The metabolic effects of hormonal treatment in transgender males: Safety of the testosterone gender-affirming therapy

Abstract

BACKGROUND:

Gender dysphoria is characterised by a sense of distress because of discordance between the self-perception of gender identity and the assigned sex. Hormonal treatment of transgender males uses testosterone to induce and preserve masculinisation.

OBJECTIVE:

The study investigated the safety of testosterone therapy in transgender males.

METHODS:

The present study used a retrospective file review of transgender male subjects who were treated with testosterone (initially transdermal testosterone gel and subsequently parenteral testosterone undecanoate) for at least 18 months and had subsequently achieved a serum testosterone level within the normal range of cisgender male counterparts. Changes in somatometric data and blood biomarkers were investigated.

RESULTS:

The mean testosterone serum levels after approximately 18 months of treatment were about 545 ng/dL (SD ± 94 ng/dL). There was a statistically significant rise in body mass index (𝜒_d = +1.23 kg/m²) with a reduction in blood glucose (𝜒_d = −5.33 mg/dL) as well as statistically significant increases in aspartate transaminase (𝜒_d = +4.3 U/L), haemoglobin (𝜒_d = +1.72 g/dL), and haematocrit (𝜒_d = +4.76%). In contrast, there were no significant changes in the lipidaemic profile of the subjects.

CONCLUSIONS:

Treatment with testosterone is routinely used for the promotion of virilising physical changes in transgender males. However, the likelihood of adverse effects of continuous treatment is still unclear. This study contributed to the notion that achieving testosterone levels within the target range is a prerequisite for the safety of the gender-affirming treatment.

Keywords

Transgender persons testosterone evidence-based medicine

1. Introduction

The major determinants of sex development in humans consist of three essential components: chromosomal sex, gonadal sex (sex determination), and phenotypic sex (sex differentiation) [1]. Chromosomal sex is defined by the karyotype (normally 46,XY or 46,XX in humans) that is established at the time of fertilisation. Most mammals, including humans, have an XY sex-determination system in which the presence of an intact Y chromosome triggers the development of a male reproductive system [2]. Gonadal sex refers to the anatomic/histologic and physiologic characteristics of the gonads (testes or ovaries). The embryonic gonad is bipotential and can develop into either a testis or an ovary under genetic regulation by specific genes [3]. Finally, phenotypic (or anatomic) sex refers to the features of the external and internal genitalia and the secondary sex characteristics [4].

The term ‘gender dysphoria’ is applied to describe the affective and cognitive discontent of individuals with their biologic sex (most usually the assigned gender at birth) [5]. ‘Transgender’ is an umbrella term which describes individuals whose gender self-perception is identified more strongly with the opposite sex or with a variance that falls outside the classical binary definition of male/female [6]. In particular, transgender males are people who self-identify as male, but were assigned female at birth. Over the past couple of decades, the prevalence of gender dysphoria has risen, probably reflecting the increase in referral rates to specialised gender identity clinics [7]. The estimation of prevalence of gender dysphoria depends on the applied methodology. According to this notion, the prevalence of transgender people seeking or receiving gender-affirmation therapy is approximately 1 in 8,000 among assigned males at birth and 1 in 20,000 among assigned females at birth (1 in 11,000 individuals in the overall population), whilst the prevalence of self-reported transgender identity is much higher (around 1:200 in assigned males at birth, 1:400 in assigned females at birth, and 1:300 in the general population) [8].

The management of gender dysphoria requires a multilevel care approach. If gender transitioning is desired, treatment focuses on three elements: support from mental health professionals (if needed), hormonal therapy, and surgeries to change genitals and other sex features (although the latter are not always performed) [9]. Hormonal treatment in transgender persons aims at suppressing the secretion of the endogenous sex hormones and replacing them with the hormones of the desired sex. In particular, virilising hormonal therapy uses testosterone to induce and preserve masculinisation and to minimize the production of oestrogens. In most cases, treatment includes parenteral (injections) or transdermal (patches, gels) regimens [10]. The target level of testosterone in the serum should be around 400–700 ng/dL which is approximately equal to the respective level in adult cisgender males [11]. A progestin can be added temporarily to the treatment to inhibit menstruation if adequate suppression of the hypothalamic-pituitary-ovarian axis has not been achieved solely by testosterone. If this addition is also not successful, a gonadotropin-releasing hormone agonist (GnRH agonist) may be used instead of progestin [12].

Hormonal therapy in transgender people aims at inducing physical changes towards the biologic features of the desired gender. In transgender males, treatment with testosterone is expected to result in increased muscle mass and reduced fat mass, increased facial and bodily hair, more intense sexual desire, enlargement of the clitoris, deepening of the voice, and cessation of menstruation [13]. However, the use of testosterone has potential metabolic adverse effects. The relevant possible risks include polycythaemia, liver toxicity, atherogenic lipid profile, glucose intolerance, and cardiovascular disease, although the existing evidence is not strong [13].

Testosterone replacement therapy has been extendedly used to treat various forms of androgen deficiency. In men with hypogonadism, it has been shown to enhance libido and overall sexual function, increase bone mineral density and skeletal muscle mass, and decrease body fat [14]. Gender-affirming hormonal therapy in transgender male persons mimics replacement treatment in hypogonadal men by administering testosterone in various formulations in order to transform and maintain secondary sex characteristics. Nevertheless, the recipients may be susceptible to potential adverse effects associated with long-term treatment. Although the evidence is not firm, testosterone replacement therapy may increase cardiovascular morbidity and mortality and it may also cause erythrocytosis. The impact on glucose homeostasis is not clear [15]. Therefore, monitoring patients to assess the clinical and biochemical course and detect potential adverse effects is essential in order to demonstrate the benefit of the treatment.

2. Materials and methods

The aim of the present study was to investigate whether testosterone treatment in transgender males is associated with increased risk for adverse metabolic effects. For the purpose of the research, this study used a retrospective file review of 65 trans male subjects having attended the Andrology Outpatient Clinic at the Hospital ‘Elena Venizelou’ in Athens, Greece. The latter is a general hospital which provides primary and secondary care specialised in reproductive health and fertility. Within the metropolitan area of Athens, the ‘Elena Venizelou’ Hospital is the sole public provider of transgender-related hormonal treatment and is currently serving a little more than 100 trans people. The department started delivering small-scale transgender care services in the early 2000s and since 2010 it has been systematically providing care to the trans population.

The study population consisted of transgender males (specifically persons who sought hormonal treatment to affirm their gender identity). The inclusion criteria were: (i) age over 17 years old at the start of the testosterone therapy, (ii) subjects with a baseline and further follow-up consultations, (iii) no use of hormones prior to the baseline consultation, and (iv) personal medical history without diseases (such as anaemia, diabetes mellitus, dyslipidaemia, hepatic disease) or use of medication (such as anabolic steroids) that could influence the metabolic factors under study. All subjects were submitted to gender-affirming treatment with testosterone for at least 18 months and had subsequently achieved a serum testosterone concentration within the target level (400–700 ng/dL). The conduction of the research complied with the Greek national code for medical ethics.

The present study compared available data from two phases: (i) a baseline consultation in which subjects were naïve to hormonal treatment and (ii) a later visit approximately 18 months after the initiation of the gender-affirming therapy with testosterone. Demographic data (age, legally recognised gender) were collected from the time of the baseline visit, whilst somatometric data, including weight, height, and body mass index (BMI) and fasting biomarkers’ serum values (glucose, alanine transaminase, aspartate transaminase, cholesterol and associated lipoproteins, triglycerides, haemoglobin, haematocrit) were recorded both from the time of the baseline visit and from the later visit. Dosage and route of administration of the testosterone treatment were also noted. Results were analysed with the use of paired t-tests in which each subject was compared to himself. A P-value <0.05 was considered as statistically significant to reject the null hypothesis. Normal distribution of the data was checked with the Kolmogorov–Smirnov test of normality.

3. Results

Data were retrieved from the files of 33 transgender males who fulfilled the inclusion criteria of the study. However, baseline measurements were not available in every file and consequently the sample size for the study of some biomarkers was less than the overall number of participants (see Table 1). The mean age of the participants at the time of the baseline visit was 23.45 years old (SD ± 5.9 years). All the subjects were initially treated with transdermal testosterone (gel 2%) until the achievement of stable desirable serum levels followed by parenteral testosterone undecanoate for maintenance. The mean testosterone serum levels after approximately 18 months of treatment were about 545 ng/dL (SD ± 94 ng/dL). The values of the laboratorial data and BMI measurements (both before and after the treatment with testosterone) were found to be normally distributed.

Table 1
Comparison of BMI and biomarkers between baseline and after 18 months of treatment

N 𝜇₀ (± SD) 𝜇_d (± SD) 𝜒_d P-value 95% region of acceptance for 𝜒_d

BMI (kg/m²)

Baseline 33 24.47 (± 4.19) +1.23 0.0054 lower limit: − 0.8397

At 18 months 25.7 (± 4.46) upper limit: + 0.8397

Serum glucose (mg/dL)

Baseline 15 86.13 (± 6.85) −5.33 0.0114 lower limit: − 3.9307

At 18 months 80.8 (± 10.37) upper limit: + 3.9307

Cholesterol (mg/dL)

Baseline 29 156.69 (± 23.55) +0.79 0.8166 lower limit: − 6.9401

At 18 months 157.48 (± 29.13) upper limit: + 6.9401

LDL-cholesterol (mg/dL)

Baseline 18 88.67 (± 25.69) +2.05 0.6388 lower limit: − 9.0746

At 18 months 90.72 (± 32.01) upper limit: + 9.0746

HDL-cholesterol (mg/dL)

Baseline 18 55.5 (± 11.05) −2.39 0.4489 lower limit: − 6.5021

At 18 months 53.11 (± 10.28) upper limit: + 6.5021

Triglycerides (mg/dL)

Baseline 29 64.93 (± 21.4) +7.21 0.2343 lower limit: − 12.146

At 18 months 72.14 (± 32.48) upper limit: + 12.146

Alanine transaminase (U/L)

Baseline 30 16.03 (± 7.94) +3.24 0.1247 lower limit: − 4.1819

At 18 months 19.27 (± 8.25) upper limit: + 4.1819

Aspartate transaminase (U/L)

Baseline 30 16 (± 4.42) +4.3 0.0199 lower limit: − 3.5697

At 18 months 20.3 (± 8.61) upper limit: + 3.5697

Haemoglobin (g/dL)

Baseline 33 12.93 (± 1.07) +1.72 <0.0001 lower limit: − 0.3149

At 18 months 14.65 (± 1.08) upper limit: + 0.3149

Haematocrit (%)

Baseline 29 38.58 (± 2.94) +4.76 <0.0001 lower limit: − 1.0124

At 18 months 43.33 (± 2.96) upper limit: + 1.0124

	N	𝜇₀ (± SD) 𝜇_d (± SD)	𝜒_d	P-value	95% region of acceptance for 𝜒_d
BMI (kg/m²)
Baseline	33	24.47 (± 4.19)	+1.23	0.0054	lower limit: − 0.8397
At 18 months		25.7 (± 4.46)			upper limit: + 0.8397
Serum glucose (mg/dL)
Baseline	15	86.13 (± 6.85)	−5.33	0.0114	lower limit: − 3.9307
At 18 months		80.8 (± 10.37)			upper limit: + 3.9307
Cholesterol (mg/dL)
Baseline	29	156.69 (± 23.55)	+0.79	0.8166	lower limit: − 6.9401
At 18 months		157.48 (± 29.13)			upper limit: + 6.9401
LDL-cholesterol (mg/dL)
Baseline	18	88.67 (± 25.69)	+2.05	0.6388	lower limit: − 9.0746
At 18 months		90.72 (± 32.01)			upper limit: + 9.0746
HDL-cholesterol (mg/dL)
Baseline	18	55.5 (± 11.05)	−2.39	0.4489	lower limit: − 6.5021
At 18 months		53.11 (± 10.28)			upper limit: + 6.5021
Triglycerides (mg/dL)
Baseline	29	64.93 (± 21.4)	+7.21	0.2343	lower limit: − 12.146
At 18 months		72.14 (± 32.48)			upper limit: + 12.146
Alanine transaminase (U/L)
Baseline	30	16.03 (± 7.94)	+3.24	0.1247	lower limit: − 4.1819
At 18 months		19.27 (± 8.25)			upper limit: + 4.1819
Aspartate transaminase (U/L)
Baseline	30	16 (± 4.42)	+4.3	0.0199	lower limit: − 3.5697
At 18 months		20.3 (± 8.61)			upper limit: + 3.5697
Haemoglobin (g/dL)
Baseline	33	12.93 (± 1.07)	+1.72	<0.0001	lower limit: − 0.3149
At 18 months		14.65 (± 1.08)			upper limit: + 0.3149
Haematocrit (%)
Baseline	29	38.58 (± 2.94)	+4.76	<0.0001	lower limit: − 1.0124
At 18 months		43.33 (± 2.96)			upper limit: + 1.0124

N: number of participants, 𝜇₀: baseline mean value, 𝜇_d: mean value at 18 months, SD: standard deviation, X _d: mean difference.

This cohort demonstrated a statistically significant rise in BMI and reduction in blood glucose during the first 18 months of testosterone therapy. In addition, there was a statistically significant increase in aspartate transaminase as well as in the values of haemoglobin and haematocrit. Nevertheless, only one value of aspartate transaminase marginally surpassed the upper limit of the normal range, whilst none of the subjects developed polycythaemia. On the other hand, there were no significant changes in the parameters of the lipidaemic profile. Table 1 presents the numeric results of the analysis of the data.

4. Discussion

The safety of chronic administration of testosterone is an important aspect of masculinising gender-affirming treatment. Most of the existing information suggests that hormonal therapy is safe, although some well-documented medical concerns exist [16]. The present study applied a retrospective file review of transgender males in order to reveal potential metabolic changes due to testosterone therapy and evaluate the associated health risks for the recipients. For this purpose, it investigated outcomes in BMI and serum biomarkers in subjects who had received testosterone treatment for approximately 18 months and had achieved serum values within the target levels. The period of 18 months was conventionally selected as a sufficient amount of time for the occurrence of possible changes in somatometric data and blood biomarkers. Indeed, the Endocrine Society clinical guidelines included trials with duration of therapy that ranged from 12 to 52 weeks for detecting potential adverse effects of testosterone treatment in hypogonadal men [14].

Testosterone is involved in carbohydrate metabolism. Indeed, there is a possible association between testosterone and insulin sensitivity. However, it is not clear whether this association is direct or indirect through changes in BMI, weight, and visceral fat [17]. Although testosterone does not seem to have any effect on insulin action in men without diabetes, it can improve glycaemic control in males with type 2 diabetes mellitus [18]. Nevertheless, the research evidence is not consistent. In case of transgender males, relevant studies have showed either a neutral effect [19] or an increase in insulin resistance [20] from the testosterone treatment. In the present study, a statistically significant reduction in blood glucose was demonstrated after 18 months of hormonal treatment. However, data on serum concentrations of insulin or other related to insulin sensitivity biomarkers were not available. Therefore, no safe conclusions can be drawn about the effect of testosterone therapy on glucose homeostasis. It is possible that the reduction in serum glucose was related to the associated body fat redistribution and increase in lean body mass percentage due to hormonal treatment.

The examination of this cohort revealed an increase in BMI after the initiation of hormonal treatment. Similarly, other studies have demonstrated an increase in BMI in transgender males [21]. This effect probably reflects the increase in muscle mass which is induced by the anabolic action of testosterone [22]. The gender-affirming therapy with testosterone in transgender males induces the formation of a more masculine body shape by reducing and redistributing fat mass and by increasing lean mass. The final outcome is a net raise in body weight over the first twelve months of the treatment [23] which is in accordance with the results of the present study.

There is evidence suggesting that hormonal therapy in trans men may adversely affect their lipid profile. Most evidence indicates that testosterone treatment may increase triglycerides and decrease HDL-cholesterol in plasma without changes in total cholesterol. LDL-cholesterol may remain stable or be elevated [24,25]. The different concentrations of gonadal hormones between sexes are thought to be important factors contributing to the differences in the lipid parameters, with cisgender males having higher total cholesterol, LDL cholesterol and triglycerides and lower plasma HDL cholesterol in comparison with cisgender females. Therefore, the effect of exogenous testosterone may imitate the transition from a female to a male lipid profile [26,27]. However, the present study did not reveal statistically significant changes in any of the lipid parameters.

Hepatic toxicity due to the administration of testosterone is a major concern during the treatment of transgender males [28], although it is primarily associated with oral formulations [29]. Alanine transaminase (ALT) and aspartate transaminase (AST) are the most reliable markers of hepatocellular injury [30]. In this study, both ALT and AST were elevated after hormonal treatment, but only the increase of AST reached statistically significant levels. Nevertheless, only in one of the participants in the study, the level of transaminases exceeded the upper normal limits. Clinicians should be aware of the possible risks associated with the administration of testosterone to transgender males, especially in the presence of hepatic dysfunction.

Polycythaemia is an unwanted side effect of testosterone treatment in trans men because high blood viscosity may increase the risk of thrombosis [31,32]. In this study, testosterone therapy induced elevations in haemoglobin and haematocrit, but none of the subjects developed erythrocytosis. The direct effects of testosterone to erythropoiesis include the stimulation of erythropoietin and the suppression of hepcidin (a regulatory peptide of iron absorption and transport). These two mechanisms reset the regulation of the secretion of erythropoietin at a higher physiologic level of haemoglobin [33]. Adult male humans have higher haemoglobin and haematocrit levels than those of their female counterparts. This gender difference is observed in almost all mammals and most probably derives from the constricting effect of testosterone on the renal microvasculature which in turn promotes the secretion of erythropoietin [34]. Due to hormonal replacement, the haematologic parameters for trans men should be evaluated against the respective cisgender males’ reference ranges [35] in order to safely monitor these individuals.

5. Conclusions

Testosterone therapy is routinely used for the management of body-related uneasiness associated with gender dysphoria among trans men. Continuous replacement treatment with androgen is necessary for the maintenance of virilising physical changes. However, the likelihood of adverse effects of long-term treatment is still not well determined [36]. The results of the present study suggest that achieving testosterone levels within the target range (400–700 ng/dL) is a prerequisite for the safety of the gender-affirming treatment. In this cohort, hormonal therapy caused no negative effects on BMI or biomarkers of cardiovascular risk, glucose homeostasis, and hepatic function in treated individuals with acceptable serum testosterone levels. Nevertheless, due to the scarcity of consultations for gender dysphoria in clinical practice, the sample size is not large. Moreover, some other important issues require further research. In particular, it should be investigated whether metabolic changes remain minimal after more extended treatment or in individuals of older age.

The benefits and risks of testosterone replacement therapy must be clearly discussed with the patient. Testosterone levels and other laboratorial parameters, including haemoglobin, haematocrit, lipid profiles, and liver function tests, should be monitored before and during gender-affirming treatment in transgender males. For this purpose, blood tests should be performed at baseline, every three months during the first year after the initiation of the treatment, and semi-annually or annually thereafter to evaluate the response to treatment and reveal potential toxicities or adverse effects. The biochemical course should be assessed along with the clinical changes of gender-affirming therapy. Failure to clinically benefit from treatment with testosterone or the occurrence of abnormal biomarkers should prompt changes in treatment. Of course, it is necessary from a health care perspective to use all the available clinical and laboratorial data to individualise patient care.

Conflict of interest

The authors declare no conflicts of interest.

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