase in lean mass (4.12 kg; 95% CI: 3.07–5.16; p<0.00001), BMI (0.78 kg/m2; 95% CI: 0.50–1.07; p<0.00001), and WHR (0.02; 95%CI: 0.01–0.03; p=0.003) in the absence of heterogeneity (I2=0%). T therapy was also accompanied by unfavorable effects on lipid profile, including increases in total cholesterol (4.95 mg/dL; 95% CI: 1.53–8.37; p=0.005), LDL (11.15 mg/dL; 95% CI: 7.57–14.74; p<0.00001), and triglycerides (9.49 mg/dL; 95% CI: 4.39–14.58; p=0.0003) and decrease in HDL concentration (−7.52 mg/dL; 95% CI: −9.38 to −5.67; p<0.00001). Finally, T therapy resulted in a significant decrease in blood glucose concentration (−2.06 mg/dL; 95% CI: −3.37 to −0.74; p=0.002), with no significant effects on homeostatic model assessment index of insulin resistance.
Conclusion:
T-based GAHT in AFAB people is associated with androgenic changes in body composition and body fat distribution, accompanied by the acquisition of a more unfavorable cardiovascular lipid profile.
Get full access to this article
View all access options for this article.
References
1.
International Statistical Classification of Diseases and Related Health Problems 11th ed,; ICD-11. World Health Organization: Geneva, Switzerland; 2021.
2.
ColemanE, RadixAE, BoumanWP, et al.Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgend Health, 2022; 23(Suppl 1):S1–S259; doi: 10.1080/26895269.2022.2100644
3.
FisherAD, SenofonteG, CocchettiC, et al.SIGIS-SIAMS-SIE position statement of gender affirming hormonal treatment in transgender and non-binary people. J Endocrinol Invest, 2022; 45(3):657–673; doi: 10.1007/s40618-021-01694-2
AsschemanH, GoorenLJ, EklundPL. Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism, 1989; 38(9):869–873; doi: 10.1016/0026-0495(89)90233-3
6.
AsschemanH, GiltayEJ, MegensJA, et al.A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol, 2011; 164(4):635–642; doi: 10.1530/EJE-10-1038
7.
van KesterenPJ, AsschemanH, MegensJA, et al.Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf), 1997; 47(3):337–342; doi: 10.1046/j.1365-2265.1997.2601068.x
8.
GoorenLJ. Management of female-to-male transgender persons: Medical and surgical management, life expectancy. Curr Opin Endocrinol Diabetes Obes, 2014; 21(3):233–238; doi: 10.1097/MED.0000000000000064
9.
WierckxK, Van CaenegemE, SchreinerT, 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(8):1999–2011; doi: 10.1111/jsm.12571
10.
PelusiC, CostantinoA, MartelliV, et al.Effects of three different testosterone formulations in female-to-male transsexual persons. J Sex Med, 2014; 11(12):3002–3011; doi: 10.1111/jsm.12698
11.
KlaverM, de BlokCJM, WiepjesCM, 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(2):163–171; doi: 10.1530/EJE-17-0496
12.
AuerMK, EbertT, PietznerM, et al.Effects of sex hormone treatment on the metabolic syndrome in transgender individuals: Focus on metabolic cytokines. J Clin Endocrinol Metab, 2018; 103(2):790–802; doi: 10.1210/jc.2017-01559
13.
ShadidS, Abosi-AppeaduK, De MaertelaereAS, et al.Effects of gender-affirming hormone therapy on insulin sensitivity and incretin responses in transgender people. Diabetes Care, 2020; 43(2):411–417; doi: 10.2337/dc19-1061
14.
van VelzenDM, NotaNM, SimsekS, et al.Variation in sensitivity and rate of change in body composition: Steps toward individualizing transgender care. Eur J Endocrinol, 2020; 183(5):529–536; doi: 10.1530/EJE-20-0609
15.
Ventura-ClapierR, PiquereauJ, GarnierA, et al.Gender issues in cardiovascular diseases. Focus on energy metabolism. Biochim Biophys Acta Mol Basis Dis, 2020; 1866(6):165722.
16.
IslamRM, BellRJ, GreenS, et al.Safety and efficacy of testosterone for women: A systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol, 2019; 7(10):754–766; doi: 10.1016/S2213-8587(19)30189-5
17.
SeidellJC, CigoliniM, CharzewskaJ, et al.Fat distribution and gender differences in serum lipids in men and women from four European communities. Atherosclerosis, 1991; 87(2–3):203–210; doi: 10.1016/0021-9150(91)90022-u
18.
CocchettiC, CastelliniG, IacuanielloD, 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(4):821–829; doi: 10.1016/j.jsxm.2021.01.185
19.
AuerMK, CecilA, RoepkeY, et al.12-months metabolic changes among gender dysphoric individuals under cross-sex hormone treatment: A targeted metabolomics study. Sci Rep, 2016; 6:37005; doi: 10.1038/srep37005
20.
ChanKJ, JollyD, LiangJJ, et al.Estrogen levels do not rise with testosterone treatment for transgender men. Endocr Pract, 2018; 24:329–333; doi: 10.4158/EP-2017-0203
21.
AllenAN, JiaoR, DayP, et al.Dynamic impact of hormone therapy on laboratory values in transgender patients over time. J Appl Lab Med, 2021; 6(1):27–40; doi: 10.1093/jalm/jfaa192
22.
MohlerER 3rd, EllenbergSS, LewisCE, et al.The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metab, 2018; 103(2):681–688; doi: 10.1210/jc.2017-02243
23.
GeerEB, ShenW. Gender differences in insulin resistance, body composition, and energy balance. Gend Med, 2009; 6 (Suppl 1):60–75; doi: 10.1016/j.genm.2009.02.002
24.
PoldermanKH, GoorenLJ, AsschemanH, et al.Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab, 1994; 79(1):265–271; doi: 10.1210/jcem.79.1.8027240
25.
BrethertonI, SpanosC, LeemaqzSY, et al.Insulin resistance in transgender individuals correlates with android fat mass. Ther Adv Endocrinol Metab, 2021; 12:2042018820985681; doi: 10.1177/2042018820985681
26.
SealLJ. A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria. Ann Clin Biochem, 2016; 53(Pt 1):10–20; doi: 10.1177/0004563215587763
27.
ResminiE, AndraghettiG, ReboraA, et al.Leptin, ghrelin, and adiponectin evaluation in transsexual subjects during hormonal treatments. J Androl, 2008; 29(5):580–585; doi: 10.2164/jandrol.108.004952
28.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71; doi: 10.1136/bmj.n71
29.
StroupDF, BerlinJA, MortonSC, et al.Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA, 2000; 283(15):2008–2012; doi: 10.1001/jama.283.15.2008
30.
MoherD, LiberatiA, TetzlaffJ, et al.PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol, 2009; 62(10):1006–1012; doi: 10.1016/j.jclinepi.2009.06.005
31.
LiberatiA, AltmanDG, TetzlaffJ, et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. PLoS Med, 2009; 6(7):e1000100; doi: 10.1371/journal.pmed.1000100
32.
ThomasBH, CiliskaD, DobbinsM, et al.A process for systematically reviewing the literature: Providing the research evidence for public health nursing interventions. Worldviews Evid Based Nurs, 2004; 1(3):176–184; doi: 10.1111/j.1524-475X.2004.04006.x
33.
Armijo-OlivoS, StilesCR, HagenNA, et al.Assessment of study quality for systematic reviews: A comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: methodological research. J Eval Clin Pract, 2012; 18(1):12–18; doi: 10.1111/j.1365-2753.2010.01516.x
HigginsJP, ThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002; 21(11):1539–1558; doi: 10.1002/sim.1186
36.
SterneJA, EggerM. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J Clin Epidemiol, 2001; 54(10):1046–1055; doi: 10.1016/s0895-4356(01)00377-8
37.
ArandaG, MoraM, HanzuFA, et al.Effects of sex steroids on cardiovascular risk profile in transgender men under gender affirming hormone therapy. Endocrinol Diabetes Nutr (Engl Ed), 2019; 66(6):385–392; doi: 10.1016/j.endinu.2018.11.004
38.
ChandraP, BasraSS, ChenTC, et al.Alterations in lipids and adipocyte hormones in female-to-male transsexuals. Int J Endocrinol, 2010; 2010:945053; doi: 10.1155/2010/945053
39.
ColizziM, CostaR, ScaramuzziF, et al.Concomitant psychiatric problems and hormonal treatment induced metabolic syndrome in gender dysphoria individuals: A 2 year follow-up study. J Psychosom Res, 2015; 78(4):399–406; doi: 10.1016/j.jpsychores.2015.02.001
40.
CupistiS, GiltayEJ, GoorenLJ, et al.The impact of testosterone administration to female-to-male transsexuals on insulin resistance and lipid parameters compared with women with polycystic ovary syndrome. Fertil Steril, 2010; 94(7):2647–2653; doi: 10.1016/j.fertnstert.2010.03.048
41.
ElbersJM, AsschemanH, SeidellJC, et al.Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab, 1997; 82(7):2044–2047; doi: 10.1210/jcem.82.7.4078
42.
ElbersJM, AsschemanH, SeidellJC, et al.Effects of sex steroid hormones on regional fat depots as assessed by magnetic resonance imaging in transsexuals. Am J Physiol, 1999; 276(2):E317–E325; doi: 10.1152/ajpendo.1999.276.2.E317
43.
ElbersJM, GiltayEJ, TeerlinkT, et al.Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol (Oxf), 2003; 58(5):562–571; doi: 10.1046/j.1365-2265.2003.01753.x
44.
FadichSK, KalayjianA, GreeneDN, et al.A retrospective analysis of creatinine-based kidney function with and without sex assigned at birth among transgender adults. Ann Pharmacother, 2022; 56(7):791–799; doi: 10.1177/10600280211050120
45.
FernandezJD, TannockLR. Metabolic effects of hormone therapy in transgender patients. Endocr Pract, 2016; 22(4):383–388; doi: 10.4158/EP15950.OR
46.
FisherAD, CastelliniG, RistoriJ, et al.Cross-sex hormone treatment and psychobiological changes in transsexual persons: Two-year follow-up data. J Clin Endocrinol Metab, 2016; 101(11):4260–4269; doi: 10.1210/jc.2016-1276
47.
GavaG, ManciniI, CerpoliniS, et al.Testosterone undecanoate and testosterone enanthate injections are both effective and safe in transmen over 5years of administration. Clin Endocrinol (Oxf), 2018; 89(6):878–886; doi: 10.1111/cen.13821
48.
GavaG, ArmillottaF, PillastriniP, et al.A randomized double-blind placebo-controlled pilot trial on the effects of testosterone undecanoate plus dutasteride or placebo on muscle strength, body composition, and metabolic profile in transmen. J Sex Med, 2021; 18(3):646–655; doi: 10.1016/j.jsxm.2020.12.015
49.
GiltayEJ, LambertJ, GoorenLJ, et al.Sex steroids, insulin, and arterial stiffness in women and men. Hypertension, 1999; 34(4 Pt 1):590–597; doi: 10.1161/01.hyp.34.4.590
50.
JacobeitJW, GoorenLJ, SchulteHM. Safety aspects of 36 months of administration of long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals. Eur J Endocrinol, 2009; 161(5):795–798; doi: 10.1530/EJE-09-0412
51.
KorpaisarnS, ChiewchalermsriD, ArunakulJ, et al.Effects of testosterone treatment on transgender males: A single-institution study. SAGE Open Med, 2021; 9:20503121211051546; doi: 10.1177/20503121211051546
52.
MaheshwariA, DinesV, SaulD, et al.The effect of gender-affirming hormone therapy on serum creatinine in transgender individuals. Endocr Pract, 2022; 28(1):52–57; doi: 10.1016/j.eprac.2021.08.009
53.
MeriggiolaMC, ArmillottaF, CostantinoA, et al.Effects of testosterone undecanoate administered alone or in combination with letrozole or dutasteride in female to male transsexuals. J Sex Med, 2008; 5(10):2442–2453; doi: 10.1111/j.1743-6109.2008.00909.x
54.
MeyerWJ 3rd, WebbA, StuartCA, et al.Physical and hormonal evaluation of transsexual patients: A longitudinal study. Arch Sex Behav, 1986; 15(2):121–138; doi: 10.1007/BF01542220
55.
MillingtonK, BarreraE, DagaA, et al.The effect of gender-affirming hormone treatment on serum creatinine in transgender and gender-diverse youth: Implications for estimating GFR. Pediatr Nephrol, 2022; 37(9):2141–2150; doi: 10.1007/s00467-022-05445-0
56.
MuellerA, HaeberleL, ZollverH, et al.Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals. J Sex Med, 2010; 7(9):3190–3198; doi: 10.1111/j.1743-6109.2010.01912.x
57.
Olson-KennedyJ, OkontaV, ClarkLF, et al.Physiologic response to gender-affirming hormones among transgender youth. J Adolesc Health, 2018; 62(4):397–401; doi: 10.1016/j.jadohealth.2017.08.005
58.
ScharffM, WiepjesCM, KlaverM, et al.Change in grip strength in trans people and its association with lean body mass and bone density. Endocr Connect, 2019; 8(7):1020–1028; doi: 10.1530/EC-19-0196
59.
SchönauerLM, DellinoM, LoverroM, et al.Hormone therapy in female-to-male transgender patients: Searching for a lifelong balance. Hormones (Athens), 2021; 20(1):151–159; doi: 10.1007/s42000-020-00238-2
60.
SchutteMH, KleemannR, NotaNM, et al.The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis. PLoS One, 2022; 17(3):e0261312; doi: 10.1371/journal.pone.0261312
61.
SequeiraGM, KiddK, El NokaliNE, et al.Effects of testosterone initiation on body mass index in transmasculine adolescents. J Adolesc Health, 2019; 65(6):818–820; doi: 10.1016/j.jadohealth.2019.06.009
62.
StoffersIE, de VriesMC, HannemaSE. Physical changes, laboratory parameters, and bone mineral density during testosterone treatment in adolescents with gender dysphoria. J Sex Med, 2019; 16(9):1459–1468; doi: 10.1016/j.jsxm.2019.06.014
63.
Van CaenegemE, WierckxK, TaesY, et al.Body composition, bone turnover, and bone mass in trans men during testosterone treatment: 1-year follow-up data from a prospective case-controlled study (ENIGI). Eur J Endocrinol, 2015; 172(2):163–171; doi: 10.1530/EJE-14-0586
64.
van der LoosMA, HellingaI, VlotMC, et al.Development of hip bone geometry during gender-affirming hormone therapy in transgender adolescents resembles that of the experienced gender when pubertal suspension is started in early puberty. J Bone Miner Res, 2021; 36(5):931–941; doi: 10.1002/jbmr.4262
65.
van KesterenP, LipsP, DevilleW, et al.The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals. J Clin Endocrinol Metab, 1996; 81(6):2227–2232; doi: 10.1210/jcem.81.6.8964856
66.
van VelzenDM, AdorniMP, ZimettiF, et al.The effect of transgender hormonal treatment on high density lipoprotein cholesterol efflux capacity. Atherosclerosis, 2021; 323:44–53; doi: 10.1016/j.atherosclerosis.2021.03.008
67.
VitaR, SettineriS, LiottaM, et al.Changes in hormonal and metabolic parameters in transgender subjects on cross-sex hormone therapy: A cohort study. Maturitas, 2018; 107:92–96; doi: 10.1016/j.maturitas.2017.10.012
68.
VlotMC, WiepjesCM, de JonghRT, et al.Gender-affirming hormone treatment decreases bone turnover in transwomen and older transmen. J Bone Miner Res, 2019; 34(10):1862–1872; doi: 10.1002/jbmr.3762
69.
YahyaouiR, EstevaI, Haro-MoraJJ, et al.Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons. J Clin Endocrinol Metab, 2008; 93(6):2230–2233; doi: 10.1210/jc.2007-2467
70.
SinghR, ArtazaJN, TaylorWE, et al.Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology, 2003; 144(11):5081–5088; doi: 10.1210/en.2003-0741
71.
SarchielliE, ComeglioP, FilippiS, et al.Testosterone improves muscle fiber asset and exercise performance in a metabolic syndrome model. J Endocrinol, 2020; 245(2):259–279; doi: 10.1530/JOE-19-0532
72.
ChangE, VargheseM, SingerK. Gender and sex differences in adipose tissue. Curr Diab Rep, 2018; 18(9):69; doi: 10.1007/s11892-018-1031-3
73.
GBD 2015 ObesityCollaborators, AfshinA, ForouzanfarMH, ReitsmaMB, et al.Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med, 2017; 377(1):13–27; doi: 10.1056/NEJMoa1614362
74.
CameronAJ, MaglianoDJ, SöderbergS. A systematic review of the impact of including both waist and hip circumference in risk models for cardiovascular diseases, diabetes and mortality. Obes Rev, 2013; 14(1):86–94; doi: 10.1111/j.1467-789X.2012.01051.x
75.
FernandezML, WebbD. The LDL to HDL cholesterol ratio as a valuable tool to evaluate coronary heart disease risk. J Am Coll Nutr, 2008; 27(1):1–5; doi: 10.1080/07315724.2008.10719668
76.
NotaNM, WiepjesCM, de BlokCJM, et al.Occurrence of acute cardiovascular events in transgender individuals receiving hormone therapy. Circulation, 2019; 139(11):1461–1462; doi: 10.1161/CIRCULATIONAHA.118.038584
77.
JanochovaK, HaluzikM, BuzgaM. Visceral fat and insulin resistance - what we know?. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2019; 163(1):19–27; doi: 10.5507/bp.2018.062
78.
LiX, LiuJ, ZhouB, et al.Sex differences in the effect of testosterone on adipose tissue insulin resistance from overweight to obese adults. J Clin Endocrinol Metab, 2021; 106(8):2252–2263; doi: 10.1210/clinem/dgab325
79.
CocchettiC, RistoriJ, RomaniA, et al.Hormonal treatment strategies tailored to non-binary transgender individuals. J Clin Med, 2020; 9(6):1609; doi: 10.3390/jcm9061609
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.
