ISSN: 2047-2919 ANDROLOGY

ORIGINAL ARTICLE

Correspondence:
Poli Mara Spritzer, Division of Endocrinology, Effects of testosterone therapy on
Hospital de Clınicas de Porto Alegre, Rua Ramiro
Barcelos, 2350, 90035 003 – Porto Alegre, RS, BMI, blood pressure, and laboratory
Brazil.
E-mail: [email protected] profile of transgender men: a
systematic review
Keywords:
cross-sex hormone therapy, female-to-male,
1,2
testosterone, transsexual men I. Velho, 1,2T. M. Fighera, 3P. K. Ziegelmann and 1,2,4P. M. Spritzer
1
Gynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clınicas de Porto Alegre,
Received: 3-Nov-2016 Porto Alegre, Brazil, 2Gender Identity Program, Hospital de Clınicas de Porto Alegre, Porto Alegre,
Revised: 5-Apr-2017 Brazil, 3Department of Statistics, Institute of Mathematics, Federal University of Rio Grande do Sul,
Accepted: 20-Apr-2017 Porto Alegre, Brazil, and 4Department of Physiology, Federal University of Rio Grande do Sul, Porto
Alegre, Brazil
doi: 10.1111/andr.12382

SUMMARY
Testosterone is the main hormonal agent used for cross-sex hormone therapy in female-to-male transgender persons. Our
aim was to systematically review the literature concerning the effects of testosterone on body mass index (BMI), blood pressure,
hematocrit, hemoglobin, lipid profile, and liver enzymes in transgender men. PUBMED and EMBASE were searched for studies
published until March 2017. Studies were included if they reported interventions with any dose of testosterone and comparison
of variables before and during treatment. Of 455 potentially eligible articles, 13 were reviewed. Study duration ranged from 6 to
60 months, sample size ranged from 12 to 97 patients, and the most common treatment was parenteral testosterone unde-
canoate 1000 mg/12 weeks. Slight but significant increases in BMI were reported (from 1.3 to 11.4%). Three out of seven studies
assessing the impact of different testosterone formulations on blood pressure detected modest increases or clinically irrelevant
changes in this variable. In another study, however, two patients developed hypertension, which was resolved after cessation of
testosterone therapy. Decreases in HDL-cholesterol and increases in LDL-cholesterol were consistently observed. Eight studies
observed a relationship between testosterone and increased hemoglobin (range: 4.9–12.5%) and hematocrit (range: 4.4–17.6%),
but discontinuation of androgen therapy was not necessary. In one study, two patients developed erythrocytosis (hematocrit
>52%) after 9 and 12 months of treatment. One study analyzing testosterone formulations observed smaller increases in hemo-
globin and hematocrit with testosterone gel. Six studies assessing liver function showed slight or no changes. Overall, the qual-
ity of evidence was low, given the lack of randomized clinical/controlled trials and the small sample sizes. In conclusion,
exogenous testosterone administration to transgender men was associated with modest increases in BMI, hemoglobin/hemat-
ocrit, and LDL-cholesterol, and with decreases in HDL-cholesterol. Long-term studies are needed to assess the long-term risks
of testosterone therapy, particularly as they relate to cardiometabolic risks such as diabetes, dyslipidemia and the metabolic
syndrome.

INTRODUCTION esters have been traditionally used, administered in doses of

Gender dysphoria is characterized by a persistent desire to live 100–250 mg every 7–21 days (Pelusi et al., 2014). A long-acting
and be accepted as a member of the opposite sex (World Health testosterone undecanoate formulation which maintains more
Organization, 1992; American Psychiatric Association, 2000, stable levels of testosterone is also available (Pelusi et al., 2014).
2013). People who experience gender dysphoria require cross- In addition, transdermal testosterone formulations, adminis-
sex hormones to induce secondary sexual characteristics of the tered as gel or patches, are another option for transgender men,
desired sex. In this context, female to male transgender persons which is available in many countries.
(transgender men) may desire treatment with androgen hor- Few studies so far have evaluated the effects of testosterone
mones to induce virilization (Moore et al., 2003; Gooren, 2005). therapy in transgender men. Some suggest that testosterone
Testosterone is the main hormonal agent used for cross-sex administration is safe and associated with low risk of adverse
hormone therapy in transgender men. Injectable testosterone effects (Hembree et al., 2009; Coleman et al., 2012). Other

© 2017 American Society of Andrology and European Academy of Andrology Andrology, 2017, 5, 881–888 881
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I. Velho et al.

studies, however, have reported hypertension, increased ery- eligible for inclusion in the systematic review. The selected arti-
thropoiesis, decreased high density lipoprotein (HDL), increased cles were read in full for confirmation of eligibility and data
low-density lipoprotein (LDL), elevation of liver enzymes, obe- extraction. Disagreements were resolved by discussion among
sity, and acne, among others, associated with this treatment in all investigators. The following information was extracted from
transgender individuals (Van Kesteren et al., 1997; Michel et al., each individual study: name of the first author, publication year,
2001; Levy et al., 2003; Moore et al., 2003). country, number of subjects, duration of the follow-up, interven-
Therefore, the aim of the present systematic review was to tion, and evaluation time.
summarize the available information regarding the effects of
testosterone administration on clinical and metabolic variables
RESULTS
of transgender men, especially body mass index (BMI), blood
pressure, and hematologic and metabolic profiles. Study selection
Figure 1 shows the flowchart of study selection. Initially, 455
potentially eligible articles were identified; 438 were excluded
MATERIALS AND METHODS
after reading the abstracts and/or titles; and 17 articles were read
Search strategy and study selection in full. After this step, three articles were excluded because the
This systematic review was performed in accordance with variables of interest were not reported, and one because a pro-
PRISMA guidelines (Stroup et al., 2000; Liberati et al., 2009). gestin was added to androgen treatment. Thirteen articles were
Medline (PUBMED) and EMBASE databases were searched for thus included in the systematic review (Giltay et al., 2004; Berra
articles published until March/2017. There were no other limits et al., 2006; Jacobeit et al., 2007, 2009; Mueller et al., 2007, 2010;
except for the end date. Chandra et al., 2010; Cupisti et al., 2010; Pelusi et al., 2014;
The following search strategy was developed for PUBMED and Wierckx et al., 2014; Deutsch et al., 2015; Quiro  s et al., 2015;
modified as needed for EMBASE: ‘transsexualism’ or ‘transgen- Fisher et al., 2016).
der person’ or ‘person, transgender’ or ‘persons, transgender’ or
‘transgenders’ or ‘transgender’ or ‘transgendered persons’ or Characteristics of included studies
‘person, transgendered’ or ‘persons, transgendered’ or ‘trans- As shown in Table 1, study duration ranged from 6 to
gendered person’ or ‘transsexual persons’ or ‘person, transsex- 60 months, sample size ranged from 12 to 97 patients, and the
ual’ or ‘persons, transsexual’ or ‘transsexual person’ and most common treatment was parenteral testosterone unde-
‘testosterone’ or ‘cross sex hormone therapy.’ canoate 1000 mg/12 weeks, which was reported in eight of 13
The selection criteria for the studies were as follows: focus on articles (Jacobeit et al., 2007, 2009; Mueller et al., 2007, 2010;
transgender men, intervention with any dose of testosterone, Cupisti et al., 2010; Pelusi et al., 2014; Wierckx et al., 2014;
and comparison of clinical and metabolic variables before and Quiro s et al., 2015; Fisher et al., 2016). The design of most stud-
during/after treatment. The main outcomes of interest were ies was observational (non-controlled).
BMI, blood pressure, hematocrit, hemoglobin, lipid profile, and Most of the studies followed a protocol in which a second
liver enzymes. injection of testosterone undecanoate was prescribed 6 weeks
after the first administration, with subsequent 1000 mg injec-
Data extraction and quality control tions recommended every 12 weeks. However, one study (Quiro s
Two investigators independently screened titles and abstracts et al., 2015) prescribed either intramuscular testosterone unde-
of all articles selected in order to evaluate if the studies were canoate 1000 mg or 1% transdermal gel, according to patient

Figure 1 PRISMA flow diagram of the study

Articles identified in PUBMED and EMBASE (n = 455) selection process.

Articles excluded based on title and abstract

screening (n = 438)

Articles selected for detailed evaluation (n = 17)

Full text articles excluded because outcomes of

interest were not reported or because a progestin was
added to androgen treatment (n = 4)

13 articles included in systematic review

882 Andrology, 2017, 5, 881–888 © 2017 American Society of Andrology and European Academy of Andrology
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TESTOSTERONE THERAPY FOR TRANSGENDER MEN

Table 1 Characteristics of the studies included in the systematic review about the effects of testosterone on transgender men

Study Country n Treatment Mean age (years) Treatment Variables assessed

duration
(months)

Giltay et al. (2004) Netherlands 81 7 36.7 (21–61)a -Testosterone esters (250 mg/2 weeks) BMI, blood pressure,
-Oral testosterone undecanoate (160–240 mg/day) lipid profile
Berra et al. (2006) Italy 16 6 30.4  3.4 Testosterone enanthate (100 mg) + BMI, blood pressure,
testosterone propionate (25 mg/10 days) lipid profile
Jacobeit et al. (2007) Netherlands 12 12 33.0  6.0 Testosterone undecanoate (1000 mg/12 weeks) Lipid profile, hematocrit/
hemoglobin
Mueller et al. (2007) Germany 35 12 29.6  8.9 Testosterone undecanoate (1000 mg/12 weeks) BMI, blood pressure,
lipid profile, liver function,
hematocrit and hemoglobin
Jacobeit et al. (2009) Netherlands 17 36 34.0  7.0 Testosterone undecanoate (1000 mg/12 weeks) Lipid profile, liver function,
hematocrit and hemoglobin
Mueller et al. (2010) Germany 45 24 30.4  9.1 Testosterone undecanoate (1000 mg/12 weeks) BMI, blood pressure,
lipid profile, liver function,
hematocrit and hemoglobin
Cupisti et al. (2010) Netherlands 29 12 29.9 (18–40)a Testosterone undecanoate (1000 mg/12 weeks) BMI
Chandra et al. (2010) United States 12 12 29.0  9.0 Testosterone cypionate or testosterone BMI, blood pressure,
enanthate (50–125 mg/2 weeks) lipid profile, liver function,
hematocrit
Pelusi et al. (2014) Italy 45 12 28.2 (25.6–30.9)a -Testosterone undecanoate (1000 mg/12 weeks) BMI, lipid profile,
29.4 (26.6–32.1)a -Testosterone gel (5 mg/day) liver function, hematocrit
30.9 (27.9–33.9)a -Testosterone enanthate (100 mg/10 days) and hemoglobin
Wierckx et al. (2014) Belgium (Ghent) 27 12 27.3  8.5 Testosterone undecanoate (1000 mg/12 weeks) BMI, blood pressure,
Norway (Oslo) 26 21.7  5.1 lipid profile, liver function,
hematocrit
 s et al. (2015)
Quiro Spain 97 24 28.6  8.6 -Testosterone gel (5 g/day) BMI, blood pressure,
-Testosterone undecanoate (1000 mg/12 weeks) lipid profile, hemoglobin
Deutsch et al. (2015) United States 31 6 27.0  6.9 -Testosterone gel (5 g/day) BMI, blood pressure,
-Testosterone cypionate (50 mg/week) lipid profile
-Testosterone patch (4 mg/day)
Fisher et al. (2016) Italy 26 24 33.9  9.2b -Testosterone undecanoate (1000 mg/12 weeks) BMI
-Testosterone enanthatec
-Transdermal testosteronec

BMI, body mass index. aMedian and interquartile interval. bAge of all sample (transgender men and women). cDose not informed.

preference and depending on the patient’s clinical condition. treatment (Table 2). In three studies using bioimpedance
Other testosterone formulations were also prescribed: testos- (Berra et al., 2006) or dual-energy X ray absorptiometry (DXA)
terone patch (4 mg/day) (Deutsch et al., 2015), testosterone gel (Pelusi et al., 2014; Wierckx et al., 2014) to assess body com-
(1%, 5 g/day) (Deutsch et al., 2015; Quiro  s et al., 2015), testos- position, an increase in lean mass and reduction in fat mass
terone cypionate (Chandra et al., 2010; Deutsch et al., 2015); were also detected during androgen treatment. One study
testosterone enanthate (100 mg) associated with testosterone observed a lean mass gain of up to 14.6% after only 6 months
propionate (25 mg/10 days) (Berra et al., 2006; Fisher et al., of androgen therapy (Berra et al., 2006). Among the studies
2016); testosterone esters (250 mg/2 weeks); and oral testos- that evaluated body composition by DXA, lean mass gain ran-
terone undecanoate (160–240 mg/day) (Giltay et al., 2004) ged from 8.5% (Pelusi et al., 2014) to 12.3% (Wierckx et al.,
(Table 1). Except for one study (Quiro  s et al., 2015), all others 2014) within 12 months of follow-up. Three other studies
included only patients without previous treatment. In the study reported no changes in BMI during testosterone therapy
by Quiro s et al. (2015), 13.4% of the patients had already used (Chandra et al., 2010; Cupisti et al., 2010; Mueller et al.,
some hormone therapy. 2010), but one had a sample limited to only 12 patients
(Chandra et al., 2010). While Mueller et al. (2010) found no
Qualitative data synthesis changes in BMI, a significant increase in 4.7% in lean mass
Most participants in the studies were around 30 years of age was detected.
(Table 1). Ten studies included participants living in Europe, Seven studies (Giltay et al., 2004; Mueller et al., 2007, 2010;
and two included participants living in the United States. Base- Chandra et al., 2010; Wierckx et al., 2014; Deutsch et al.,
line prevalence of obesity and hypertension varied among the 2015; Quiro  s et al., 2015) assessed the impact of various
studies, as can be inferred from baseline BMI and blood pressure testosterone formulations on blood pressure levels in trans-
values (Tables 2 and 3). gender men. One of these studies (Mueller et al., 2007)
The prevalence of smoking was high in the five studies that observed a slight increase in systolic and diastolic blood
reported this cardiovascular risk factor: 37% (Mueller et al., pressure during testosterone treatment; two studies found a
2007), 30% (Chandra et al., 2010), 51% (Pelusi et al., 2014), modest increase only in systolic blood pressure (Mueller
20% (Wierckx et al., 2014), and 60% (Quiro  s et al., 2015). et al., 2010 and Wierckx et al., 2014) while two did not
Slight but significant increases in BMI were observed in most observe significant changes (Deutsch et al., 2015 and Quiro s
studies, ranging from 1.3 to 11.4%, during testosterone et al., 2015) and one reported a decrease in systolic and

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I. Velho et al.

Table 2 Effects of testosterone administration on BMI, lipid profile and liver enzymes in transgender men

Study BMI Lipid profile Liver enzymes (U/I)

Giltay 22.89  4.53 and TC (mmol/L): 4.57  0.87 and 4.53  1.12; ↓0.8%, p = NS NA
et al. (2004) 24.46  3.85; HDL (mmol/L):1.41  0.43 and 1.14  0.29; ↓19.1%, p < 0.001
↑6.8%, p < 0.001 LDL (mmol/L): 2.72  0.86 and 3.03  1.14; ↑11.3%, p = 0.002
TGL(mmol/L): 0.70 (0.55–1.20) and 0.80 (0.60–1.05); ↑14.2%, p = NS
Berra 21.8  2.9 and TC (mmol/L): 4.5  0.8 and 4.7  0.7; ↑4.4%, p = NS NA
et al. (2006) 22.8  25.6; ↑4.5%, HDL (mmol/L):1.7  0.4 and 1.5  0.4; ↓11.7%, p < 0.005
p < 0.001 LDL (mmol/L):2.5  0.8 and 2.8  0.8; ↑12%, p = NS
TGL (mmol/L): 0.6  0.1 and 0.7  0.1, ↑16.6%, p = NS
Jacobeit NA TC (mg/dL); 215.8  58.5 and 196.7  39.6; ↓8.8%, p < 0.05 NA
et al. (2007) HDL (mg/dL): 51.7  10.8 and 52.2  11.6; ↑0.9%, p = NS
LDL (mg/dL): 140.5  47.0 and 118.3  30.7; ↓15.8%, <0.05
Mueller 23.94  4.86 and TC (mg/dL): 187.26  45.65 and 191.00  42.09; ↑1.9%, p = NS AST: 18.9  6.3 and 21.7  6.8;
et al. (2007) 24.29  4.64; ↑1.4%, ↑14.9%, p = 0.05
p = 0.03 HDL (mg/dL): 59.00  10.88 and 48.29  9.77; ↓18.1%, p < 0.0001 ALT:20.3  9.9 and 24.5  9.4;
↑20.4%, p = 0.05
LDL (mg/dL):126.60  35.27 and 133.49  36.87; ↑5.4%, p = NS GGT:15.8  11.0 and 20.7  12.2;
TGL (mg/dL): 122.14  54.67 and 152.43  51.24; ↑24.7%, p = 0.02 ↑30.8%, p = 0.05
Jacobeit NA TC (mg/dL): 218  47 and 188  42; ↓13.7%, p < 0.05 AST:24  9 and 23  9; ↓4.1%, p = NS
et al. (2009) HDL (mg/dL): 50  11 and 51  10; ↑2%, p = NS ALT:22  7 and 22  7; 0%, p = NS
LDL (mg/dL): 139  48 and 119  46; ↓14.3%, p < 0.05
TGL (mg/dL): 88  14 and 87  15; ↓1.1%, p = NS
Mueller 24.1  4.5 and TC (mg/dL):185.8  33.4 and 185.8  34.0; 0%, p = NS AST: 19.6  6.4 and 21.3  4.5;
et al. (2010) 24.2  3.8; HDL (mg/dL): 61.8  16.3 and 47.3  13, ↓23.4%; p < 0.0001 ↑8.6%, p = NS
↑0.4%, p = NS LDL (mg/dL): 131.2  32.4 and 141.4  29.0; ↑7.7%, p = 0.05 ALT: 19.9  9.6 and 22.9  4.6;
↑15%, p < 0.01
TGL (mg/dL): 120.5  64.0 and 148.3  43.2; ↑23%, p < 0.01 GGT:16.4  12.7 and 25.2  11.0;
↑53.5%; p < 0.0001
Cupisti 23.5 (21.6–26.0) and NA NA
et al. (2010) 24.2 (22.0–26.5);
↑2.9%; p = 0.001
Chandra 27.5  5.2 and TC(mg/dL):184  26 and 181  34; ↓1.6%, p = NS AST: 21  5 and 25  7;
et al. (2010) 27.6  3.9; HDL (mg/dL): 52  11 and 40  7; ↓23%; p < 0.001 ↑19%; p = NS
↑0.3%, p = NS LDL (mg/dL):113  22 and 121  29; ↑7.0%, p = NS ALT: 19  7 and 24  10;
TGL (mg/dL);92  72 and 94  41;↑2.1%, p = NS ↑26.3%; p < 0.01
Pelusi 22.1 (19.5–24.6) and TC(mg/dL): 161.5 (145.8–177.1) and 172.6(152.5–192.7); AST: 16.9 (13.7–20.1) and
et al. (2014) 22.4 (20.0–24.8); ↑1.3% a ↑6.8%a 161.3 (145.6–176.9) and 155.7(135.6–175.8); 19.4 (16.5–22.3);
23.9 (21.2–26.6) and ↓3.4% b 174.4 (158.7–190.1) and 178.6 (158.7–198.7); ↑2.4% c p = NS ↑14.7% a 20.2 (16.9–23.4)
24.3 (21.8–26.9); HDL (mg/dL): 62.9 (52.9–70.8) and 58.9(50.167.7); and 18.8 (15.9–21.7);
↑1.6% b ↓6.3%a 67.8 (60.2–75.4) and 58.0(49.6–66.4); ↓6.9% b 16.6 (13.7–19.5) and
↓14.4%b 70.2 (62.6–77.8) and 58.3 (49.9–66.6); 18.4 (15.7–21.1); ↑10.8% c p = NS
↓16.9% c p < 0.0005
LDL (mg/dL): 83.3 (67.3–99.3) and 98.9(79.8–118.2);
↑18.7%a 82.0 (66.8–97.3) and 84.9(66.6–103.1);
↑3.5%b 92.6 (77.4–107.8) and 107.0 (88.7–125.3);
↑15.5% c p = 0.001
22.3 (19.9–24.6) and TGL (mg/dL):72.5 (54.0–90.9) and 68.7(41.3–96.2); ALT:12.8 (9.5–16.1) and
23.6 (21.4–25.8); ↓5.2% a 60.8 (40.4–81.2) and 71.1(40.8–101.5) b 57.4 (38.1–76.7) 17.4 (11.9–22.8);
↑5.8% c; p < 0.0005 and 62.6 (33.8–91.4); ↑9.0% c p = NS ↑35.9% a 15.2 (11.9–18.5)
and 15.0 (9.6–20.4);
↓1.3% b 14.5 (11.5–17.6) and
15.3 (10.3–20.3) c ↑5.5% c p = NS
Wierckx 24.8  5.3 and TC (mg/dL): 171.9  28.1 and 178.2  30.6; ↑3.6%, p = 0.04 AST: 20.0 (17–23) and 24 (18–29.5);
et al. (2014) 25.6  4.4; HDL (mg/dL): 56.3  12.7 and 47.8  10.7; ↓15%; p < 0.001 ↑20%; p = 0.01
↑3.2%; p = 0.01 LDL (mg/dL): 98.4  26.3 and 116.1  28.9; ↑17.9%; p = 0.006 ALT: 16.0 (11.5–20) and 20 (15–25);
TGL(mg/dL): 69.0 (51.7–89.5) and 81.1 (65.3–124.6); ↑17.5%; p < 0.001 ↑25%; p = 0.02
Quiros 25.0  4.7 and TC (mg/dL):166.0  35.1 and 175.6  38.2; ↑5.7%; p = 0.001 NA
et al. (2015) 26.0  3.8; HDL (mg/dL): 52.2  12.2 and 45.4  13.8; ↓13%; p = 0.001
↑4%; p = 003 LDL (mg/dL): 103.8  28.7 and 112.8  30.3; ↑8.6%; p = 0.013
TGL (mg/dL): 70.6  30.7 and 102.3  68.5; ↑44.9%; p < 0.001
Deutsch 29.1  11.2 and TC (mg/dL): 177  38 and 178  42; ↑0.5%; p = NS NA
et al. (2015) 30.0  11.4; HDL (mg/dL): 58  22 and 56  29; ↓3.4%; p = 0.006
↑3%; p = 0.024 LDL (mg/dL): 93  33 and 97  38; ↑4.3%; p = NS
TGL (mg/dL): 75  56 and 73  69; ↓2.6%; p = NS
Fisher 24.9  0.5 and NA NA
et al. (2016) 27.7  4.0;
↑11.4% p < 0.01

Data are expressed as before and during treatment and %change. BMI, body mass index; TC, total cholesterol; TGL, triglycerides; HDL, high-density lipoprotein; LDL,
low-density lipoprotein; NA, not available; NS, not significant.

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TESTOSTERONE THERAPY FOR TRANSGENDER MEN

Table 3 Effects of testosterone administration on blood pressure, hemoglobin and hematocrit in transgender men

Study Blood pressure (mmHg) HB HT

Giltay et al. (2004) SBP: 126.62  13.14 and NA NA

122.02  10.75; ↓3.6%; p = 0.005
DBP: 79.80  8.00 and
77.72  6.81; ↓2.6%; p = 0.032
Berra et al. (2006) NA NA NA
Jacobeit et al. (2007) NA 13.8  1.22 and 15.1  0.68, ↑9.4%, p < 0.05 41.0  3.6 and 44.3  1.4, ↑8%, p < 0.05
Mueller et al. (2007) SBP:129.43  13.38 and 13.17  1.35 and 14.83  1.15; ↑12.6%; p < 0.0001 41.50  3.33 and 46.25  3.35,
133.71  11.33;↑3.3%; p = 0.04 ↑11.4%, p < 0.0001
DBP: 81.14  8.14 and
84.00  5.25; ↑3.5%; p = 0.02
Jacobeit et al. (2009) NA 13.6  1.2 and 16.0  1.5; ↑17.6%; p < 0.05 41.0  4.0 and 46.0  4.0; ↑12.1%; p < 0.05
Mueller et al. (2010) SBP: 129.3  12.0 and 13.2  1.5 and 14.6  0.7; ↑10.6%; p < 0.0001 41.2  3.2 and 44.7  3.7; ↑8.4%; p < 0.0001
135.1  10.3: ↑4.4%; p = 0.01
DBP: 81.0  8.1 and
83.8  9.1; ↑3.4%; p = 0.21
Cupisti et al. (2010) NA NA NA
Chandra et al. (2010) MBP: 87  14 and NA 40  2 and 45  5; ↑12.5%; p < 0.001
91  16; ↑4.5%; p = NS
Pelusi et al. (2014) NA 13.3 (12.7–13.8) and 14.6 (13.8–15.4); ↑9.7% a 39.1 (37.7–40.5) and 43.4 (41.5–45.3);↑10.9% a
13.5 (12.9–14.0) and 14.1 (13.2–14.9); ↑4.4% b 40.6 (39.1–42.2) and 42.6 (40.5–44.6); ↑4.9 b
12.6 (12.0–13.2) and 14.3 (13.5–15.2); 38.4 (36.8–39.9) and 43.1 (40.9–45.2);
↑13.4% c; p < 0.0005 ↑12.2% c; p < 0.0005
Wierckx et al. (2014) SBP: 111.5  12.6 and NA 40.8  2.9 and 45.8  3.0; ↑12.2%; p < 0.001
115.6  11.7; ↑3.6%; p = 0.05
DBP: 70.2  10.5 and
72.5  9.2; ↑3.2%; p = NS
 s et al. (2015)
Quiro SBP: 118.2  9.1 and 13.5  12.1 and 15.3  18.0; ↑13.3%; p < 0.001 NA
120.4  13.0; ↑1.8%; p = NS
DBP: 75.2  8.9 and
76.7  9.4; ↑1.9%; p = NS
Deutsch et al. (2015) SBP:120  23 and NA NA
123  14; ↑2.5%; p = NS
DBP: 72  16 and
70  16; ↓2.7%; p = NS

HB, hemoglobin; HT, hematocrit; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean arterial blood pressure; NA, not available; NS, not significant.

diastolic blood pressure levels (Giltay et al., 2004). In one

Adverse effects
study, blood pressure was expressed as mean arterial pres-
Severe adverse effects were not reported by any of the 12 stud-
sure, and no changes were observed (Chandra et al., 2010)
ies. However, in one study (Mueller et al., 2007), two patients
(Table 3).
developed hypertension. Arterial blood pressure returned to nor-
Data on changes in lipid profile are presented in Table 3.
mal after cessation of testosterone therapy. In another study
While decreases in HDL-c and increases in LDL-c were consis-
(Wierckx et al., 2014), two patients developed erythrocytosis (he-
tently observed in most studies, unfavorable changes in total
matocrit levels above 52%, the upper limit of the normal adult
cholesterol and triglycerides were less uniform and varied
male range) after 9 and 12 months of treatment. In the same
between studies.
study, two subjects were switched from testosterone unde-
Eight studies assessed hemoglobin and/or hematocrit levels
canoate to short-acting testosterone esters after 9 and
(Table 3), and all observed a relationship between testos-
12 months, mainly because of muscle and joint aches.
terone administration and increased hemoglobin and hemat-
In one study, hair loss was associated with the duration of
ocrit levels. Reference values for males were not exceeded in
androgen administration, and was present in about 50% of
any of these studies, as inferred from the study results or, in
subjects after 13 years (Giltay et al., 2004). Hair loss was not
three studies, explicitly reported (Jacobeit et al., 2007; Muel-
associated with BMI, blood pressure or lipid profile during the
ler et al., 2007, 2010); discontinuation of androgen therapy
first 3–4 months of androgen therapy. Acne was observed in
was not required. The increase in hemoglobin ranged from
approximately 15% of patients in two studies (Mueller et al.,
4.9% (Pelusi et al., 2014) to 12.5% (Chandra et al., 2010),
2007, 2010).
while the increase in hematocrit levels ranged from 4.4%
(Pelusi et al., 2014) to 17.6% (Jacobeit et al., 2009). The only
study performing a separate analysis of different testosterone DISCUSSION
formulations observed smaller increases in hemoglobin and The present systematic review summarizes the literature on
hematocrit in patients treated with testosterone gel (Pelusi the effects of testosterone therapy on BMI, blood pressure, meta-
et al., 2014). bolic profile, hematocrit, hemoglobin, and liver enzymes in
The six studies assessing liver function showed only slight or transgender men. Although only a few studies are available,
no changes during testosterone administration (Table 2). The there is agreement regarding the relative safety of short term
increases did not exceed male reference values. testosterone treatment in transgender men (Gooren et al., 2008;

© 2017 American Society of Andrology and European Academy of Andrology Andrology, 2017, 5, 881–888 885
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I. Velho et al.

Irwig, 2016). The studies analyzed describe various periods of testosterone therapy found that exogenous testosterone was
exposure to different testosterone formulations and show only associated with lower serum concentrations of total cholesterol
modest unfavorable changes in BMI, lipid profile, and hemato- only after long-term therapy (Guo et al., 2016). In turn, a study
logical variables. with 120 hypogonadal men showed an increase in LDL levels
Indeed, until now, only two meta-analyses of data on testos- after 8 years of treatment (Permpongkosol et al., 2016). There-
terone treatment of transgender men have been published (Ela- fore, further long-term clinical trials are needed to confirm the
min et al., 2010; Klaver et al., 2016): the first of these studies impact of androgen treatment on LDL-cholesterol in transgen-
addressed cardiovascular risk events, blood pressure, and lipid der men.
profile (Elamin et al., 2010), and the second examined the effects Erythropoiesis is one of the many physiological functions
of cross-sex hormone therapy on body composition (Klaver stimulated by androgens. Studies suggest that androgens act
et al., 2016). Elamin et al. (2010) found mild changes in lipids indirectly to stimulate erythropoietin and directly to stimulate
and in blood pressure levels. However, because of methodologi- erythropoiesis in bone marrow (Shahani et al., 2009; Bachman
cal limitations, the data were inconclusive regarding relevant et al., 2014). In a recent meta-analysis about the adverse effects
outcomes such as mortality, stroke, myocardial infarction, or of testosterone treatment in hypogonadal men, Fernandez-Bal-
venous thromboembolism. sells et al., (2010) found a positive association between increased
Sex steroid hormones are important determinants of regional testosterone levels and higher hematocrit and hemoglobin,
fat deposition (Elbers et al., 1999). In this study, only a very which is in agreement with our review. In fact, we found a mild
modest increase in BMI was observed in most, but not all, stud- increase in hematocrit and hemoglobin in some studies; the final
ies. This finding is in line with data from the European Network values, however, were still within the physiological male range.
for Investigation of Gender Incongruence (ENIGI), which did not While a study of long-term and side effects of cross-sex hormone
report changes in BMI after 1 year of parenteral testosterone therapy in transgender people did not observe cardiovascular
treatment (Van Caenegem et al., 2015). In turn, a recent meta- events or deep venous thrombosis in transgender men (Wierckx
analysis about the effects of testosterone on body composition et al., 2012), increases in hematocrit and hemoglobin related to
in 354 transgender men found an increase in total body weight sex-hormone therapy may represent a concern in older trans-
and lean body mass, and a decline in body fat (Klaver et al., gender men, in those who are obese, dyslipidemic and/or hyper-
2016). These results may reflect the use of different androgen tensive, and therefore at higher risk of cardiovascular events
formulations and/or treatment duration, which ranged from 3 to such as thrombosis. Indeed, the goal of cross-sex hormone treat-
24 months. Interestingly, in our review, the studies analyzing ment for transgender men should be to achieve equal or slightly
body composition also reported a significant increase in lean lower male physiological levels of serum testosterone to main-
mass, suggesting a link between increased BMI and lean mass tain adequate androgenization (Hembree et al., 2009; Traish &
gain. Gooren, 2010; Meriggiola & Gava, 2015).
Regarding the effects of testosterone treatment on blood pres- Regarding liver enzymes, the studies included in our system-
sure in transgender men, mild, clinically irrelevant, or no atic review again showed inconsistent results; AST and ALT
changes were found in most studies. However, one study levels remained unchanged in some studies, while others
reported two case of hypertension, with return to normal blood reported increases in these variables after testosterone treat-
pressure values after cessation of testosterone therapy. Other ment. It should be noted, however, that the reported increases
studies beyond the ones included in the present review have were not clinically relevant (Mueller et al., 2010). Our data are
reported similar increases (Emi et al., 2008) and decreases (Goo- consistent with the results reported by other studies showing
ren et al., 2008) in blood pressure during/following testosterone no significant alterations (Meriggiola et al., 2008; Traish &
treatment in transgender men. This discrepancy could be Gooren, 2010). Nevertheless, a retrospective study of morbidity
explained by differences in ethnicity or treatment duration. In aspects in 293 transgender men found a transient elevation
addition, no data are yet available regarding older patients or (<6 months) in liver enzymes in 13 patients, and a persistent
hypertensive transgender men receiving cross-sex hormone elevation (more than 6 months) in 20 patients during testos-
therapy. terone treatment (Van Kesteren et al., 1997). Therefore, long-
In the present review, the effect of the various testosterone term studies are needed to assess the impact of androgen ther-
formulations seemed to be more unfavorable for HDL- and LDL- apy on liver function. Meanwhile, monitoring liver enzymes
cholesterol as compared to the other lipid profile-related might be restricted to transgender men presenting other medi-
variables. Indeed, discrepant results were observed for total cal conditions related to risk of potential liver dysfunction,
cholesterol and triglycerides. A previous systematic review and such as obesity, dyslipidemia, insulin resistance associated to
meta-analysis addressing the effects of different androgen for- type 2 diabetes.
mulations on cardiovascular risk has reported an increase in Limitations of the present systematic review are the small
triglycerides after testosterone treatment of transgender men number of published articles and the small sample sizes. How-
(Elamin et al., 2010). ever, similar analyses are not available in the literature, and
In addition, considering that the treatment of hypogonadal since the impact of androgen treatment on transgender men is
men involves testosterone replacement in similar doses to those not fully established, the present findings may serve as basis for
administered to transgender men, data regarding that popula- future studies.
tion may also be relevant to assess the effects of testosterone In conclusion, the present review showed that exogenous
treatment on lipid profile in transgender men. In this sense, a testosterone administration to transgender men was associated
recent review and meta-analysis including 16 studies and 1921 with modest increases in BMI, hemoglobin/hematocrit, and
hypogonadal individuals to evaluate the efficacy and safety of LDL-cholesterol and decreases in HDL-cholesterol. Less

886 Andrology, 2017, 5, 881–888 © 2017 American Society of Andrology and European Academy of Andrology
 ANDROLOGY

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TESTOSTERONE THERAPY FOR TRANSGENDER MEN

consistent results were observed for blood pressure values, total Elamin MB, Garcia MZ, Murad MH, Erwin PJ & Montori VM. (2010)
cholesterol, triglycerides and liver enzymes. Overall, the studies Effect of sex steroid use on cardiovascular risk in transsexual
included in this review had low quality of evidence, mainly individuals: a systematic review and meta-analyses. Clin
because of the absence of clinical randomized trials or con- Endocrinol 72, 1–10.
Elbers J, Asscheman H, Seidell J & Gooren L. (1999) Effects of sex
trolled studies and to low sample sizes, suggesting that caution
steroid hormones on regional fat depots as assessed by magnetic
is still necessary when prescribing hormone therapy to transgen-
resonance imaging in transsexuals. Am J Physiol Endocrinol Metab
der men, especially those presenting risk factors. Further studies 276, 317–325.
are needed in order to verify the impact of age and car- Emi Y, Adachi M, Sasaki A, Nakamura Y & Nakatsuka M. (2008) Increased
diometabolic comorbidities on safety, and to investigate if speci- arterial stiffness in female-to-male transsexuals treated with androgen.
fic formulations are more adequate for transgender men at J Obstet Gynaecol Res 34, 890–897.
metabolic or cardiovascular risk. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF,
Albuquerque F, Mullan RJ & Wang AT. (2010) Adverse effects of
ACKNOWLEDGEMENTS testosterone therapy in adult men: a systematic review and meta-
We thank Cintia Tusset for her assistance with data collection. analysis. J Clin Endocrinol Metab 95, 2560–2575.
Fisher AD, Castellini G, Ristori J, Casale H, Cassioli E, Sensi C, Fanni E,
Support for this work was provided by Conselho Nacional de
Amato AM, Bettini E, Mosconi M, D ettore D, Ricca V & Maggi M.
Desenvolvimento Cientıfico e Tecnolo  gico/Brazilian National
(2016) Cross-sex hormone treatment and psychobiological changes in
Institute of Hormones and Women’s Health (CNPq INCT
transsexual persons: two-year follow-up data. J Clin Endocrinol Metab
573747/2008-3), Brazil; the funding sources had no influence in 101, 4260–4269.
the writing or decision to submit the article for publication. Giltay E, Toorians A, Sarabdjitsingh A, De Vries N & Gooren L. (2004)
Established risk factors for coronary heart disease are unrelated to
DISCLOSURES androgen-induced baldness in female-to-male transsexuals.
The authors declare no competing interests. J Endocrinol 180, 107–112.
Gooren L. (2005) Hormone treatment of the adult transsexual patient.
AUTHORS’ CONTRIBUTIONS Horm Res Paediatr 64, 31–36.
IV was involved in data collection, analysis/interpretation, Gooren LJ, Giltay EJ & Bunck MC. (2008) Long-term treatment of
transsexuals with cross-sex hormones: extensive personal experience.
drafting of article. TF was involved in data collection, analysis/
J Clin Endocrinol Metab 93, 19–25.
interpretation, critical revision of article. PZ was involved in data
Guo C, Gu W, Liu M, Peng B, Yao X, Yang B & Zheng J. (2016) Efficacy and
analysis/interpretation, critical revision of article. PMS was safety of testosterone replacement therapy in men with
involved in concept/design, data analysis/interpretation, draft- hypogonadism: a meta-analysis study of placebo-controlled trials. Exp
ing of article, critical revision of article. All authors read and Ther Med 11, 853–863.
approved the final manuscript. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ,
Meyer WJ III, Spack NP & Montori VM. (2009) Endocrine treatment of
REFERENCES transsexual persons: an Endocrine Society clinical practice guideline.
American Psychiatric Association. (2000) Diagnostic and Statistical J Clin Endocrinol Metab 94, 3132–3154.
Manual of Mental Disorders DSM 4, Revised 4th edn. American Irwig MS. (2016) Testosterone therapy for transgender men. Lancet
Psychiatric Press, Washington, DC. Diabetes Endocrinolol pii, S2213–S8587.
American Psychiatric Association. (2013) Diagnostic and Statistical Jacobeit JW, Gooren LJ & Schulte HM. (2007) Long-acting intramuscular
Manual of Mental Disorders DSM 5, 5th edn. American Psychiatric testosterone undecanoate for treatment of female-to-male
Press, Washington, DC. transgender individuals. J Sex Med 4, 1479–1484.
Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M & Bhasin S. Jacobeit J, Gooren L & Schulte H. (2009) Safety aspects of 36 months of
(2014) Testosterone induces erythrocytosis via increased erythropoietin administration of long-acting intramuscular testosterone undecanoate
and suppressed hepcidin: evidence for a new erythropoietin/ for treatment of female-to-male transgender individuals. Eur J
hemoglobin set point. J Gerontol A Biol Sci Med Sci 69, 725–735. Endocrinol 161, 795–798.
Berra M, Armillotta F, D’Emidio L, Costantino A, Martorana G, Pelusi G & Klaver M, Dekker M, Mutsert R, Twisk J & Heijer M. (2016) Cross-sex
Meriggiola MC. (2006) Testosterone decreases adiponectin levels in hormone therapy in transgender persons affects total body weight,
female to male transsexuals. Asian J Androl 8, 725–729. body fat and lean body mass: a meta-analysis. Andrologia 1–11. [Epub
Chandra P, Basra SS, Chen TC & Tangpricha V. (2010) Alterations in ahead of print]
lipids and adipocyte hormones in female-to-male transsexuals. Int J Levy A, Crown A & Reid R. (2003) Endocrine intervention for
Endocrinol, article ID 945053 transsexuals. Clin Endocrinol (Oxf) 59, 409–418.
Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G, Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis
Feldman J & Meyer WJ. (2012) Standards of care for the health of JP & Moher D. (2009) The PRISMA statement for reporting
transsexual, transgender, and gender-nonconforming people, version systematic reviews and meta-analyses of studies that evaluate
7. Int J Transgend 13, 165–232. health care interventions: explanation and elaboration. J Clin
Cupisti S, Giltay EJ, Gooren LJ, Kronawitter D, Oppelt PG, Beckmann MW Epidemiol 62, el 34.
& Mueller A. (2010) The impact of testosterone administration to Meriggiola MC & Gava G. (2015) Endocrine care of transpeople part I. A
female-to-male transsexuals on insulin resistance and lipid review of cross-sex hormonal treatments, outcomes and adverse
parameters compared with women with polycystic ovary syndrome. effects in transmen. Clin Endocrinol (Oxf) 83, 597–606.
Fertil Steril 94, 2647–2653. Meriggiola MC, Armillotta F, Costantino A, Altieri P, Saad F, Kalhorn T &
Deutsch MB, Bhakri V & Kubicek K. (2015) Effects of cross-sex hormone Pelusi G. (2008) Effects of testosterone undecanoate administered
treatment on transgender women and men. Obstet Gynecol 125, alone or in combination with letrozole or dutasteride in female to
605–610. male transsexuals. J Sex Med 5, 2442–2453.

© 2017 American Society of Andrology and European Academy of Andrology Andrology, 2017, 5, 881–888 887
 ANDROLOGY

20472927, 2017, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/andr.12382 by CAPES, Wiley Online Library on [02/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
I. Velho et al.

Michel A, Mormont C & Legros J-J. (2001) A psycho- Shahani S, Braga-Basaria M, Maggio M & Basaria S. (2009)
endocrinological overview of transsexualism. Eur J Endocrinol Androgens and erythropoiesis: past and present. J Endocrinol
145, 365–376. Invest 32, 704–716.
Moore E, Wisniewski A & Dobs A. (2003) Endocrine treatment of Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D &
transsexual people: a review of treatment regimens, outcomes, and Thacker SB. (2000) Meta-analysis of observational studies in
adverse effects. J Clin Endocrinol Metab 88, 3467–3473. epidemiology: a proposal for reporting. JAMA 283, 2008–2012.
Mueller A, Kiesewetter F, Binder H, Beckmann MW & Dittrich R. (2007) Traish AM & Gooren LJ. (2010) Safety of physiological testosterone
Long-term administration of testosterone undecanoate every therapy in women: lessons from female-to-male transsexuals (FMT)
3 months for testosterone supplementation in female-to-male treated with pharmacological testosterone therapy. J Sex Med 7, 3758–
transsexuals. J Clin Endocrinol Metab 92, 3470–3475. 3764.
Mueller A, Haeberle L, Zollver H, Claassen T, Kronawitter D, Oppelt PG & Van Caenegem E, Wierckx K, Taes Y, Schreiner T, Vandewalle S, Toye K &
Dittrich R. (2010) Effects of intramuscular testosterone undecanoate T’Sjoen G. (2015) Body composition, bone turnover, and bone mass in
on body composition and bone mineral density in female-to-male trans men during testosterone treatment: 1-year follow-up data from a
transsexuals. J Sex Med 7, 3190–3198. prospective case–controlled study (ENIGI). Eur J Endocrinol 172, 163–
Pelusi C, Costantino A, Martelli V, Lambertini M, Bazzocchi A, Ponti F & 171.
Meriggiola MC. (2014) Effects of three different testosterone Van Kesteren PJ, Asscheman H, Megens JA & Gooren LJ. (1997) Mortality
formulations in female-to-male transsexual persons. J Sex Med 11, and morbidity in transsexual subjects treated with cross-sex
3002–3011. hormones. Clin Endocrinol (Oxf) 47, 337–343.
Permpongkosol S, Khupulsup K, Leelaphiwat S, Pavavattananusorn Wierckx K, Mueller S, Weyers S, Van Caenegem E, Roef G, Heylens G &
S, Thongpradit S & Petchthong T. (2016) Effects of 8-year T’sjoen G. (2012) Long-term evaluation of cross-sex hormone
treatment of long-acting testosterone undecanoate on metabolic treatment in transsexual persons. J Sex Med 9, 2641–2651.
parameters, urinary symptoms, bone mineral density, and sexual Wierckx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher A, Toye K &
function in men with late-onset hypogonadism. J Sex Med 13, T’Sjoen G. (2014) Cross-sex hormone therapy in trans persons is safe
1199–1211. and effective at short-time follow-up: results from the European
Quir
os C, Patrascioiu I, Mora M, Aranda GB, Hanzu FA, G omez-Gil E & network for the investigation of gender incongruence. J Sex Med 11,
Halperin I. (2015) Effect of cross-sex hormone treatment on 1999–2011.
cardiovascular risk factors in transsexual individuals. Experience in a World Health Organization. (1992) The ICD-10 International Statistical
specialized unit in Catalonia. Endocrinol Nutr (English Edition) 62, Classification of Diseases and Related Health Problems, 10th Revision.
210–216. World Health Organization, Geneva.

888 Andrology, 2017, 5, 881–888 © 2017 American Society of Andrology and European Academy of Andrology