The importance of addressing the research gap in transmasculine
individuals: pharmacokinetic and research considerations
Transgender and gender diverse (TGD) individuals have been both
understudied and underrepresented in research,1 and
many of our epidemiological estimates have been based on those TGD
individuals who sought care specific to medical transition with hormones
or surgery. Overall, the number of TGD individuals seeking care is
growing. Historically, transfeminine individuals sought care more
frequently than transmasculine individuals; however, recent trends in
North America suggest that these populations are now approximately equal
in size overall, with a notable shift towards a predominantly
transmasculine demographic in children and
adolescents.1 In this commentary, the term
”transmasculine” is used rather than ”transgender men” or ”trans men” to
more inclusively refer to all individuals who were assigned female at
birth but identify with masculinity in some way, aiming to encompass a
broader range of gender identities and experiences within the
transmasculine community. While language evolves to align with patient
identifications, there may be continued discrepancy in terms of the
language used in this article and community preferences—it is always
best to ask each patient what language they use to describe their gender
and reflect this language in your conversations with them.
Despite an increasing proportion and total number of transmasculine
individuals seeking transition-related care, including testosterone
provision, research into the testosterone doses or serum concentrations
required to reliably achieve specific effects is limited. Much of the
existing literature on gender-affirming hormone therapy is focused on
outcomes like safety, morbidity, and mortality. There is comparatively
little research on the outcomes that patients are most interested in,
such as ‘masculinizing’ changes and subjective satisfaction. In general,
testosterone prescribing should be guided by each individual’s
embodiment goals, while also taking into consideration concerns around
individualized risks and side effects. Being able to counsel clients on
what formulation, dose and frequency might be needed to realistically
achieve each of their goals—and recognizing that this may vary based
on genetic and other factors—would allow for more fulsome shared
decision-making. While this has been better studied for certain clinical
effects, such as deepening of the voice and facial and body hair
growth,2,3 many would benefit from further evaluation.
Recent research has attempted to predict testosterone dosage necessary
to achieve outcomes such as cessation of menses and body fat
redistribution. However, methodological limitations hinder applicability
of these findings. In these clinical datasets, there is either no
protocol to standardize testosterone dosing,4 or no
standardization of timing between testosterone dosing and serum level
measurement,5,6,7 making it difficult to draw
clinically-relevant conclusions. In certain circumstances, there is no
reporting of serum testosterone levels at all.4 With
respect to cessation of menses, results conflict as to the extent to
which testosterone dose or serum testosterone levels correlate with the
time required to reliably achieve amenorrhea. Some studies evaluating
cessation of menses and body fat redistribution suggest that
testosterone gel may be less efficacious as opposed to injectable
testosterone.5,6 However, these studies used only 50mg
per day of testosterone gel, which is in the lower end of the typical
dosage range cited by various guidelines.8 Indeed,
lower achieved serum testosterone levels with this dose of testosterone
gel was observed.6 Thus, future studies should
evaluate the impact of different doses of transdermal testosterone and
other formulations for these purposes using comparable serum levels and
standardized testosterone measurement strategies, which could even
include multiple measurements such as peak and trough concentrations or
area-under-the-curve, to clarify contributions of dosage and formulation
to clinical outcomes.
Certain questions with respect to desired testosterone effects remain
largely unanswered. For instance, there are still no studies to date
that compare different testosterone regimens and dosages and the extent
to which they induce clitoral enlargement. This outcome can be
gender-affirming in its own right, and can also enhance satisfaction
with metoidioplasty, a genital surgery in which the hormonally-enlarged
clitoris is reconstructed to become a penis. As well, there is
substantial interest by patients and providers in determining whether
topical testosterone or topical DHT applied directly to the clitoris, in
addition to receiving parenteral testosterone, can lead to additional
clitorophallus growth.9 Local effects and systemic
absorption of clitorally-applied testosterone are largely unknown,
highlighting the need for pharmacokinetic research into this area.
Another critical area deserving attention is the differential risk
profiles associated with various testosterone formulations. While some
studies provide reassurance regarding the risks of conditions like
ischemic heart disease and cerebrovascular disease, these data are not
consistent. Some studies have found an elevated risk of ischemic heart
disease among transmasculine individuals on
testosterone,10,11 but without reporting the specific
hormone regimen(s) in the cohorts, making it challenging to identify
whether dosing or frequency could exacerbate or mitigate this risk. A
systematic review and meta-analysis evaluating various cardiovascular
outcomes concluded that a longer duration of gender-affirming
testosterone therapy is associated with undesirable effects on the lipid
profile, but recognizes the potential for confounding variables that
were not consistently reported in the studies it drew from, such as
smoking history, testosterone dosage, and formulations
used.11 Similarly, the effects of testosterone therapy
on diabetes mellitus risk and blood pressure are areas with conflicting
evidence.10 This inconsistency in data highlights the
need for more robust and longitudinal studies to better understand the
long-term implications of testosterone therapy. With regards to these
potentially-increased metabolic risks, it would be also relevant to
understand whether exogenous testosterone has similar metabolic effect
to endogenous testosterone, making it possible to compare risk profiles
between cis men and transmasculine people.
In conclusion, while the state of research in testosterone therapy for
transmasculine individuals has progressed substantially, some
significant gaps persist in our understanding of how effects and risks
of testosterone may differ based on its formulation, dosage, frequency,
and pharmacokinetic profiles. Future studies should evaluate these
principles, and in many cases, incorporating consistent serum
testosterone measurements relative to dose administrations—for
instance, measuring trough levels or area-under-the-curve—may help to
enable more definitive conclusions. This information would ultimately
allow us to better tailor hormone prescribing to patients based on their
unique goals and avoid concerning adverse effects, important tenants in
shared decision-making between patients and clinicians.
Conflict of interest : None.
Funding information : None.
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