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Pharmacology
2.0
Contact Hours
Pharmacotherapy of Transgender
Children and Adolescents
Elizabeth Farrington, PharmD, FCCP, FCCM, FPPA, BCPS, BCNSP
Abstract: This article will review the pharmacology used for
patients with gender dysphoria who wish to use puberty blockers
or cross-sex hormonal support. Dosages, proper usage, adverse ef
fects, and monitoring parameters for each treatment period are
described.
KEY WORDS: transgender, pharmacology, pubertal blockade, trans
gender men, transgender women
INTRODUCTION
Gender dysphoria has been reported to affect an esti
mated 0.39% of adults in the United States and approx
imately 0.69% of adolescents. The American Psychiatric
Association has removed the word "disorder" from the
definition for gender dysphoria, and the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edi
tion has changed the term "gender identity disorder" to
"gender dysphoria." The clinician providing care for
the transgender patient should be familiar with the
common terminology used in transgender medicine.
They are summarized in Table 1 found in the Supplemen
tal Material, available at http://links.lww.com/JPSN/A15.
When a clinician wishes to prescribe gender-affirming
medication, the first step is to evaluate if the patient meets
the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition criteria for gender dysphoria
Elizabeth Farrington, PharmD, FCCP, FCCM, FPPA,
BCPS, BCNSP
Clinical Pharmacist - Pediatrics, New Hanover Regional
Medical Center, Betty H. Cameron Women's and Children's
Hospital, Wilmington, NC.
The author declares no conflict of interest.
Supplement digital content is available for this article.
Direct URL citations are provided in the HTML and PDF
versions of this article.
Correspondence: Elizabeth Farrington, PharmD, FCCP,
FCCM, FPPA, BCPS, BCNSP, New Hanover Regional Medical
Center, Betty H. Cameron Women's and Children's Hospital,
2131 S. 17th Street, Box 9000, Wilmington, NC 28402.
E-mail: elizabeth.farrington@nhrmc.org
Journal of Pediatric Surgical Nursing. 2021;10(1):17-21.
DOI: 10.1097/JPS.0000000000000295
(see Table 2, available at http://links.lww.com/JPSN/
A16, and Table 3, available at http://links.lww.com/
JPSN/A17, in the Supplemental Materials). If the ado
lescent chooses to start gender-affirming medical
treatments, short- and long-term risks of medical treat
ments need to be reviewed at each medical visit be
cause the patient's views and understanding of the
information will change over time as they mature. This
article provides an overview to medications, proper us
age, monitoring, and side effects.
PUBERTAL BLOCKADE
For patients who present with gender dysphoria in
early puberty (Tanner Stage 1 or 2), suppression of pu
berty will allow them more time to explore their gen
der identity with their mental health professional and
family without continued progression into biological
puberty. For girls, Tanner Stage 2 includes breast devel
opment and elevated papilla plus increased areolar
diameter. For boys, Tanner Stage 2 includes genital
development including penile enlargement and testicu
lar volume of 4 ml. Initiation of puberty-suppressing
medical treatment at this stage will allow for reversal
of the early changes. In addition, suppression of puber
tal hormones at Tanner Stage 2 allows for better cos
metic outcomes for those youth who proceed with
gender-affirming hormone treatment (Hembree et al.,
2017; Wiepjes et al., 2018).
Puberty begins with the activation of gonadotropin
releasing hormone (GnRH) within the hypothalamus.
The pulsatile release of GnRH, in turn, causes the release
of luteinizing hormone (LH) and follicle-stimulating hor
mone (FSH) within the anterior pituitary gland. These hor
mones effect both female development of breasts and
male development of gonads. GnRH analogs (GnRHa)
are the preferred agents for the suppression of puberty
(Wiepjes et al., 2018). They are Food and Drug Admin
istration approved for the treatment of central preco
cious puberty, and their mechanism of action is to
suppress luteinizing hormone and follicle-stimulating
hormone release from the anterior pituitary gland. They
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Page 2
are considered safe and reversible medications. Agents
in this class include leuprolide acetate, histrelin acetate,
and triptorelin pamoate. They can be dosed monthly;
every 3, 4, or 6 months; or annually (see Table 4 in
the Supplemental Material, available at http://links.
lww.com/JPSN/A18). The depot options (leuprolide
and triptorelin) are sustained-release formulations and
administered in various doses and intervals. The subcu
taneous histrelin implant requires a minor surgical pro
cedure for insertion and removal and is replaced
annually. The starting dose of monthly depot leuprolide
acetate ranges from 7.5 to 15 mg; and that for the
12-week preparation, either 11.25 or 30 mg. Doses
are increased as needed to achieve adequate suppres
sion (Bangalore Krishna et al., 2019). There is no evi
dence that one agent or dosing regimen is superior to
another. Clinicians should discuss all the available dos
ing options with patients and supporting adults, includ
ing the expected duration of therapy, the frequency of
administration and short- and long-term side effects,
and out-of-pocket costs. For those with insurance, which
may or may not cover these medications, prior insurance
approval may be necessary.
Adverse Effects of GnRHa Treatment
The peak time for bone formation is during puberty
and is supported by optimal nutrition, calcium intake,
and Vitamin D status plus weight-bearing exercise. How
ever, the rise in sex steroids during puberty is an impor
tant and contributing factor. Therefore, the primary risk
of pubertal suppression in gender dysphoria may include
adverse effects on bone mineralization. This may be re
versed with sex hormone treatment (Vlot et al., 2017),
and calcium supplementation may be beneficial in
optimizing bone health in GnRHa-treated individuals
(Antoniazzi et al., 2003). Hot flashes are occasionally
seen in the initial phases of GnRHa treatment in fe
male patients because of declining estrogen concen
trations. This, however, resolves quickly. Finally,
there are unknown effects on brain development.
Once transgender adolescents are started on puber
tal suppression, regular monitoring at 3-month intervals
is recommended (Hembree et al., 2017). This should in
clude a physical examination, laboratory testing, and
bone density testing using dual-energy x-ray absorpti
ometry (DXA). Recommended test and frequency are
summarized in Table 5 in the Supplemental Material
(available at http://links.lww.com/JPSN/A19). Although
measurement of gonadotropin and  sex steroid  levels  is
recommended, there is no precise level that is currently
recommended. Efficacy is based on clinical efficacy and
the mental well-being of the adolescent.
HORMONE THERAPY FOR TRANSGENDER
INDIVIDUALS
For Transgender Adolescents
The overall goal of treatment should be discussed
with the patient with the treating mental health profes
sional, medical practitioner, patient, family, and/or
supportive adults before initiating gender affirming hor
mone (GAH) treatment. Some patients may wish to
achieve full masculinization or feminization possible
from hormone intervention, whereas others may only
want sufficient hormones to achieve an androgenous
appearance or to relieve symptoms of gender dyspho
ria. In addition, some patients will be happy with hor
mone treatment only and do not care to progress to
surgery for a complete transition, whereas others would
like to complete the process for full transition. The goals
of the patient should be established before initiating any
GAH therapy. Finally, the risk of adverse effects associ
ated with treatment should be discussed with the pa
tient. Adverse effects of feminizing and masculinizing
therapies are outlined in Table 6 in the Supplemental Ma
terial (available at http://links.lww.com/JPSN/A20).
Once the decision is made to proceed with GAH, it
is recommended that all transgender persons be
counseled on the effects of transition on their fertility
preservation. In addition, GAH treatment is not a reli
able for of contraception, and testotosterone is a terato
gen that is contraindicated in pregnancy, therefore all
transgender people who have gonads and engage in
sexual activity that could result in pregnancy should
be counseled on the need for contraception.
The key principle for GAH therapy is to replicate as
closely as possible the hormone environment of the
patient's gender identity. The Endocrine Society sug
gests that transgender children can make their own
medical decisions at the age of 16 (Hembree et al,
2017). It should be noted that the age of consent to
medical treatments without parental consent varies
and clinicians should be familiar with the regulations
in the area in which they practice. In addition, some
specialty clinics now initiate GAH treatment at a youn
ger age based on the patient's state of development
(transcare.ucsf.edu). Hormone doses are initiated at a
low dose and slowly increased to mimic the changes
that occur with puberty.
TRANSGENDER WOMEN
Optimal medical treatment includes an estrogen in
combination with an androgen blocker to reduce exog
enous testosterone levels. The most common estrogen
formulation used is 17- estradiol, which may be
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administered by oral, transdermal, or parenteral routes
(Hembree et al., 2017). Oral estradiol is typically the
least expensive formulation. Historically, other estro
gen formulations (ethinyl estradiol, conjugated estro
gens) were used; however, their use was discontinued
because of high rates of venous thromboembolism
(Streed et al., 2017). For initiation of puberty, oral estra
diol is initiated at 5 mcg/kg per day (max: 0.25 mg)
daily, and transdermal estradiol is initiated at 6.5 mcg
twice weekly. Titration occurs at 6-month intervals
and is outlined in Table 7 in the Supplemental Material
(available at http://links.lww.com/JPSN/A21). Intra
muscular (IM) estradiol is used less commonly and is
typically reserved for patients who do not achieve hor
monal goals despite using the maximum recommended
dose of either oral or transdermal estrogen.
The physical feminizing effects will occur gradually
with dose titration. In the first 1-3 months, the patient
will experience decreased libido and decreased sponta
neous erections (Abramowitz & Tangoricha, 2018).
Within 3-6 months, body fat will redistribute to the
hips and buttocks, and the patient will experience de
creased muscle strength, skin texture change (less oily),
decreased testicular volume, and breast growth. At the
6- to 12-month period, hair growth will decrease, and
by 2 years, most of the physical changes will occur
(Hembree et al., 2017).
Treatment with estrogen alone is usually insuffi
cient to reduce testosterone levels to the physiologic
range for cis women, so transgender women will re
quire the addition of adjunctive antiandrogen therapy
for lowering testosterone to the female range. This
should be initiated in adolescents once they reach their
adult dose of estradiol. In the United States, spironolactone
is used most commonly (Abramowitz, 2019; Abramowitz
& Tangpricha, 2018). Spironolactone inhibits testosterone
 secretion, blocks androgen receptor binding, and may
also have estrogenic activity (Hembree et al., 2017). The
typical dose range is 100-300 mg daily. Spironolactone is
a diuretic that does not cause renal losses of potassium
and is associated with the risk of hyperkalemia. There
fore, the dose is started low and titrated slowly. In addi
tion, potassium levels must be monitored during
treatment. Cyproterone acetate and GnRHa are the
androgen blockers used most in Europe. Cyproterone
acetate is not available in the United States because
of concerns for liver toxicity (Meriggiola & Gava,
2015b), and GnRHa are significantly more expensive
than oral spironolactone. The 5-reductase inhibitor fi
nasteride blocks the conversion of testosterone to dihy
drotestosterone. Although it does not reduce testosterone
levels, it may be used in patients with contraindications to
spironolactone (Coleman, 2012). Dosing of antiandrogen
agents is summarized in Table 6 in the Supplemental
Material (available at http://links.lww.com/JPSN/A20).
Monitoring of Transgender Women
Routine monitoring should take place every 3 months
during the first year of treatment (Hembree et al., 2017).
The key to close monitoring is to avoid supratherapeutic
levels of estrogen that may lead to an increased risk of ad
verse events. Goal hormone levels should correspond to
those of cis women: testosterone levels < 50 ng/dl and
serum estradiol levels that should not exceed the peak
physiologic range of 100-200 picograms/ml. If there
are no complications and hormone levels are stable,
monitoring may be extended to every 6 months to 1 year.
All aspects of monitoring visits are summarized in Table 8
in the Supplemental Material (available at http://links.
lww.com/JPSN/A22).
TRANSGENDER MEN
There are several androgen preparations available for
the treatment of male transgender patients (see Table
7 in the Supplemental Material, available at http://
links.lww.com/JPSN/A21). Testosterone is most often
administered either parenterally or transdermally. The
enanthate or cypionate formulation can be adminis
tered IM or subcutaneously every 1-2 weeks,  whereas
the undecanoate salt may be administered IM every
10-12 weeks. Transdermal testosterone may be admin
istered as a gel or patch. The transdermal route of ad
ministration may be associated with skin irritation and
risk of testosterone gel transfer to others. Short-term
studies comparing parenteral with topical administra
tion have shown no difference with regard to body
composition, metabolic parameters, safety, compliance,
or satisfaction (Meriggiola & Gava, 2015a). Recommen
dations are to initiate treatment with a parenteral for
mulation, and once adult-level doses are reached, a
transdermal formulation of testosterone may be consid
ered (Abramowitz, 2019).
The physical masculinizing effects will occur gradu
ally with dose titration. During the first 1-6 months  of
treatment, the following changes are expected: increased
muscle mass, redistribution of fat mass, increased sexual
desire, increased oiliness of the skin, increased facial and
body hair, and cessation of menses. Expected changes
from 6 months to 1 year include deepening of the voice,
clitoromegaly, and, sometimes, male-pattern hair loss
(Hembree et al., 2017; Meriggiola & Gava, 2015a). For
transgender men who transition after puberty, testoster
one therapy may decrease glandular activity of the breast
but will not decrease breast size (Gooren, 2005). The
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Page 4
main undesired adverse effect of testosterone therapy is
acne. Acne prevalence and severity will peak at
6 months but may resolve in transgender men who
continue treatment.
Monitoring of Transgender Men
As with transgender women, transgender men should
be monitored closely in the first year, every 3 months. The
major goal of monitoring treatment is to achieve testoster
one levels in the normal cis male range, that is,
400-700 ng/dl (normal range may vary based on assay).
According to the national guidelines, for testosterone
enanthate/cypionate injections, the testosterone level
should be measured midway between injections and,
for the undecanoate injection, it should be obtained im
mediately before the injection. For the long-acting
undecanoate formulation, if the serum level is <400 ng/dl,
the dosing interval should be adjusted. For the transdermal
formulations of testosterone, the testosterone level should
be measured 2 hours after application; however, the
patient must receive transdermal therapy for a mini
mum of 1 week before obtaining a level (Hembree
et al., 2017). Since testosterone normal serum levels
may be assay dependent, it is essential to be familiar
with the assay your laboratory uses and its normal
range. If there are no complications and hormone
levels are stable, monitoring may be extended to every
6 months to annually. Details of recommended moni
toring are summarized in Table 9 in the Supplemental
Material (available at http://links.lww.com/JPSN/A23).
RISK AND ADVERSE EVENTS
The largest concern of testosterone therapy is the possi
ble increased risk of cardiovascular events (Streed et al,
2017). Testosterone therapy in transgender men has
been associated with increased low-density lipoprotein
(LDL) and triglycerides and a decreased high-density li
poprotein (HDL); therefore, close monitoring of the
patient is essential. Elevations in hemoglobin and he
matocrit have been reported in patients treated with
testosterone; therefore, it is recommended to closely
monitor hemoglobin and hematocrit. As with transgen
der women, there is a possibility of bone loss, so base
line studies and follow-up are critical.
GENDER-AFFIRMING SURGERY
A complete review of gender-affirming surgeries is out
of the scope of this publication; however, it is impor
tant for the clinician to be familiar with recommenda
tions concerning hormone therapy and surgery. Current
guidelines recommend that transgender adolescents
reach a stable adult dose and are maintained for 1 year
before any gender-affirming surgeries involving the
genitals or gonads. For transgender adolescent women,
it is recommended that breast augmentation surgery be
delayed until they have been titrated to stable mainte
nance therapy and then continued for a full 2 years.
There is a theoretical increased risk of thromboem
bolism in transgender women treated with estrogen
and surgical procedures. The associated immobility of
the procedure confers additional thromboembolic risk.
Given the perceived increased risks, hormone therapy
is frequently held perioperatively. The endocrine guide
lines by Hembree et al. do not offer advice for what to
do with hormone therapy surrounding surgery, and
there are minimal data to guide the decision. Gooren
suggests that estrogen therapy be held 2-4 weeks  be
fore gender-affirming surgery and should not be reinitiated
until 3-4 weeks postoperatively or once the patient is fully
mobile (Gooren, 2005). Hormones may be continued for
outpatient procedures or shorter procedures (4-5 hours)
where the patient is mobile after the procedure. Due
to the lack of clear guidelines, the surgeon and the
hormone-prescribing clinician should collaborate to de
cide on when to hold and when to resume hormones
for surgical procedures.
CONCLUSIONS
The recognition and acknowledgment of gender dys
phoria in children and adolescents is evolving. Children
with gender dysphoria that persist or worsens with the
initiation of puberty can be treated with pubertal sup
pression with GnRHa. This treatment has been shown
to be safe and effective and can give the child more
time to make decisions about further treatments.
Treatment with GnRHa is reversible, and adoles
cents may decide later to remain with the puberty of
their gender assigned at birth or continue life with
gender-affirming hormone therapy (GAHT). Decisions
about which options to pursue should be made with
collaboration with a mental health professional, the pa
tient, their family and/or supportive adults, and the pri
mary care provider. Decisions should include the
patient's goals of therapy balanced with possible risk
factors. Treatment must be individualized for each pa
tient. It is recognized that treatment with GnRHa at
the onset of puberty and GAHT are associated with sig
nificant improvements in mental health, specifically de
creased depression and anxiety. Clinicians should be
aware of the current dosing guidelines for initiating
and maintaining patients on GAHT and the recom
mended monitoring to prevent adverse effects. The pri
mary care provider should be a partner in the care of the
transgender individual.
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