Endocrinology of Transgender Medicine: Endocrine Reviews

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Endocrinology of Transgender Medicine
Guy T’Sjoen, Jon Arcelus, Louis Gooren, Daniel T. Klink, Vin Tangpricha
ADVANCE ARTICLE: Endocrine Reviews
Endocrine Reviews
Endocrine Society
Submitted: January 14, 2018

Accepted: June 21, 2018
First Online: October 10, 2018
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Endocrine Reviews; Copyright 2018 DOI: 10.1210/er.2018-00011
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Authors’ full names and institutions
Guy T’Sjoen,
Department of Endocrinology & Center for Sexology and Gender, Ghent University, Belgium
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Jon Arcelus,
Institute of Mental Health, Jubilee Campus, University of Nottingham, Nottingham, UK
and Nottingham Centre for Transgender Health, Nottingham, UK
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Louis Gooren,
emeritus professor of medicine at the hospital of the Vrije Universiteit of Amsterdam, the Netherlands.
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Daniel T. Klink,
ZNA Queen Paola Children’s Hospital, Antwerp, Belgium
Vin Tangpricha, R
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Emory University, Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Atlanta, United
States
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ORCiD numbers:
0000-0003-0457-9673
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T'Sjoen
N
Guy
0000-0002-3805-0180
A
Arcelus
V
Jon
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0000-0002-4021-5853
Tangpricha
A
Vin
Received 14 January 2018. Accepted 21 June 2018.

Gender affirming treatment for transgender people requires a multidisciplinary approach in
which endocrinologists play a crucial role. The aim of this paper is to review recent data on
hormonal treatment of this population and its effect on physical, psychological and mental
health. The Endocrine Society guidelines for transgender women include estrogens in
combination with androgen lowering medications. Feminizing treatment with estrogens and anti-
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androgens has desired physical changes, such as enhanced breast growth, reduction of facial and
body hair growth and fat redistribution in a female pattern. Possible side effects should be
discussed with patients, particularly those at risk of venous thromboembolism. The Endocrine
Society guidelines for transgender men include testosterone therapy for virilization with
deepening of the voice, cessation of menses plus increase of muscle mass, facial and body hair.

Due to the lack of evidence, treatment for gender non-binary people should be individualized.
Young people may receive pubertal suspension, consisting of gonadotrophin-releasing hormone
analogs, later followed by sex steroids. Options for fertility preservation should be discussed
before any hormonal intervention. Morbidity and cardiovascular risk with cross-sex hormones is
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unchanged among transgender men and unclear among transgender women. Sex steroid-related
malignancies can occur, but are rare. Mental health problems such as depression and anxiety
have been found to reduce considerably following hormonal treatment. Future studies should aim
to explore the long-term outcome of hormonal treatment in transgender people and provide
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evidence as to effect of gender affirming treatment in the non-binary population.
Essential points
Transgender people pre-gender affirming treatment present with higher levels of mental health
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problems, particularly depression, anxiety and self-harm than cisgender people.
Gender affirming treatment has been found to reduce mental health problems in transgender people.
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Long term estrogen and androgen lowering medications may be associated with increased risk of
thromboembolism, which can be mitigated by changing the formulation and route of estrogen therapy.
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Testosterone treatment in transgender men is seen as safe regarding cardiovascular and oncological
disease in the short- and mid-term, but long-term effects need to be elucidated.
The endocrine treatment of adolescents with gender dysphoria consists of two phases, first pubertal
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suppression followed by the addition of hormones

The little somatic data available in adolescents is favorable and hitherto supports the fact that the
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proven psychological benefits of early medical intervention outweigh the potential medical risks.
In well-informed transgender people regrets of gender-confirming treatment are very rare.
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Introduction
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The acceptance by society, reflected in the media, that gender identity may not always match the
assigned sex at birth, has provided the option and permission for individuals to question their
gender identity more freely. Consequently, in some countries, transgender health services have
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expanded and developed so that gender diverse people wishing physical change are able to
access gender affirming medical interventions. Hormone treatment, pivotal for those who wish to
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transition into their affirmed gender that differs from their sex that is assigned at birth, is ideally
prescribed under the supervision of endocrinologists. However, many endocrinologists may feel
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uneasy and unskilled when working with the transgender population since the field of
transgender medicine is relatively new. This paper aims to summarize the endocrine treatment
for transgender people wishing to undergo gender affirmation therapies. The paper will first
describe the terminology used in the field of transgender medicine, followed by a critical review
of the diagnostic criteria currently in use, and summarize the mental health difficulties that
transgender people may present with and the benefits of gender affirming treatment on
wellbeing. Finally, the major focus of this paper will be to provide a critical review of the
published literature on the hormonal treatment and long term monitoring for transgender children
and adults.
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Terminology
The term “gender non-conforming” is used to describe individuals whose gender identity, role or
expression differs from what is normative for their assigned sex at birth in a given culture and
historical period (1). Transgender is used as an umbrella term to describe individuals, whose

gender identity differs from the assigned sex at birth. Transgender males are people assigned
female at birth but who self-identify as male. Transgender females are people assigned male at
birth, but who self-identify as female. When a person’s identity matches the sex assigned at birth,
the term “cisgender” is used. The term “non-binary” describes people whose gender identity, role
or expression does not conform to the binary understanding of gender (male or female). This can
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be used as an umbrella term to include people with no gender (agender), two genders (bigender),
multiple genders (pangender), or with a fluid gender (gender fluid)(2,3), among others. Non-
binary people prefer for people to use the pronouns of “they” and “them” when addressing
them(3).
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Terminology changes all the time and terms used in the past may become outdated and can
be perceived as pejorative. For example, the term transsexual which has been used since 1949(4),
is largely now confined to the legal and medical literature. The International Classification of
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Diseases and Health Related Problems (ICD-10)(5) still uses the term “transsexualism” as a
diagnostic term to describe individuals whose sex assigned at birth does not match their gender
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identity and wish gender affirming treatment. This term is likely to change to “gender
incongruence” in the forthcoming 11th edition of the ICD(6). Other terms still used but
considered outdated (although they can still be found in the literature) are: “FtM” (Female to
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Male) to describe transgender men or “MtF” (Male to Female) to describe transgender women.
Gender dysphoria refers to a profound distress or discomfort caused by the discrepancy
between a person’s assigned sex at birth and gender identity(1). Not every transgender person
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suffers from gender dysphoria and the urgency for medical intervention among transgender
people may vary(1). For some people, social change may be enough without the need for further
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physical intervention. For others, due to their personal circumstances, physical intervention may
not be opportune or appropriate. Many however, will access transgender health services in order
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to obtain gender-affirming treatment whether in the form of hormone treatment and/or through
gender affirming surgery. Research in the field of transgender medicine has primarily focused on
transgender people accessing transgender health services (7). Due to the requirement in certain
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countries, to provide funded health services only to those with a medical diagnosis, terms
describing the gender related suffering of transgender people have remained part of current
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diagnostic criteria(5,8). In this manuscript, the term transgender will be used throughout to
describe individuals who seek access to medical treatment in order for their bodies to become
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more congruent to their identified gender. A summary of some of the terms used in transgender
health can be found in table 1.
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Methodology
Eligibility criteria
Studies were selected only if participants were described as transgender (whether self-identified
or diagnosed by health professionals), and had empirical data relating to the hormonal treatment
in this population. Only studies in English, published in peer reviewed journals and with more
than ten participants were selected. This is a critical review with a focus on recent and original
data. This paper describes and reviews the available literature since the last published review
study by one of the co-authors of the current review(9).
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Information Sources and Search

An electronic literature search was conducted between January 1999 and November 2017 using
Medline/Pubmed, PsycINFO and Embase. Additionally, reference sections of identified articles
and Google Scholar were examined for further relevant publications. The search used the
following keywords: for terms referring to Transgender people (Transsexualism, transgender,

Gender Dysphoria, Gender Identity Disorder, Trans*), for hormonal treatment, (cross-sex
hormones, Testosterone, Estrogen, Blockers, GnRH agonist). Every term used for Transgender
people was combined using the “OR” and the “AND” operate with every term used for
Hormonal treatment. Articles of interest were those that included the transgender population and
had empirical data relating to hormonal treatment within this population. Articles describing the
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effects of treatment, side effects, risk and long-term outcome were also collected and reviewed in
order to help the discussion of the paper. If information was only to be retrieved from case
reports, such as oncology, both the case reports and recent reviews on the specific topic were
examined. The results of the review will be presented by describing the treatment in adults
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(transgender women and men) first followed by the treatment in adolescents.
Diagnosis
Currently the International Classification of Disease - version 10 (ICD-10) includes the diagnosis
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of transsexualism as part of the diagnostic category of “Gender Identity Disorders” (F64). It is
expected that the new edition of the ICD (ICD-11) will change this term and move it out of the
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mental health chapter. It is likely that the new term to be used will be Gender Incongruence of
Adolescence and Adulthood’ (GIAA)(6,10-11).
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The desire to de-pathologise being transgender and the importance of securing access to
healthcare has been a dilemma in both the development of the DSM-5 and the new edition of the
ICD (ICD-11). The American Psychiatric Association’s diagnosis in the current edition of the
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DSM (DSM-5), diagnoses the distress caused by the incongruence between assigned sex at birth
and experienced gender as gender dysphoria. This diagnosis aims to classify the symptoms
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(dysphoria) and not the individual. For an individual to fulfill the diagnostic criteria for gender
dysphoria they need to present with a marked incongruence between one’s
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experienced/expressed gender and assigned gender, of at least 6 months duration (APA(8)).

If reaching a consensus to develop terms to classify transgender adults has been complicated,
creating criteria for children has been even more complex. The ICD-11 is proposing the
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diagnosis of gender incongruence of children (10) while the DSM-5 uses the diagnosis of gender
dysphoria in children.
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Prevalence
More than 20 studies have aimed to investigate prevalence rates of transgender people. Although
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more recently prevalence rates of transgender identities have been reported using population
studies, most of the available literature has extrapolated prevalence rates from people attending
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transgender health clinics (7).

Some of the first epidemiological studies, which focused on individuals seeking services in
order to undergo gender affirming genital surgery(12), found prevalence rates of 0.40 per
100,000 people. The ratio between male assigned at birth and female assigned at birth was found
to be 4 to 1(11). Other European studies, based on people attending transgender health services,
provide different prevalence rates over time; 1.22 per 100,000 (1976-1980), 1.58 per 100,000
(1976-1983), 2.77 per 100,000 (1976-1986)(13). Once again rates of male assigned at birth
transgender people have been found to be higher than female assigned at birth transgender
people at a ratio of 3 to 1. Studies looking at more recent periods (between 1972 and 1996)
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provide higher prevalence rates of 3.42 per 100,000 with ratios between birth assigned females
and males being more similar (1.4 to 1)(14).
Studies have also examined the number of people that have petitioned governmental agencies
in order to change their gender status legally. Those studies have described prevalence rates
ranging from 2.1 (15) to 16.6 (16) per 100,000 people. A recent meta-analysis found an overall

prevalence for transsexualism (as this is the diagnosis and term used in the published papers) of
4.6 in 100,000 individuals; 6.8 for transgender women and 2.6 for transgender men with an
increase in reported prevalence over the last 50 years(7).
However, not every transgender person wishes and/or seeks medical care to affirm their
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gender(1). In order to identify the overall prevalence of transgender people (including those not
accessing services) population studies may be more representative of the transgender
community. Population based studies have found a considerably higher prevalence rate than
those reported in clinical studies. For example, a study asking a sample of community
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participants in the United States (28,045 aged 18-64) as to whether they considered themselves
transgender found a prevalence rate of 0.5% (17). Studies from the Netherlands and Belgium
described that 0.7%(18) and 1.1%(19) of people assigned male at birth and 0.6%(18) and
0.8%(19) of people assigned female at birth reported an incongruent gender identity.
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The majority of the epidemiological studies have been conducted in Western countries,
particularly in Europe and the United States. Societies which are more egalitarian and open will
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facilitate the expression of gender diversity, hence prevalence rates in those countries may be
reported higher than in more restrictive societies. Low prevalence rates in certain societies may
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need to be regarded with caution as it may reflect a symptom of repression. A ban on gender
identity expression for personal, cultural or religious reasons, may manifest itself as distress and
profound unhappiness and may lead to the development of mental health problems(20).
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Mental health in transgender people and effect of hormonal treatment

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Overall prevalence of mental health diagnoses

Studies investigating rates of mental health diagnoses in the transgender population, once again,
have focused on those attending transgender health services(21). Most of the studies have been
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cross- sectional and report high rates of affective disorders (38%)(22) such as depression(23) and
adjustment disorders(24) as well as anxiety disorders (17%)(25,26). Young transgender people
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are found to have high rates of non-suicidal self-injuries have also been found to be very high,
particularly among young people (46%) as well as suicide attempts(27,28,29). The few studies
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that compared their findings to the general cisgender population (controlled by age and sex)
found certain mental health diagnoses, such as anxiety disorders, are 3 times more prevalent
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among transgender people compared to cisgender people(25).

Differences in prevalence according to gender
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There are some discrepancies as to whether mental health diagnoses are more common among
transgender men or among transgender women. Some studies have found mental health
diagnoses were not related to assigned or identified gender(30,31), while other studies have
demonstrated higher rates of mood disorders(23,32), anxiety disorders(32), adjustment
disorders(18), and substance abuse(24) among transgender women than transgender men. Most
of those studies are biased by not controlling for factors known to influence mental health
diagnoses, particularly hormone treatment. This means that people have been recruited for
studies independently as to whether they are on hormone treatment or not, while research has
confirmed that such treatment reduces mental health problems. Interestingly, more recent large
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controlled studies involving only transgender people not on treatment have found anxiety
disorders were more prevalent among transgender men than among transgender women(25). A
similar study also found levels of self-harm were also higher among the same group(28).
Predictors of mental health problems

Several factors have been found to predict mental health issues among the transgender
population attending transgender health services, such as experiences of victimization (or
transphobic experiences), low self-esteem(27), and interpersonal problems(28,33). Lack of
hormone treatment for those wishing physical change has been found to be the strongest
predictor of mental health diagnoses(21,25,31).
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The role of hormone treatment in mental health
A number of longitudinal studies have explored the role of hormonal treatment in mental health
and quality of life among transgender people wishing gender affirmation treatment. These
studies, which have mainly been conducted in Europe (Sweden(34), Italy(35), Belgium(36) or
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Germany(37)), have all demonstrated that people’s mental health (levels of depression and
anxiety) significantly improved following hormone treatment. Long-term follow-up studies and
studies involving large groups of people are needed to evaluate whether these improvements
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remain. Hence, hormone treatment for those wishing physical change needs to be accessible, as
this will reduce morbidity and improve quality of life of transgender people.
Post treatment regrets
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The literature in posttreatment regret is complex to interpret. Overall satisfaction post gender-
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affirming treatment is high. A study from more than 20 years ago found 2% of transgender
women and 1% of transgender men later regretted their decision to undergo hormonal and/or
surgical treatment (38). There are many causes of regret. Frequently dissatisfaction following
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gender affirming surgery has been interpreted as regret regarding social and medical transition.
In order to distinguish those people who express dissatisfaction following gender affirming
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treatment, from those who wish to de-transition and return to their sex assigned at birth, Pfäfflin
(1993) differentiates minor from major regrets. In one of the largest gender clinics (Amsterdam),
2034 individuals received treatment between 1975 and 1998. Ten of these people subsequently
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indicated that they regretted their decision to have undergone the treatment (nine transgender
women and one transgender man)(39). The reason for those regrets varied from identifying with
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the sex assigned at birth and wanting de-transition (n=6) (classified as major regrets) from
dissatisfaction of the outcome of surgery or loss of support following gender affirming treatment
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(n=4) (minor regrets). Upon review in 2005 the number of major and minor regrets increased by
five out of a total of 3090 subjects. In 2015 the total number of subjects treated had risen to 6793
but there was no further increase in those expressing regret. The fact that fewer people have been
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having doubts about their treatment decisions over time may reflect the much-improved
understanding of gender incongruence both by transgender people themselves and by the medical
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profession, as well as much greater acceptance of transgender people in society(39).

Summary
Mental health diagnoses are common in the transgender population, possibly due to negative
societal values, but do improve once gender affirming treatment is initiated. This highlights the
importance of hormone treatment and access to adequate transgender healthcare. Although state
funded health services, which are primarily available in Europe, may develop services where the
needs of the transgender population can be provided for, including assessment, psychological
support (if needed), hormonal treatment and gender affirming surgery, other healthcare systems
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may not be so fortunate and transgender people may find themselves searching for professionals
who are able to confidently prescribe and monitor hormone treatment.
Results

I. Hormonal treatment in transgender women
Initial evaluation of transgender women
Transgender women seek hormone therapy to change their physical appearance to better match
their gender identity and expression(40,41). Furthermore, transgender women experience
improved quality of life and decrease in gender dysphoria upon initiation with hormone
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therapy(42,43). In the United States, Canada and most of Europe, transgender women must seek
medical professionals for hormone therapy since these medications are available only by
prescription but there is a black market also particularly for oral contraceptives. For non-
Western countries, hormone therapy is often self-prescribed without supervision by a medical
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professional. Available evidence from the United States and Europe suggest that hormone
therapy initiated and monitored under the supervision of a medical professional is associated
with very low rates of adverse events(44,45).
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The Endocrine Society guidelines recommend that a medical professional confirms the
diagnosis of gender dysphoria and/or gender incongruence in transgender women prior to the
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initiation of hormone therapy. Medical professionals should document that the gender dysphoria
has been persistent and that the individual is able to make an informed decision and consent for
treatment(40). However, there are no validated psychological tests or imaging studies that have
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been clinically useful to diagnose gender dysphoria(46), this is likely due to the fact that people
with gender non-conforming expression and behaviors represent a very large and heterogeneous
population. There is no demonstrable biological substrate for gender incongruence. In this
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regard, medical professionals have been moving towards a more gender affirmative model
whereby the medical professional provides a more patient centered approach to care and
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understands the needs of the person rather than making a diagnosis of the patient(47,48).
Screening for conditions prior to initiation of hormone therapy
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Medical professionals should evaluate transgender women for conditions that can be exacerbated
by hormone therapy. History of thromboembolic diseases such as deep vein thrombosis and
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pulmonary embolism should undergo evaluation and treatment prior to the initiation of hormone
therapy(40). In addition, risk factors that can increase the risk of thromboembolic conditions
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should be modified such as smoking, obesity, and sedentary lifestyle. In patients with modifiable
risk factors such as known thrombophilia, past history of thrombosis, or strong family history of
thromboembolism, treatment with transdermal estrogen and/or concomitant treatment with anti-
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coagulation therapy may need to be considered; although there are limited data to guide
treatment decisions (49,50). Other diseases such as hormone sensitive cancers, coronary artery
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disease, cerebrovascular disease, hyperprolactinemia, hypertriglyceridemia, and cholelithiasis

should be evaluated prior to the initiation of estrogen therapy as these conditions can be
exacerbated by estrogen.
Modalities of hormonal therapy in transgender women
There are two main classes of medications used in transgender women: 1) estrogens and 2)
androgen lowering hormones therapies.
Estrogen Therapies
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The synthetic estrogen ethinyl estradiol was a widely used estrogen in Europe prior to 2003.
However, given recent safety concerns about its pro-thrombotic potential and its potential role in
cardiovascular disease, most clinics have now switched to oral, cutaneous or intramuscular
estradiol(51). A few commonly used estrogen regimens in transgender women have been
reported (Appendix B of reference 40); however, there are very few head to head studies

comparing the efficacy and safety of estrogen regimens. In a large multi-national cohort study
(entitled European Network for the Investigation of Gender Incongruence (ENIGI)) of 4
European countries (Belgium, The Netherlands, Italy and Norway), over 300 transgender women
were prescribed oral estradiol valerate 4 mg daily or estradiol valerate 20 mg intramuscularly
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every two weeks or estradiol patch 100 mcg daily, each with cyproterone acetate (CPA) 50 mg
daily(52). In the short-term (< 5 years), these regimens are associated with mild elevations of
prolactin(53) and improvements in bone mineral density after 1 year of therapy (54). No short- or
long- term adverse events have been published from this cohort using this hormone regimen.
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In a German cohort, transgender women were treated with a regimen of estradiol valerate 10
mg intramuscularly every 10 days. The authors also report short term gains in bone density after
24 months of therapy along with higher BMI with an increase of fat mass and decrease of lean
body mass(55).
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In the United Kingdom, transgender women were previously prescribed ethinyl estradiol or
conjugated equine estrogen are now changed to oral estradiol at a dose of approximately 4 mg
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daily(56). In a retrospective review of transgender women in the UK, transgender women
prescribed oral conjugated equine estrogens had increased risk of thromboembolism compared to
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transgender women taking oral estradiol valerate or ethinyl estradiol. In this cohort, 4.4% of
transgender women on oral conjugated equine estrogen experienced a thromboembolic event
compared to <1% in transgender women or estradiol or ethinyl estradiol (p=0.026).
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In the United States, estrogen therapy can be prescribed as oral tablets, intramuscular
injections, and transcutaneous preparations(41). Most commonly published in the United States
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is the prescription of oral estradiol 4-5 mg daily(57,58). Studies that compare the long-term
safety and effectiveness among the different formulations of estrogen are lacking. The Endocrine
Society Guidelines recommend that the doses of estradiol be titrated to serum estradiol levels
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around 200 pg/mL (734 pmol/L)(40).

Androgen Lowering Therapies
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Transgender women will often require the addition of a medication to lower testosterone levels
into the female range(59). In most European countries, the most commonly prescribed androgen
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lowering medication is oral CPA 50 mg daily (44,52,60). Cyproterone acts primarily as an

androgen receptor blocker but also has some progesterone like activity(61). However, given
reports of increased risk of meningiomas(62-64), association with depression(56), and increased
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risk of hyperprolactinemia(53) with CPA use, in the United Kingdom (UK), transgender women
are now prescribed gonadotropin-releasing hormone (GnRH) agonists to lower testosterone
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concentrations(65). In contrast to the rest of Europe and the United States, GnRH agonists are
provided free of charge to transgender women by the National Health Service in the UK (56).
Spironolactone is the most commonly prescribed testosterone lowering medication in the
United States(57,58). Spironolactone is classically known as an antagonist of the
mineralocorticoid receptor and a potassium sparing diuretic. It also has anti-androgen properties
by directly lowering testosterone synthesis and testosterone action at the androgen receptor(40).
One U.S. cohort of about 100 transgender women found estrogen therapy in combination with
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oral spironolactone 200 mg daily was effective in lowering serum testosterone levels in to the
cisgender female range for serum testosterone after about 1 year of therapy(66).
Peripheral androgen receptor blockers such as flutamide or dutasteride have not been
recommended for use in transgender women since these agents do not lower serum testosterone
levels and there are limited published studies in this population(40).

Other Second Line Hormonal Therapies
Progesterone
Progesterone therapies such as medroxyprogesterone have been used as a second agent to lower
testosterone concentrations in transgender girls and women(57). Some transgender women may
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request progesterone to enhance breast development; however, there are no clinical studies to
support a positive effect of progesterone on breast development(67). Furthermore, there are
concerns regarding potential increased risk of thromboembolism and stroke found in cisgender
women taking progesterone(68,69). Therefore, progesterone therapy is not a routinely used
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medication in transgender women.
5α-Reductase Inhibitors
Some transgender women may experience male pattern hair loss and may seek treatments to
arrest hair loss and/or restore hair. In general, lowering serum testosterone levels into the
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cisgender female range is often adequate to arrest hair loss in most transgender women; however,
there are still some transgender women who experience hair loss despite lowered serum
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testosterone levels. A few case series in transgender women with androgenetic alopecia have
demonstrated finasteride therapy to be effective to improve hair loss without significant side
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effects(70,71). The routine use of 5α-reductase inhibitors has been limited over previous
concerns of long-term sexual dysfunction and depression reported to be found in cisgender
men(72,73).
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Feminization in transgender women

Treatment with estrogen and testosterone lowering medications will induce feminine and reduce
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masculine physical characteristics. The most studied physical change in transgender women is
the development of breast tissue. An Italian cohort study found increases in breast size were the
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only physical feature that was significantly associated with improvement in body uneasiness
scores(43). However, less than 20% of transgender women reach Tanner Breast stage 4-5 after
24 months of hormone therapy and thus often seek mammoplasty. Early studies in transgender
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women indicated breast development reached a maximum size by 2 years(74). However, a more
recent study of 229 transgender women participating in the ENIGI cohort found breast
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development reached a plateau within the first 6 months of therapy and half of the transgender
women had a AAA cup size or less(75). Fisher and colleagues also found testicular volume
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decreased by approximately 60% after 24 months of transfeminine hormone therapy(43).

Body composition
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A meta-analysis of studies published prior to 2015, transfeminine hormone therapy was

associated with increased body fat and decreased in lean body mass in 171 transgender
women(76). More recent studies from Europe have documented that BMI increases in
transgender women after transfeminine hormone therapy(43,77). Klaver et al also demonstrated
increases in body weight in 179 transgender women and transfeminine hormone therapy was
associated with in increase in body fat, specifically in the android, leg and gynoid regions (78).
However, recent studies from the USA have demonstrated that significant changes in BMI in
transgender girls and women do not occur over a short term (< 6 months)(56,79).
Voice
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Transgender women will have improved self-perceived feminine quality in their voice after the
initiation of hormone therapy(80). However, many transgender women still have difficulty with
their voice quality and are misperceived in the wrong gender by others(81). Transgender women
may undergo voice training exercises to improve their voice quality(82). Laryngeal surgical
treatment has been described as an option for transgender women to improve voice quality;

however, a meta-analysis failed to demonstrate significant benefit of surgical techniques to
improve the quality of the voice(83).
Skin and Hair
Transgender women will also experience reduction in facial hair after transfeminine hormone
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therapy. Fisher et al reported that Ferriman and Gallwey scores improved after two years of
transfeminine hormone therapy(43). Transfeminine hormone therapy may arrest male pattern
hair loss(71). A survey of transgender women reported interest in having facial hair removal
procedures however very little data on the effectiveness of such procedures have been
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published(84).
Safety data specific to transgender women
1. Cardiovascular and thromboembolic safety
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There have been some concerns about long-term effects of transfeminine hormone therapy on
cardiovascular outcomes. A single center study of over 200 transgender women from Belgium
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reported increased rates of myocardial infarction, venous thrombosis, and cerebrovascular
disease compared to cisgender men and women(85). A recently commissioned systematic
review and meta-analysis of cardiovascular outcomes in transgender individuals did not find an
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increased risk of myocardial infarction, stroke or venous thrombosis in transgender women due
to lack of reported outcomes from 29 eligible studies(86). This systematic review also found
transfeminine hormone therapy was associated with increased serum triglyceride levels of 31.9
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mg/dL (95% CI: 3.9 to 59.9) in transgender women treated for greater than 24 months with no
changes in serum LDL or HDL. Thrombosis risk in transgender women is likely increased given
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the known pro-thrombotic actions of estrogen. However, under medical supervision, the risks of
transfeminine hormone therapy appears to be safer than self-prescribed transfeminine hormone
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therapy(45). A large study conducted in 162 transgender women treated with transdermal
estrogen in Austria found only 19 had a genetic mutation associated with venous thrombosis (1
protein C deficiency and 18 with activated protein C resistance) and none developed a
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thrombotic event, suggesting that estrogens that avoid the hepatic first pass effect may have less
pro-thrombotic risk (87). Furthermore, given the low frequency of genetic mutations associated
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with thrombosis (19 out of 162), the authors do not recommend routine screening for
thrombophilia. There have been reports of transgender women who developed a thrombotic
D
event and successfully treated with anti-coagulation therapy (88,89). However, there are no long
time studies to guide treatment for transgender women following a thrombotic event.
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2. Bone Health
The fracture rate associated transfeminine hormone therapy is unknown. Estrogen is critically
important for preserving bone mineral density in post-menopausal women and in men who lack
estrogen action at the bone, (e.g. mutations in the estrogen receptor or aromatase
enzyme)(90,91). A recent meta-analysis of 392 transgender women found a significant increase
in lumbar spine bone mineral density but no changes in hip bone mineral density. The rates of
fracture were found to be low with no fractures found in 53 transgender women after 12 months
in this review(92). A recent multi-center study of 231 transgender women in Europe treated with
transfeminine hormone therapy found a 3.67% increase in lumbar spine bone density and a
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0.97% and 1.86% increase in total hip and femoral neck bone density, respectively, after 1 year
of therapy(54).
Transgender women have been found to have lower bone mineral density even prior to the
start of hormone therapy(93). Van Caenegem and colleagues found 16% had T-scores at the
lumbar spine <-2.5 and approximately one third of transgender women had T-scores between -1

and -2.5 at the lumbar spine or total hip. The reasons why transgender women had lower bone
density than expected for age is not clear but the authors hypothesize decreased outdoor physical
activity as vitamin D status was found to be low in 72% of the cohort.
3. Oncological data and mortality
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The prevalence of hormone sensitive cancers such as breast and prostate cancer appears to be
low among transgender women. Initial studies from a cohort of over 2000 transgender women
reported no increase in breast cancer incidence compared to the expected rate of breast cancer in
cisgender women(94). A large cohort of over 5000 transgender military veterans in the USA
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reported only 9 cases of breast cancer in transgender veterans, two in transgender women and
seven in transgender men(95). All of the transgender women presented with late stage breast
cancer that proved to be fatal, whereas the transgender men before or after breast ablation
presented with earlier disease(96). One the largest studies examining cancer risk in transgender
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women in the USA utilized data from one large healthcare system (Kaiser Permanente: Georgia,
Northern and Southern California (97). Using an electronic database method to identify
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transgender women in this cohort, they identified 2791 transgender women subjects. Based on
ICD-9 codes, the investigators found no increased risk of breast cancer or any cancer compared
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in transgender women to matched cisgender women. However, there was an increased risk of
breast cancer and endocrine gland cancers in transgender women compared to matched cisgender
men. Furthermore, there was a decreased risk of prostate cancer compared to matched cisgender
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men. Other studies have reported a low risk of prostate cancer in transgender women. A recent
review of literature of prostate cancer in transgender women only found 10 cases reported(98).
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Other Considerations
Fertility
All transgender women should be aware of the potential fertility preservation options such as
N
sperm cryopreservation. Transgender women report that they are interested in having their own
biologic children but very few transgender women utilize fertility preservation
A
technologies(99,100), possibly due to the lack of funding for fertility preservation in many
countries. Since sperm production will decline after the initiation of hormone therapy, the
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Endocrine Society guidelines recommend that all transgender women discuss fertility options
with their healthcare team prior to the initiation of hormone therapy (40).
Monitoring of feminizing hormone therapy
D
Transgender women who take hormone therapy under medical supervision experience very low
rates of complications (44,45). Transgender women should maintain serum estradiol and
A
testosterone concentrations within the expected physiologic female range (40). The Endocrine
Society recommends hormone measurements every 3 months in the first year of initiating
hormone therapy until the hormone concentrations reach the desired concentrations. Once the
hormone dose is achieved, the hormone concentrations of both testosterone and estrogen can be
measured once yearly or when there is a dose change to ensure that levels remain in the range
expected for cisgender females (40). Transgender women taking spironolactone should have
measurement of potassium and kidney function on a regular basis. Following surgery,
11
transgender women can have a final measurement of serum testosterone to confirm levels in the
male range are eliminated.
Measurement of prolactin levels during the course of gender affirming hormone therapy has
been suggested by the Endocrine Society guidelines. However, recent reports indicate that
elevated prolactin levels seem to occur in transgender women on cyproterone acetate and not on

spironolactone. Defreyne et al demonstrated that prolactin levels increased in transgender women
receiving cyproterone but decreased after discontinuation (101). Furthermore, a recent study by
Fung et al demonstrated that transgender women treated with cyproterone had significant higher
prolactin levels compared to those treated with spironolactone (102).
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Insert Fig. 1 about here
II. Hormonal treatment in transgender men
Initial evaluation of transgender men
During the first outpatient consultation, the same principles apply as described for transgender
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women above.
Screening for conditions prior to initiation of hormone therapy
Transgender men must be informed on the possibilities, consequences, limitations and risks of
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testosterone treatment. Fertility preservation options are to be discussed before starting a medical
intervention. Pregnancy is an absolute contraindication for testosterone therapy, and relative
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contraindications include severe hypertension, sleep apnea and polycythemia(40). Conditions
that can be exacerbated by testosterone therapy are presence of erythrocytosis, baseline high
A
hematocrit levels (e.g. secondary to smoking or COPD), sleep apnea and congestive heart failure.
Knowledge on the presence of menstruation problems prior to initiation of testosterone treatment
and on sexual practices will guide the need for follow-up procedures such as pelvic ultrasounds
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and pap smears.

Modalities of hormonal treatment in transgender men
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Testosterone
The principal hormonal treatment used to induce virilization is testosterone. Under medical
N
supervision, testosterone therapy is safe based on short and longer-term safety

studies(44,103,104). Different testosterone formulations may be available depending on
geographical location. Most commonly prescribed are injectable testosterone esters (40). More
A
recently subcutaneous administration of testosterone was shown to be effective and preferred by

transgender men at a median dosage 75 mg weekly in 63 transgender men (105,106), confirming
V
an earlier intervention study (106). Long acting testosterone undecanoate is also being used for
treatment of transgender men (107). However, in the United States, the prescription of
D
testosterone undecanoate is limited due to the potential risk of oil pulmonary embolus and both
patient and provider must undergo Risk Evaluation and Mitigation Strategy (REMS) training to
A
receive this therapy. Other intervention studies (Appendix A of reference 40) have also used
topical androgen gel or transdermal patches. The use of oral testosterone (testosterone
undecanoate), axillary solutions, patches, nasal sprays, buccal tablets or pellets is rarely reported
for treatment in transgender men. In one study the effects of three different testosterone
formulations were evaluated at baseline and after 12 months of treatment and no differences
were found regarding short-term safety, compliance, body composition, metabolic parameters
and general life satisfaction (108). Androgen therapy will need to be continued lifelong to
maintain the achieved virilization and to avoid symptoms of hypogonadism such as vasomotor
symptoms or osteoporosis.
12
Progestational agents
If menstrual bleeding does not stop after initiation of testosterone, a progestational agent, such as
oral lynestrenol 5-10 mg daily or medroxyprogesterone 5-10 mg, might be considered. This
occurs frequently with the use of transdermal or oral testosterone undecanoate, which are both
associated with lower testosterone levels compared to injectable testosterone. GnRH analogs to

halt menses are theoretically possible, but rarely reported in adults given the costs of therapy. If
ovariectomy is performed, the progestational medication can be discontinued (109-111).
Virilization in transgender men
Treatment in transgender men is intended to induce virilization. This includes cessation of
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menses, development of male physical contours, a deepening of the voice, clitoral growth,
increased sexual desire and increased facial and body hair(110,112,113). Male-pattern baldness
may also occur. Changes in body composition; with redistribution of body fat, increased muscle
mass and strength have been described extensively (40,44,114). The time period before cessation
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of menses may vary from 1-12 months after testosterone initiation, sometimes requiring the
addition of a progestational agent (40,115). Mean clitoral length may reach 3.83 +/- 0.42 cm
after 2 years of testosterone therapy (43)
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It is important that transgender men understand the possibilities but also the limitations of
testosterone treatment. Height and bone structure (broader hips) and the larger degree of
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subcutaneous fat remain largely unchanged when therapy is started after puberty(110). Most of
the published guidelines have been developed with the Caucasian transgender person in mind,
but ethnic differences may warrant tailoring of standard doses (116). Recommendations based on
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clinical experience are in favor of continuing testosterone treatment for elderly transgender
men(117).
Body composition
E
Testosterone therapy will enhance a more masculine musculature, body shape and body fat
distribution. Testosterone therapy will result in changes in body composition. A meta-analysis of
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10 studies examining body composition changes in response to testosterone over 12 months

found body weight increased by +1.7 kg (0.7-2.7), body fat decreased by 2.6 kg (-3.9; -1.4) and
N
lean body mass increased by +3.9 kg (3.2; 4.5) (76). Another systematic review, focusing among
other parameters on BMI, revealed an increase in BMI from 1.3 to 11.4% (118). Grip strength
increased with 18% in a study with 23 participants and one-year parenteral testosterone
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undecanoate treatment (93).

Voice
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Testosterone therapy at doses in the physiological range for men will induce acoustic changes
occurring from effects on the larynx (119). In a cross-sectional study of 38 transgender men,
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acoustic voice variables and voice quality was similar between the transgender men and
cisgender controls. However, 10% of the transgender men experienced issues with pitch quality,
A
needing voice therapy and sometimes pitch-lowering surgery (120). Transgender men (n = 77)
whose voices sounded more congruent with their experienced gender reported greater well-being
than those with less gender congruent voices (121). There is very little prospective data on the
voice changes in transgender men upon testosterone treatment. Seven transgender men on
intramuscular testosterone esters, all reached a cisgender male mean fundamental frequency
within 6 months of testosterone therapy. A mean decrease of 49 Hz was measured (122). In the
largest longitudinal study to date (n = 50, with 36 having data for baseline and 12-month follow-
up) acoustic analysis of fundamental frequency of the habitual voice showed a significant
decrease after 3 (- 37 Hz), up to 12 (-67 Hz) months, with group data congruent with cisgender
13
male reference data. In 24% of participants additional voice therapy was necessary. When using
an adapted version of the transsexual voice questionnaire (123) for transgender men (TVQMtF)
looking at self-perception of voice prospectively during intramuscular testosterone undecanoate
therapy in 80 participants, improvements during the first 3 months were attributed to the
hormonal intervention (80).

Skin and hair
Both androgens and estrogens are known to affect the pilosebaceous unit of the skin, as in the
sebocytes and hair follicle dermal papilla androgen and estrogen receptors are expressed. In a
study of 17 transgender men, intramuscular testosterone therapy was associated with increases in
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the Ferriman-Gallwey hirsutism scores (124). After 12 months facial and abdominal hair had not
yet reached diameters found in cisgender males. An increase in acne on the face and back was
present in 94% and 88% after four months, respectively. Data on both shorter and longer term
dermatological effect of IM testosterone undecanoate were available from a prospective
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intervention study in 20 hormone naïve transgender men, combined with a cross-sectional part
with 50 transgender men with an average of 10 years on various testosterone treatments (103).
The Ferriman-Gallwey score (in cisgender women usually <8) increased in a time –dependent
manner from median 0,5 to 12 after one year, while long-term testosterone treatment resulted in
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a median score of 24. The presence and severity of acne based on the Gradual Acne Grading
Scale increased during the first year and peaked at 6 months; facial acne was present in 82%, and
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back acne was present in 88%. Long-term data from this study showed 94% of transgender men
had no to mild acne. In a study with 45 transgender men, 16% developed troublesome acne when
A
treated with testosterone undecanoate for two years (125).
In a retrospective, observational study 81 transgender men treated with testosterone esters or
testosterone undecanoate self-assessed the degree of male pattern baldness (MPB) using a five-
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point scale (i.e. type I (no hair loss) to type V (complete hair loss)). The authors found 38% of
transgender men had MPB type II-V. Thinning of hair was related to the duration of androgen
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administration and present in half of the transgender men after 13 years (126). Wierckx et al
reported that (44), 17% of participants developed androgenic alopecia based on the Norwood-
Hamilton classification after 1 year of treatment. Longer-term (10 years on average) testosterone
N
treatment was associated with 32% of mild frontotemporal hair loss and 31% moderate to severe
androgenetic alopecia (103). In 10 transgender men with androgenetic alopecia, treatment with
A
oral finasteride 1 mg daily for 12 months, induced improvement with one grade on the Norwood-
Hamilton scale after a mean of 5,5 months since the start of treatment (70).
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Safety data specified for transgender men

1. Cardiovascular safety
D
Adult cisgender men have higher cardiovascular mortality rates than women, which has been
attributed to differences in sex hormone levels. However, the available cardiovascular outcome
A
data in transgender men show that testosterone treatment does not result in adverse
cardiovascular outcomes(127). Four different recent review papers (86,118,128,129) summarized
the effects of testosterone on surrogate risk factors of cardiovascular disease. These studies
demonstrated despite a perceived negative impact on a number of risk factors including an
increase in hematocrit, a decrease in high-density lipoprotein cholesterol, increase in
triglycerides, low-density lipoprotein cholesterol levels, and inflammation parameters (130),
small increase in systolic blood pressure (44,125), decrease in adiponectin and leptin (131) no
significant increase in cardiovascular outcomes (77). Furthermore, there have been no elevated
rates of cardiovascular deaths when compared with cisgender men and women at short and
14
medium follow-up in the larger studies (except for one study (30)). However, data on
cardiovascular outcomes in older (65+ years) transgender men are mostly lacking (86). In a
cross-sectional study of 50 transgender men on testosterone treatment for an average of 10 years,
no subject had experienced myocardial infarction, stroke or deep venous thrombosis (132). In a
similar case-control study 138 transgender men 7.4 years on average on testosterone therapy

showed a low cardiovascular morbidity (85). In a prospective study with 43 transgender men,
who were treated with testosterone esters every 3 weeks, there was an increased incidence of
previously absent metabolic syndrome after 1 (16,3%) and 2 years (18,6%), especially in those
with psychiatric comorbidity(133). Furthermore, most studies in transgender men report no
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adverse impact of testosterone treatment on fasting glucose or insulin sensitivity
(44,108,131,133).
Many studies report an association between testosterone therapy and increased hemoglobin
(+ 4.9-12.5% range) and hematocrit (+ 4.4-17.6% range) during the first year of treatment, which
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then plateaus after the initial year of treatment (107,125). Clinically significant erythrocytosis
has been reported but is likely very uncommon (118). In such cases, practitioners sometimes
advise change of the testosterone route of administration or reduction of dosage, despite the
absence of outcome data showing risk reduction of thrombotic events. In one study use of
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testosterone gel showed smaller increases in hemoglobin (+4%) and hematocrit (+2%) compared
to injectable testosterone(108).
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A prospective study of 89 transgender men treated with parenteral testosterone undecanoate
and lynestrenol for about 4 years found no cases of venous thromboembolic disease despite 5
A
subjects who had the activated protein C mutation. The authors concluded that general screening
for thrombophilic defects is not recommended (134). In a similar study, fifty transgender men
followed for about 10 years found no cases of venous thromboembolism (132)
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It is important to stress that most transgender men are still relatively young, at an age when
the risk of cardiovascular events is low. Long-term data and data from older transgender men are
C
needed.
2. Bone health
Sex steroid hormones play important roles in bone growth and maintenance. Men develop
N
larger, longer and stronger bones during puberty, explained through the combination of sex
steroids and mechanical loading. Testosterone therapy in transgender men preserves bone density
A
with adequate dosing due to aromatization of testosterone to estradiol (135). There are very
limited data on the risk of osteoporotic fractures in transgender men (92). Transgender men have
V
similar BMD compared to cisgender females prior to testosterone therapy (93,136,137).

Following ovariectomy, testosterone substitution therapy appears to prevent short term (<2
years) (54,93,108,125,136,138-140) and long term (10 + years) (141-144) bone loss due to
D
estrogen deficiency. Transgender men have larger cortical bone size compared to cisgender
females in a cross-sectional study (143). An additional study confirmed the higher cortical
A
thickness by histomorphometric bone biopsy study (145) and higher aBMD at cortical sites
(139,142). This reflects the effect of androgens on the periosteal circumference of cortical bone.
The androgen-induced higher muscle mass also induces a higher mechanical load on the bone,
possibly stimulating bone formation according to the mechanostat theory (146). Higher bone
formation was observed in transgender men on testosterone (93,136,141,143) and both muscle
mass and strength were positively associated with trabecular and cortical parameters and bone
size. Nearly all studies reported a maintained aBMD, which argues against bone loss (92).
However, in transgender men who underwent ovariectomy, bone loss has been described when
15
they irregularly used or stopped androgen therapy or when dosage was inadequate
(137,138,141).
3. Oncological data and mortality
Both practitioners and transgender men express concern around carcinogenicity of long-term
hormonal therapy, although these concerns are not supported by the available data. Recently the

published cancer case reports in transgender men were summarized (147): 1 vaginal, 1 cervical,
7 breast, 3 ovarian and 1 endometrial cancers have been described to date. The association to risk
factors such as smoking and alcohol use, sexually transmitted infections and lack of adequate
access to screening programs has to be acknowledged and be included in future research (147).
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In transgender men on testosterone treatment and not undergoing surgical interventions, breast
and cervical cancer screening protocols are advised, but timing and frequency of monitoring of
female internal organs in transgender men are a matter of debate.
The available data on cancer mortality are limited and based on studies on 4 different
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populations (Belgium, Sweden, The Netherlands and United States). Despite low statistical
power, these studies demonstrate very few cancer events in the population of transgender men
(30,85,94,104,132,148,149). The data on overall mortality in transgender men, specifically
related to testosterone treatment, are scarce and the few available studies are underpowered (30).
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A study from the Dutch cohort with 122 transgender men (148), with a later follow-up on 293
(149) and 364 transgender men (104), reported mortality to be similar to those of the general
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population. The lack of cancer outcome data underlines the need for studies of a large and
inclusive sample size and long-term follow-up from multiple specialized centers.
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Other considerations
Fertility
There is a clear need to discuss reproductive option with transgender men, before starting
E
testosterone treatment (99). From a study based on a questionnaire, 54% of the transgender men
desired to have children and 37% would have banked oocytes, if this had been possible (150).
C
Genital reconstructive surgery results in an irreversible loss of natural reproductive capacities,

while testosterone therapy has an important, but partially reversible impact on fertility. In theory,
embryo and oocyte cryopreservation as established techniques, and ovarian tissue
N
cryopreservation more experimentally can be mentioned as examples of fertility preservation

options (151). The necessary hormonal stimulation with multiple endovaginal ultrasound
A
monitoring are likely to be perceived as physically and emotionally difficult, making oocyte
cryopreservation not the preferred fertility preservation technique in this group and some wish to
V
postpone this towards the time of hysterectomy and oophorectomy. A strong suppression of
AMH has been described in 22 transgender men treated with a GnRH agonist, combined with
testosterone gel and an aromatase inhibitor (152). Reassuringly, androgen treatment did not
D
deplete the primordial follicles in the ovarian cortex strips and a normal distribution of cortical
follicles in the ovaries remained intact in 40 transgender men after more than one year of
A
testosterone treatment (153). However, the use of in vitro maturation without the use of
xenotransplantation is far from implementation in a clinical setting (154). Once a mature oocyte
is obtained, the use of partner sperm or donor sperm and a recipient uterus upon thawing of the
oocytes, or a female partner or surrogate mother will enable conception.
Based on an online survey in 41 transgender men who had been pregnant, of which 25 had
used testosterone, 80% reported resuming menstruation within 6 months upon interrupting
testosterone treatment, while 20% experienced no menses before pregnancy. Of note, exogenous
testosterone is not an adequate mean of birth control. Testosterone has teratogen effects on the
16
fetus; therefore transgender men should avoid pregnancy while on testosterone therapy. This is
included in preconception counseling that addresses stopping testosterone while trying to
conceive and during pregnancy, with the possibility of increasing gender dysphoria during and
after the pregnancy. Postpartum the options for breast feeding and when to reinitiate testosterone
have to be discussed (155).

Monitoring of virilizing hormone therapy
Monitoring is advised 3-4 monthly in the first year of treatment and 1 to 2 per year thereafter,
according to the Endocrine Society Guidelines (40). Aiming at testosterone levels in the
physiologic normal male range and measuring hematocrit or hemoglobin in order to avoid
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erythrocytosis are the most important parameters. Bone densitometry in transgender men should
be performed if risk factors (smoking, excessive alcohol use, family history of osteoporosis,
history of fracture, use of glucocorticoids, anorexia nervosa) for osteoporosis exist, and more
specifically in those who stop or temporarily interrupt hormone therapy after gonadectomy.
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Screening for breast and cervical cancer in transgender men who do not undergo surgical
interventions is advised (40).
Insert fig. 2 about here
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III. Hormonal treatment in adolescents
The endocrine treatment of transgender adolescents consists of two phases: pubertal suspension
or gonadal suppression followed by the addition of hormones. During the first phase (further)
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pubertal development is halted and adolescents can further explore their gender identity and
prepare for the next phase.
A
Gonadal suppression in adolescents
Gonadal suppression using gonadotropin releasing hormone analogues (GnRHa)
To achieve gonadal suppression generally gonadotropin releasing hormone analogues (GnRHa)
E
are used (156). GnRHa have been used since 1981 in the treatment of central precocious puberty
(157,158) and their benefits are well established and the use of GnRHa is regarded as both safe
C
and effective, with no long-term adverse effects (159).

Treatment can generally start when the adolescent is in Tanner stage 2-3. In clinical practice,
N
transgender boys usually can start when in Tanner stage Breast 2 and transgender girls when they
have a testicular volume of 6-8 ml. Also, adolescents who have already physically matured can
A
use GnRHa to inhibit unwanted pubertal development, such as breast formation and menses in
girls or further male phenotype development and erections in boys, until the adolescent’s gender
identity is more stable (40).
V
The general safety and efficacy of GnRHa have been studied (160,161). Anthropometry and
body development, hormonal status and metabolic parameters were followed prospectively in 49
D
transgender girls (median age at start 13.6 years, Tanner stage Genital 4) and 67 transgender
boys (median age 14.2 years, Tanner Breast 4) during 12 months of GnRHa mono-therapy.
A
Puberty was adequately suppressed with a decrease of testicular volume from 13.9 ml (± 6.5) to
8.6 ml (±4.7) in 33 transgender girls. In transgender boys, who initiated GnRHa early in puberty
at Tanner Breast 2 and early menarche, breast tissue fully regressed to stage 1 (n=4) and menses
ceased. Effective gonadal suppression was also reflected in a decrease in gonadotropins levels
after a period of three months to nearly undetectable levels and a coinciding decrease in sex
hormones. Testosterone decreased from 262 ng/dL (9.1 nmol/L) to lower than 29 ng/dL (1.0
nmol/L) in transgender girls. In transgender boys, estradiol decreased from a median of 123
pmol/L to 29 pmol/L. As for anthropometry, height velocity decreased in both transgender boys
and transgender girls while BMI-SDS calculated for sex assigned at birth increased significantly.
17
Body composition and the lean body mass percentage decreased and fat percentage increased
significantly. Regarding safety monitoring, glutamyl transferase, AST, ALT and creatinine levels
did not significantly change from baseline to 12 months of treatment but alkaline phosphatase
decreased, most likely reflecting the decrease in growth velocity (160).
GnRHa is generally well tolerated with the exception of hot flushes early in treatment (161).

However, hypertension in transgender adolescents under triptorelin treatment was reported in
three transgender boys in a cohort of 138 subjects. Hypertension was reversible upon cessation
of triptorelin but in one case increased intracranial pressure occurred, requiring the temporary
use of acetazolamide (162). GnRHa induced hypertension is an uncommon side effect and has
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only been reported incidentally in children (163, 164).
Gonadal suppression in adolescents using other regimes
When resources cannot provide for GnRHa alternative treatment regimens should be considered
such as progestagens in transgender boys or CPA in transgender girls(40). Similar to transgender
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women, endogenous androgen production can be suppressed using anti-androgens such as CPA
or spironolactone in late pubertal girls. The effects of prolonged CPA mono-therapy were studied
retrospectively in 27 transgender girls who were in Tanner Genital stage 4. After 6 months of
CPA 50 mg once daily testosterone decreased from 432 ng/dl (15.8 nmol/L) to 248 ng/dl (8.6
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nmol/L) and remained stable at 226 ng/dl (7.8 nmol/L). LH and FSH however were not
suppressed at 5.0 IU/L and 5.1 IU/L during this period. Prolactin increased from 318.2 pmol/L to
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760.8 pmol/L but none developed galactorrhea. Clinically more than half of the subjects reported
reduced shaving frequency and in approximately one third had breast development (Tanner
A
stage Breast 2-3). There was no increase in BMI-SDS. Fatigue was the only reported side effect.
As for safety monitoring, only a transient increase of liver enzymes was seen in 15% of the study
subjects. The levels remained under the threshold of three times the upper limit and therefore
E
treatment was not stopped. Metabolic parameters such as lipid profile and glucose homeostasis
were not negatively affected(165).
C
In post-menarche adolescent transgender boys an alternative for GnRHa to stop or decrease

menses frequency may be the use of progestagens. A cohort of 42 transgender boys (mean age of
15 years and in Tanner Breast 4) was retrospectively studied during 11.6 months of lynestrenol
N
mono-therapy. After 6 months metrorrhagia occurred in 50% but reduced to 18% in the
following 6 months. Subjects reported headache (12%) and hot flushes (10%). Serum LH
A
decreased from 7.56 IU/L to 2.58 IU/L but levels of FSH and estradiol remained unchanged.
Weight increased during the first 6 months but returned to baseline value after 12 months.
V
Regarding safety monitoring hemoglobin and hematocrit increased but remained in the normal
male range. Liver enzymes, lipid profile and glucose homeostasis were not negatively
affected(166).
D
The addition of gender affirming hormones to GnRHa monotherapy

A
Hormone therapy in adolescents generally has two treatment regimes. In the case when GnRHa
treatment is initiated in the early stages of pubertal development, the “new” puberty is induced
with a dosage scheme that is also common in hypogonadal patients. Alternatively, when GnRHa
treatment is initiated in late puberty and thus the duration of the hypogonadal state was limited,
hormones can be given at a higher initial dose and more rapidly increased until the expected
adult dose. An additional advantage of GnRHa treatment is that hormones do not have to be
administered in supraphysiological dosages, which would otherwise be needed to suppress
endogenous sex steroid production (40).
18
The timing of starting sex hormones in transgender adolescents continues to be an issue of

debate. The recommended age of 16 years (40) is based on local jurisdiction, and not on
cognitive maturation or pubertal development. In most countries at age 16 one is considered to
be legally adult and one can make medical decisions. Indeed, when the first studied cohort was
started in the Netherlands the age of 16 was chosen for this very reason. As a consequence there

is little data available on starting GnRHa at an earlier age. The Endocrine Society guidelines
make a recommendation to allow hormone therapy to be initiated at ages younger than 16 when
the transgender child is evaluated by a multi-specialty team with expertise in gender identity
development in children. However, the need for re-evaluating the recommended age for starting
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GnRHa may shift in the future (1).
Transgender girls
For a pubertal induction, it is recommended to start 17-beta estradiol at a dosage of 5 mg/kg/day,
followed by 6 monthly increments of 5 mg/kg until a maintenance dosage of 2 mg is reached.
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The second treatment regime is more suitable for transgender girls who initiated gender
affirming treatment when at least 15.5 years old. After a period of gonadal suppression varying
from 3 to 6 months, estrogens can be given at a daily start dosage of 1 mg and increased to 2 mg
after 6 months (40).
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The effects of the addition of 17-beta estradiol were studied prospectively in 28 transgender
girls (158). Estrogen treatment was started at a median age of 16.0 years after median duration of
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24.8 months of GnRHa mono-therapy. Breast development had started within 3 months and after
1 year median Tanner breast stage was 3 progressing to 5 after 3 years (n=16) with a variability
A
of all breast stages. With respect to body shape, hip circumference increased and waist
circumference decreased. Although BMI increased, BMI-SDS did not. When bone age was < 15
years at the start of estradiol, median height gain was 6.8 cm after 3 years of estrogen therapy.
E
Overall final height was 182.7 cm corresponding to +1.9 SD for Dutch adult women. When the
adult dose of 2 mg estradiol daily was used during a median duration of 2 years the median
C
serum estradiol was 27 pg/mL (100 pmol/L) (range, 6,5-103 pg/mL (24 to 380 pmol/L). A
change in prolactin levels was not seen. In addition, hemoglobin, hematocrit, HbA1c, liver
enzymes and creatine remained unchanged (167).
N
Transgender boys
For pubertal induction the use of testosterone-esters injections is recommended. The initial dose
A
is 25 mg/m2 every two weeks IM; and is increased with 25 mg/m2 every 6 months. The
maintenance dosages vary from 200 mg per two weeks for testosterone mono-esters, such as
V
testosterone enanthate, to 250 mg per 3-4 weeks for testosterone esters mixture. For transgender
boys who started treatment in late puberty, testosterone can be started at 75 mg IM every two
weeks, followed by the maintenance dosage after 6 months(40). It is advised to continue GnRHa
D
at least until maintenance dosage of testosterone is reached and preferred to continue until
gonadectomy. With androgens, virilization of the body occurs: lowering of the voice, more
A
muscular development, particularly in the upper body, facial and body hair growth and clitoral
growth(40,161).
Other considerations
Bone health in transgender adolescents
During puberty the bone mass increases and peak bone mass is only achieved at the age of 20-30
years (168-169). Bone mass accrual is regulated by genetic factors, gonadal hormones, and
environmental factors such as physical activity and adequate supply of nutrients (calcium,
vitamin D). During the hypogonadal state induced by GnRHa mono-therapy bone mineral
19
density (BMD) is affected(170-171). In transgender girls BMD of the lumbar spine remained
stable but Z-score decreased during 1.5-2 years of gonadal suppression. In the femoral region
BMD and Z-score decreased but not significantly. In contrast, in transgender boys the BMD of
lumbar spine and femoral region decreased together with the corresponding Z-scores(170).
When sex steroids are added, bone mass accrual reassumes. In transgender girls, absolute

BMD and Z-scores in the lumbar spine but not the hip increased (170,171) but after two years of
estrogen their Z-scores were still below that of age- and sex assigned-matched norms (171). In
transgender boys (153,154), the bone density and Z-scores of the lumbar spine and the femoral
region increased (n=42) after 2 years of testosterone therapy but were still not at pretreatment
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level (171).
When BMD development was assessed until young adulthood, however, it was found that the
loss in Z-score was still partially present at the age of 22 implying a possible delay in or loss of
peak bone mass(170). To this date only one case report has been published on long term BMD
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development and it was shown that absolute BMD and Z-scores of a transgender man, treated
with GnRHa in his adolescence was in the normal range at age 35. However pre-treatment data
was not provided(172).
The addition of gender affirming hormones to other methods of gonadal suppression
T
Transgender girls
Two retrospective studies reported on the addition of estrogens to anti-androgen therapies in
R
transgender adolescents. In one study the subjects received CPA (165) and in the other study
spironolactone (79) was used. The addition of estrogens to CPA mono-therapy in transgender
A
girls resulted in either the initiation or further progression of breast development. Oral 17-beta
estradiol was started at 0.5 mg daily and increased to 0.75 mg after 6 months. After 12 months of
estrogen therapy 66.7 % reached Tanner Breast 3 and 9.5% reached Tanner Breast 4. After 12
E
months, both testosterone and LH decreased significantly to 168 ng/dl (5.8 pmol/L) and 3.2
IU/L, respectively and FSH demonstrated a declining trend to 2.8 IU/L. The mean 17-beta
C
estradiol level was 33 pg/mL (121.1 pmol/L). The most common adverse event reported by the
transgender girls was fatigue but resolved in almost all. BMI-SDS remained stable. In addition
metabolic parameters, lipid profile and glucose homeostasis did not change(165).
N
In a study of 44 transgender girls (mean age 18 years; range 14-25) of whom 38 received
spironolactone (dosage 50 -200 mg daily) oral estrogen was added in three routes, oral (dosage
A
between 1 to 8 mg daily), intramuscular (dosage 20 to 80 mg monthly) or transdermal (dosage

0.025 to 0.200 mg weekly). There were no changes reported in BMI, metabolic parameters, lipid
V
profile and prolactin and there were no differences in the methods of administration. Among the
38 subjects taking spironolactone potassium levels did not change(79).
Transgender boys
D
Testosterone can be added to progestagens as previously described (40) The clinical effects and
effects on metabolic parameters in adolescent transgender boys have been investigated
A
retrospectively in two studies, one single center study (n=42)(166) and one multicenter study
center (n=72)(79); albeit in the later study 7 subjects had received GnRHa prior to the
testosterone therapy. Only the single center study reported on side effects, which were fatigue
and acne. Clinically, there was a weight gain as both BMI (79) and BMI-SDS increased (166).
Although testosterone preparation and dosing differed, both studies reported an increase in both
hemoglobin and hematocrit. With a testosterone-ester mixture on a biweekly frequency, values
remained within the normal male range(166), whereas when treated with testosterone-ester on a
weekly base, hematocrit increased to supraphysiological levels of above 50% in 3% of the cohort
20
(2 cases) with no adverse events reported(79). ALT, AST, creatinine increased but remained in
the normal range. Lipid profile was more unfavorable with an increase of cholesterol and LDL
and a decrease of HDL. Glucose homeostasis parameters HbA1c (79,166) and insulin, glucose,
or HOMA index (157) were not affected.
Final considerations

Knowledge regarding the treatment of gender dysphoria and non-conforming has steadily
advanced over the past 10 years (173). While the psychological benefits of gender affirming
treatment for young adolescents with gender dysphoria using GnRHa have been
established(174,175), data on long term health outcome are still sparse. GnRHa treatment in
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adolescents is both clinically and biochemically effective in suppressing the hypothalamic-
pituitary-gonadal axis and appears to be well tolerated and safe(160). However, transgender boys
may be more susceptible for the development of arterial hypertension(162). Studies regarding
treatment with estrogen on pubertal development and short-term safety demonstrate feminization
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of the body without adverse events (167). In transgender boys, data on combined GnRHa and
androgens is lacking. Retrospective reports on bone mineral density development demonstrated a
loss of Z-scores in transgender boys and transgender girls during gonadal suppression, followed
by an increase after the addition of hormones but at the age of 22 years Z-scores were still under
T
pretreatment-level. Other long-term follow-up data is not available. Also the afore mentioned
studies mainly describe a relatively older and mature group, mid-teens and Tanner 4 and up,
R
which coincides with a relatively shorter duration of an induced hypogonadal state. There are
currently no publications available focusing on treatment of the young and less matured (Tanner
A
2 or 3) adolescent with gender dysphoria and therefore the effects of prolonged gonadal
suppression i.e. 3 to 4 years; short- or long-term are unknown. There needs to be investigation if
the initiation of sex steroid hormones before the recommended age of 16 may prevent the
E
negative sequelae of hypogonadism on the skeleton. Finally, when GnRHa are not available,
alternative methods to suppress puberty can be used in the more sexually matured adolescent.
C
Short-term data on the use of anti-androgens in transgender girls and progestagens in transgender
boys demonstrated its efficacy and safety(165,166).
N
Key Conclusions and Recommendations for Future Clinical Research

The current available research is based mostly on cross-sectional studies, with limited
longitudinal data. There is also paucity of information on diverse ethnic and socioeconomic
A
populations and papers on treatment outcome in adolescents. The current literature comes from
mostly Western-European and from higher income countries, where many participants undergo
V
surgical procedures, and has at best intermediate duration follow-up. Limited data exists on the
hormonal treatment in gender non-binary persons. For specific analyses such as outcome or
D
mortality, no single center has a sufficiently large patient base to study the population with
statistical rigor.
A
An important barrier to better care is the diversity of training and practice across providers.
Health care professionals continue to face challenges in providing optimal care for the
transgender population, also due to a lack of education on the topic. The improvement of formal
transgender education in medical schools and among health care providers in the broadest sense
is timely (176). Professionals working in health services need to understand that patients’ gender
identity is important and needs to be considered during any consultation. Treating people with
respect requires a good understanding of people’s identity regarding their gender. Transgender
health care has to be included in national and international conferences of all involved
specialties. We feel strong about the fact that involving the transgender community at all stages
21
of research is vital. This patient-centered research will progressively lead towards more studies
where transgender community involvement is crucial in identifying research priorities, research
design, helping recruitment, dissemination of study results. Patient centered outcome priorities in
endocrinology are breast development in transgender women, time to menstrual cessation in
transgender men, dose-related responses to hormonal interventions, effect on sexual function and

fertility among many others (177).
Transgender medicine research is finally moving away from case reports and small series.
Many efforts have gone into summarizing available data in numerous recent systematic reviews,
from which we have to internalize the findings, avoid repeating the same research, and take the
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investigations further. The collection and reporting of original good quality data through
networks has to be higher on the agenda. Innovative and patient-centered long-term research
with randomized controlled trials if possible, to advance of the safety and efficacy of hormonal
interventions is a priority. In doing so, clinicians and academics must listen to the voices of
IC
transgender people, recognizing and respecting the internal diversity within the transgender
community.
Any grants or fellowships supporting the writing of the paper: none
T
Corresponding author’s contact information: Guy T’Sjoen, Ghent University
Hospital, Department of Endocrinology and Center for Sexology and Gender, 9 K 12 IE,
R
Corneel Heymanslaan 10, 9000 Gent, Belgium. [email protected]
Name and address of person to whom reprint requests should be addressed: Guy T’Sjoen,
A
as above
Disclosure summary:
Guy T’Sjoen: Scientific Grants as prinicipal investigator: Ipsen, Bayer Shering, Sandoz,
E
Consulting fee as advisory board member: Ipsen, Novartis, Lecturer fee as speaker: Ferring,
Novartis
C
Jon Arcelus, Louis Gooren, Daniel Klink, Vin Tangpricha: none

N
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Figure 1Effects of estrogen and antiandrogen treatment in transgender women, reproduced with
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Figure 2. Effects of testosterone treatment in transgender men, reproduced from (112).

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Table 1: Terminology used in transgender health

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Cisgender- A person whose identity matches the sex assigned at birth.
Gender affirming treatment- Physical treatment that some transgender people access in order for their bodies to be adapted to the bodies of
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their experienced gender or gender identity by means of hormones and/or surgery.
Gender dysphoria- A profound distress or discomfort caused by the discrepancy between assigned sex at birth and gender identity. This is the
same term as the current diagnostic term of the DSM-5.
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Gender expression- The external manifestations of someone’s gender, which can include name, pronouns, clothing, haircut, behavior, voice,
or body characteristics.
Gender identity / experienced gender- A person's internal sense of gender. Unlike gender expression, gender identity is not visible to others.
Gender identity disorder- Diagnostic term used in previous versions of the DSM. The term is still used for the child diagnosis in the ICD-10,
but the proposed name for ICD-11 is gender incongruence of childhood. Currently this term is not preferred given the term “disorder”.
Gender Incongruence- The proposed diagnostic term to be used in the new edition of the ICD-11. Not all individuals with gender
incongruence have gender dysphoria or seek gender-affirming treatment.
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Gender reassignment- Previously used term to describe what is known now as gender-affirming treatment.
Gender role- The behaviors, attitudes, and personality traits that a society, in a historical period, designates as masculine or feminine.
Natal sex- The term “sex assigned at birth”, which is usually based on genital anatomy, is more appropriate.

Sex- Attributes that characterize biological maleness or femaleness. They can include the sex-determining genes, the sex chromosomes, the
H-Y antigen, the gonads, sex hormones, internal and external genitalia and secondary sex characteristics.
Sexual orientation - An individual's physical and emotional attraction to another person. Gender identity and sexual orientation are not the
same. Irrespective of their gender identity, transgender people may be attracted to women (gynephilic), attracted to men (androphilic), or be
bisexual, asexual, pansexual, etcetera.
Transgender (adj.) - An umbrella term to describe individuals, whose gender identity differs from the sex assigned at birth based on their
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sexual characteristics.
Transgender male - A person whose sex was assigned female at birth (based on their sexual characteristics) but self-identifies as male.
Transgender female - A person who self-identifies as female, but whose sex was assigned male at birth.
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Transition - The process during which transgender people change their physical, social, and/or legal characteristics consistent with their
gender identity.
Transsexual (adj.)- A diagnostic term used in the ICD-10. The term is currently used in some of the medical literature when discussing
diagnoses. The term transgender should now be used instead except when referring to the current ICD-10 diagnosis.
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Endocrinology of Transgender Medicine

Endocrinology of Transgender Medicine

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Received 14 January 2018. Accepted 21 June 2018.

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suppression followed by the addition of hormones

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Information Sources and Search

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experienced/expressed gender and assigned gender, of at least 6 months duration (APA(8)).

transgender health clinics (7).

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Mental health in transgender people and effect of hormonal treatment

Overall prevalence of mental health diagnoses

among transgender people compared to cisgender people(25).

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profession, as well as much greater acceptance of transgender people in society(39).

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Western countries, hormone therapy is often self-prescribed without supervision by a medical

disease, cerebrovascular disease, hyperprolactinemia, hypertriglyceridemia, and cholelithiasis

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around 200 pg/mL (734 pmol/L)(40).

lowering medication is oral CPA 50 mg daily (44,52,60). Cyproterone acts primarily as an

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Feminization in transgender women

decreased by approximately 60% after 24 months of transfeminine hormone therapy(43).

A meta-analysis of studies published prior to 2015, transfeminine hormone therapy was

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and pap smears.

supervision, testosterone therapy is safe based on short and longer-term safety

recently subcutaneous administration of testosterone was shown to be effective and preferred by

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10 studies examining body composition changes in response to testosterone over 12 months

undecanoate treatment (93).

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Safety data specified for transgender men

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similar BMD compared to cisgender females prior to testosterone therapy (93,136,137).

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Genital reconstructive surgery results in an irreversible loss of natural reproductive capacities,

cryopreservation more experimentally can be mentioned as examples of fertility preservation

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and effective, with no long-term adverse effects (159).

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In post-menarche adolescent transgender boys an alternative for GnRHa to stop or decrease

The addition of gender affirming hormones to GnRHa monotherapy

The timing of starting sex hormones in transgender adolescents continues to be an issue of

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between 1 to 8 mg daily), intramuscular (dosage 20 to 80 mg monthly) or transdermal (dosage

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Key Conclusions and Recommendations for Future Clinical Research

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Jon Arcelus, Louis Gooren, Daniel Klink, Vin Tangpricha: none

Transgenderism 2012; 13:165-232

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19. Van Caenegem E, Wierckx K, Elaut E, Buysse A, Dewaele A, Van Nieuwerburgh F, De

Behav 2015; 44:1281-1287