Review: Puberty blockers for transgender and gender diverse youth—a critical review of the literature

Abstract

Background
Increasingly, early adolescents who are transgender or gender diverse (TGD) are seeking gender‐affirming healthcare services. Pediatric healthcare providers supported by professional guidelines are treating many of these children with gonadotropin‐releasing hormone agonists (GnRHa), which reversibly block pubertal development, giving the child and their family more time in which to explore the possibility of medical transition.

Methods
We conducted a critical review of the literature to answer a series of questions about criteria for using puberty‐blocking medications, the specific drugs used, the risks and adverse consequences and/or the positive outcomes associated with their use. We searched four databases: LGBT Life, PsycINFO, PubMed, and Web of Science. From an initial sample of 211 articles, we systematically reviewed 9 research studies that met inclusion/exclusion criteria.

Results
Studies reviewed had samples ranging from 1 to 192 (N = 543). The majority (71%) of participants in these studies required a diagnosis of gender dysphoria to qualify for puberty suppression and were administered medication during Tanner stages 2 through 4. Positive outcomes were decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life. Adverse factors associated with use were changes in body composition, slow growth, decreased height velocity, decreased bone turnover, cost of drugs, and lack of insurance coverage. One study met all quality criteria and was judged ‘excellent’, five studies met the majority of quality criteria resulting in ‘good’ ratings, whereas three studies were judged fair and had serious risks of bias.

Conclusion
Given the potentially life‐saving benefits of these medications for TGD youth, it is critical that rigorous longitudinal and mixed methods research be conducted that includes stakeholders and members of the gender diverse community with representative samples.

Full text

Review: Puberty blockers for transgender and
gender diverse youth—a critical review of the
literature
Lynn Rew
1
, Cara C. Young
1
, Maria Monge
2
& Roxanne Bogucka
3
1
School of Nursing, The University of Texas at Austin, Austin, TX, USA
2
Dell Medical School, The University of Texas at Austin, Austin, TX, USA
3
Life Science Library, The University of Texas at Austin, Austin, TX, USA
Background: Increasingly, early adolescents who are transgender or gender diverse (TGD) are seeking gender-
affirming healthcare services. Pediatric healthcare providers supported by professional guidelines are treating
many of these children with gonadotropin-releasing hormone agonists (GnRHa), which reversibly block puber-
tal development, giving the child and their family more time in which to explore the possibility of medical tran-
sition. Methods: We conducted a critical review of the literature to answer a series of questions about criteria for
using puberty-blocking medications, the specific drugs used, the risks and adverse consequences and/or the posi-
tive outcomes associated with their use. We searched four databases: LGBT Life, PsycINFO, PubMed, and Web of
Science. From an initial sample of 211 articles, we systematically reviewed 9 research studies that met inclusion/ex-
clusion criteria. Results: Studies reviewed had samples ranging from 1 to 192 (N=543). The majority (71%) of
participants in these studies required a diagnosis of gender dysphoria to qualify for puberty suppression and
were administered medication during Tanner stages 2 through 4. Positive outcomes were decreased suicidality
in adulthood, improved affect and psychological functioning, and improved social life. Adverse factors associ-
ated with use were changes in body composition, slow growth, decreased height velocity, decreased bone
turnover, cost of drugs, and lack of insurance coverage. One study met all quality criteria and was judged ‘ex-
cellent’, five studies met the majority of quality criteria resulting in ‘good’ ratings, whereas three studies were
judged fair and had serious risks of bias. Conclusion: Given the potentially life-saving benefits of these medica-
tions for TGD youth, it is critical that rigorous longitudinal and mixed methods research be conducted that
includes stakeholders and members of the gender diverse community with representative samples.
Key Practitioner Message
What is known?
•Increasing numbers of early adolescents who are transgender or gender diverse (TGD) and seeking profes-
sional help.
•Pubertal development may lead to (a) greater anxiety about sexual identity and (b) suicidal thoughts
among TGD.
•Professional organizations, such as the Endocrine Society and the World Professional Association for Trans-
gender Health (WPATH), have recommended the use of puberty-blocking hormones to arrest pubertal
development, thus allowing early adolescents and their families more time to consider the possible out-
comes of gender reassignment.
What is new?
•This article is a report of a critical and systematic review of literature about the use of puberty-blocking hor-
mones among TGD, the positive, and the negative outcomes associated with their use.
•The findings of this systematic review can guide healthcare professionals in their discussions with TGD
youth and their families as they consider the risks and benefits of puberty suppression.
What is significant for clinical practice?
•A summary of current research on the use of puberty-blocking hormones suggests that clinicians follow the
guidelines offered by the Endocrine Society and WPATH to enhance the positive outcomes associated with
use of these medications.
•Clinicians and researchers should work together to conduct well-designed and rigorous longitudinal and
mixed methods studies of TGD youth using GnRHa.
Keywords: Transgender; adolescent; puberty blockers; critical review
©2020 Association for Child and Adolescent Mental Health
Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
Child and Adolescent Mental Health 26, No. 1, 2021, pp. 3–14 doi:10.1111/camh.12437

Introduction
Recently, there has been an increase in the number of
parents seeking medical advice and care for their early
adolescent children who are transgender or gender
diverse [TGD] (Bonifacio & Rosenthal, 2015; Turban,
2017). A study of a representative sample of middle
school youth in San Francisco using the Youth Risk
Behavior Survey (YRBS) showed that 1.3% self-identified
as transgender (Shields et al., 2013); in the 2017, YRBS
data collected from a nationally representative sample of
high school students (N=131,901), 1.8% responded
‘Yes, I am transgender’, and another 1.6% responded, ‘I
am not sure if I am transgender’(Johns et al., 2019, p.
68). Compared to their cisgender peers, these gender
diverse youth bear a disproportionate burden for mental
health problems including substance use and suicide
attempt (Lowry et al., 2018).
Hormonal treatment, including the use of puberty
suppressing drugs, provides a potentially life-saving
solution for these patients, yet for this specific popula-
tion of patients, the long-term consequences of these
drugs are relatively unknown (Drummond, Bradley,
Peterson-Badali, & Zucker, 2008; Vrouenraets, Fre-
driks, Hannema, Cohen-Kettenis, & DeVries, 2015). For
children and adolescents who experience gender dys-
phoria (GD), the possibility of receiving this treatment
provides hope; however, the lack of longitudinal evidence
may lead to barriers in accessing and receiving treat-
ment. Two groups, the World Professional Association
for Transgender Health (WPATH, s2011) and the global
Endocrine Society in the United States (Hembree et al.,
2009, 2017), have provided consensus expert guidelines
for the use of puberty-blocking agents in children and
early adolescents with GD. The use of these medications,
in many early pubertal children, is an important compo-
nent of gender-affirming care (Edwards-Leeper, Leibow-
itz, & Sangganjanavanich, 2016). These consensus
guidelines have been critical in supporting the work of
medical professionals who are balancing clinical judg-
ment and evidence-based research in the care of these
patients.
In a descriptive study of the physiological and psycho-
logical characteristics of 101 transgender youth between
the ages of 12 and 24 years, Olson, Schrager, Belzer,
Simons, and Clark (2015) found that these youth were
aware of their gender incongruence at a mean age of
8.3 4.5 years, over one-third experienced symptoms
of clinical depression, and over half reported having sui-
cidal thoughts at least once and about one in three had
made one or more suicide attempts. Liu and Mustanski
(2012) followed a community sample of 246 LGBT youth
between the ages of 16 and 20 years prospectively and
found that previous victimization predicted both self-
harm and suicidal ideation. Clearly, the risk of adverse
mental and physical outcomes among this population of
youth is high. Thus, the need to find a way to prevent
such dire consequences is equally high.
Researchers in the Netherlands conducted a qualita-
tive study of 13 early adolescents (five trans girls and
eight trans boys) and explored the perceptions of these
adolescents (average age of 16 years 11 months) and the
professional teams working with them about the use of
puberty suppression in the form of gonadotropin-releas-
ing hormone agonists (GnRHa) (Vrouenraets, Fredriks,
Hannema, Cohen-Kettenis, & DeVries, 2016). Themes
derived from interviews with these adolescents were that
relative to using GnRHa for puberty suppression, (a) it is
difficult to determine the appropriate age for starting the
use of these hormones, (b) long-term effects of using
suppression are unknown, and (c) both stereotypes and
greater media attention create a social context that can
be positive or negative. These themes were compared
with data collected previously from professionals work-
ing with TGD youth and results in that study revealed
that professionals worried more about long-term effects
than did the youth, yet the youth worried more about the
appropriate age for starting puberty suppression.
The advantages of using puberty suppression in chil-
dren and adolescents with gender dysphoria have been
identified as improving some psychological functioning
such as decreased depression and improved global func-
tioning. Identified disadvantages were unpleasant side
effects such as hot flashes in AFAB youth treated later in
puberty (e.g., Tanner stages 4–5), decreased growth
velocity, and increased body mass index (Chew, Ander-
son, Williams, May, & Pang, 2018). In addition, bone
turnover and bone mineral density have been shown to
decrease with use of GnRHa, particularly in young trans-
women (Vlot et al., 2017). A significant barrier to use of
puberty suppressing medications is the high cost of the
medications with insurance coverage for treatment of GD
in children and early adolescents being highly variable
and, in some cases, specific insurance plan exclusions
(Stevens, Gomez-Lobo, & Pine-Twaddel, 2015).
The use of puberty suppressing drugs (e.g., gonado-
tropin-releasing hormone agonists or GnRHa) has long
been viewed as the standard of care for children with
central precocious puberty (Lee et al., 2014) and adverse
physical and psychological effects have been rare
(Krishna et al., 2019; Yu, Yang, & Hwang, 2019). GnRHa
have also been used in adolescent females with
endometriosis with mixed results (DiVasta & Laufer,
2013; Gallagher et al., 2018). Although these uses are
beyond the scope of this review, it is important to
acknowledge that risks and benefits among these dis-
parate populations could differ.
Purpose
Despite the increase in demand for more healthcare ser-
vices for TGD youth, research is still in its relative
infancy. The purpose of this critical review is to present
the current state of research on the use of puberty-
blocking hormones in prepubescent TGD children/early
adolescents.
Method
As authors of this review, we followed a seven-step method for
critical reviews of the literature described by Cooper (2017). The
seven steps are as follows: (a) formulate the problem; (b) search
the literature; (c) gather information/data from the published
studies; (d) evaluate the quality of the studies found; (e) analyze
and integrate outcomes of the studies; (f) interpret the evidence
found; and (g) present the results. Because there were no
human subjects involved, we did not request institutional
review board approval. We adhered to the Preferred Reporting
Items for Systematic Reviews and Meta-Analysis (PRISMA) as a
guideline for reporting our process and displaying our decision
©2020 Association for Child and Adolescent Mental Health
4Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14

points as shown in Figure 1 (Moher, Liberati, Tetzlaff, Altman,
& the PRISMA Group, 2009).
Problem identification
The problem addressed in this review was identified in the intro-
duction as a lack of knowledge about (a) the criteria for using
puberty-blocking drugs; (b) the known risks associated with
use of these drugs; and (c) the benefits of using such drugs with
early adolescents. We specifically sought to answer the following
questions relative to TGD early adolescents:
1 What prerequisite criteria (e.g., diagnosis of gender dys-
phoria; Tanner stage of sexual maturation) are being met
before physicians administer gonadotropic-releasing hor-
mone agonists (GnRHa)?
2 What specific drugs are used to suppress puberty in early
adolescents?
3 What are the known risks and adverse outcomes of using
GnRHa in early adolescents?
4 What have been the positive outcomes of using puberty
suppression drugs in early adolescents?
Inclusion/exclusion criteria and literature search
Inclusion/Exclusion Criteria: Our inclusion criteria were that
articles had to be either qualitative or quantitative research
papers, written in English with a focus on the use of puberty-
blocking drugs/hormones in early adolescents (e.g., ages 10–
14) who self-identified as transgender or who had a medical
diagnosis of gender dysphoria. The researchers had to identify
risks and/or benefits associated with the use of these medica-
tions. Our exclusion criteria were editorials, letters to the editor,
systematic reviews, and opinion pieces.
We consulted a health sciences librarian skilled in searching
the literature on healthcare topics. She performed the search
using four relevant and accessible databases: LGBT Life, Psy-
cINFO, PubMed, and Web of Science. Search strategies were
composed for each database, using subject headings and key-
words to recover articles on transgender persons and puberty
Records identified through
database searching
(n = 211)
Screening
Included Eligibility noitacifitnedI
Additional records identified
through other sources
(n = 0)
Records after duplicates removed
(n = 151)
Records screened
(n = 151)
Records excluded
(n = 8)
Not in English = 7
Abstract = 1
Full-text articles assessed
for eligibility
(n = 143)
Full-text articles excluded
(n = 143)
Commentaries/Essays = 17
CPG/Position Statements = 24
Literature Reviews = 28
Not on topic (e.g., did not discuss
risks of puberty blockers) = 65
Studies included in
quantitative synthesis
(meta-analysis)
(n = 9)
Figure 1. PRISMA flow diagram. CPG, Clinical Practice Guidelines [Colour figure can be viewed at wileyonlinelibrary.com]
©2020 Association for Child and Adolescent Mental Health
doi:10.1111/camh.12437 Review of puberty blockers 5

blockers, puberty suppressors, or puberty inhibitors. Table 1
details the search terms for each database.
Our search resulted in a sample of N=211 (Figure 1). We first
removed duplicates, then divided the identified articles evenly
among the first three authors. Using a screening checklist
designed specifically for this review, we examined the abstract
and the entire published paper to answer the following questions:
1 Was the paper written in English?
2 Was the focus of the paper on transgender youth/children
or prepubescent children/early adolescents with gender
dysphoria?
3 Did the article focus on the use of puberty-blocking drugs/
hormones such as gonadotropin-releasing hormone analog
(GnHRa)?
4 Did the authors identify risks and/or benefits associated
with the use of these hormones?
5 Did the study use a qualitative or quantitative research
design?
6 Was the paper a systematic or integrative literature review?
All papers for which the first five questions were answered
affirmatively and the last question was not, were retained for full
review.
Data extraction
After screening the articles, we developed a data extraction tool
that included the name of the first author and date of the publi-
cation, the purpose of the study, a description of the sample
(e.g., number and age of participants), prerequisites identified
prior to use of puberty-blocking drugs, the names or types of
drugs used, the youth’s Tanner stage at the time the drugs were
first administered, identified risks or adverse outcomes, positive
outcomes, and our quality assessment value (see details below,
in Step Four). We then extracted data from each article included
to describe our sample and to address our research questions.
Evaluation of quality of studies
To determine the quality of each paper, two authors indepen-
dently completed a checklist for each of the studies, compared
their ratings and discussed differences until coming to consen-
sus. We used one of three checklists, depending on the type of
study design, to evaluate the quality of the information found in
our literature sample and to report any type of bias found in the
process. The three checklists were specific for evaluating the
quality of retrospective chart reviews (Vassar & Holzmann,
2013), Joanna Briggs Institute (JBI) Critical Appraisal Checklist
for cross-sectional and observational studies, and the JBI Criti-
cal Appraisal Checklist for Case Reports (Joanna Briggs Insti-
tute, 2018). In assessing the quality of retrospective chart
reviews, we created a checklist with the 10 questions specified
by Vassar and Holzmann (2013) and arbitrarily created ratings
of poor (1–3 yes answers), fair (4–6 yes answers), and good (7–10
yes answers). In using the JBI checklists, we computed a per-
centage of met criteria to determine quality and followed the
same rating categories of poor,fair, and good. For all checklists
used, if all criteria were met, the study was given a rating of
excellent.
Analysis of outcomes and interpretation of evidence
Data analyzed for the nine articles included in this review were
derived from retrospective chart reviews, case reports, a cross-
sectional study, and prospective, observational studies. Thus,
no statistical analysis nor meta-analysis could be done. Rather,
data derived to answer our research questions are presented in
the next step showing our results.
Table 1. Terms used to search four databases related to use of
puberty blockers for early adolescents
Step Term(s)
Database: LGBT
Life
1 puberty
2 suppress OR suppression OR suppressing OR
suppressor OR suppressors OR inhibit OR
inhibitor OR inhibitors OR inhibiting OR
block OR blocker OR blockers OR blocking
3 1 AND 2
Database:
PsycINFO
1 transgender OR gender nonconforming OR
nonbinary
2 puberty
3 suppress OR suppression OR suppressing OR
suppressor OR suppressors OR inhibit OR
inhibitor OR inhibitors OR inhibiting OR
block OR blocker OR blockers OR blocking
4 2 AND 3
5 1 AND 4
Database:
PubMed
1 (‘Transgender Persons’[Mesh] OR transgender
[Title/Abstract] OR gender [2:17PMitle/
Abstract][9:27 AMitle/Abstract] OR
nonbinary[Title/Abstract]
2 puberty[Title/Abstract] OR prepuberty[Title/
Abstract] OR prepubertal [Title/Abstract] OR
prepubescent[Title/Abstract] OR
prepubescence[Title/Abstract]
3 blocker[Title/Abstract] OR blockers[Title/
Abstract] OR suppressor[Title/Abstract] OR
suppressors[Title/Abstract] OR inhibitor
[Title/Abstract] OR inhibitors[Title/Abstract]
OR hormone suppressor[Title/Abstract]
4 bicalutamide[Title/Abstract] AND anastrozole
[Title/Abstract]
5 3 OR 4
6 2 AND 5
7 ‘Gonadotropin-Releasing Hormone’[Mesh]
OR gonadotropin- Releasing hormone[Title/
Abstract] OR GnRH[Title/Abstract] OR
histrelin[Title/Abstract] OR leuprorelin[Title/
Abstract]
8 6 OR 7
9 1 AND 8
Database: Web of
Science
1 transgender OR gender nonconforming OR
gender nonconforming OR nonbinary
2 puberty OR prepuberty OR prepuberty OR
pubescent OR pubescence
3 suppress OR suppression OR suppressing OR
suppressor OR suppressors OR inhibit OR
inhibitor OR inhibitors OR inhibiting OR
block OR blocker OR blockers OR blocking
4 2 AND 3
5 gonadotropin-releasing hormone OR GnRH
or histrelin OR leuprorelin
6 bicalutamide OR anastrozole
7 5 OR 6
8 4 OR 7
9 1 AND 8
©2020 Association for Child and Adolescent Mental Health
6Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14

Results
Our searches yielded a total of 151 unique articles (after
all duplicates were removed) related to the search terms.
Details of the nine articles retained for review are in
Table 2; all were published recently, between 2011 and
2020. Of these, four articles were retrospective chart
reviews, two were case reports, one was cross-sectional,
one was a prospective study to evaluate the efficacy and
safety of using a GnRHa (triptorelin) drug over time in
transgender adolescents (Schagen, Cohen-Kettenis,
Delemarre-van de Waal, & Hannema, 2016). Sample
sizes in these studies ranged from 1 to 192. The samples
were 9–35 years of age and included a total of 296 trans-
gender females, assigned male at birth (AMAB) and 404
transgender males, assigned female at birth (AFAB) and
2 who were undecided patients assigned male at birth
(N=702). Race/ethnicity was not reported in 6/9
(66.7%) of the studies reviewed. In the other three stud-
ies, the vast majority of the samples (96%, 83.5%, and
68.5% respectively) were Caucasian/White.
Prerequisite criteria
The prerequisite criteria that were met before physicians
administered GnRHa drugs to early adolescents were
not reported in four of the studies (Klaver et al., 2018;
Nahata, Quinn, Caltabellotta, & Tishelman, 2017; Tur-
ban, King, Carswell, & Keuroghlian, 2020; de Vries,
2011). Other criteria mentioned were as follows: (a) being
screened by a mental health professional who made a
diagnosis of gender dysphoria (Khatchadourian, Amed,
& Metzer, 2014; Vlot et al., 2017); and (b) diagnosis of
gender identity disorder or lifelong extreme gender dys-
phoria and living in a supportive environment (Cohen-
Kettenis, Schagen, Steensma, DeVries, & Delemarre-
van de Waal, 2011; Schagen et al., 2016); and (c) gender
dysphoria and gender incongruence (Schneider et al.,
2017).
Drugs used to suppress puberty
The GnRH analogue drug named to suppress puberty in
children in four of the reviewed studies was triptorelin
Table 2. Articles in a critical review of literature on use of puberty blockers in prepubescent child
Author, date Purpose Sample
Prerequisites for
Drug Use
Tanner
Stage at
Initiation
Hormones or
Drugs Used
Risks or
Adverse
Outcomes Positive Outcomes
Cohen-Kettenis
et al. (2011)
Case report to
describe a 22-
year follow-up
of FtM treated
with GnRH
analogs at age
13.
N=1 AFAB;
age
35 years.
Race/ethnicity
not
reported.
States ‘fulfilled
the current
criteria for
GnRH analog
treatment
eligibility’ (p.
844). Does not
explicitly list
what these
were.
Diagnosis of
gender identity
disorder at age
16 (p. 843).
B3; P3 Triptorelin at age
13.7 years
3.75 mg q
4 weeks IM.
Age 18.6 stopped
triptorelin and
initiated
testosterone-
ester mixture.
None reported
directly for
GnRHa use.
At age 35 FSH
and LH were
elevated
owing to
gonadectomy
At age 35, all
anthropomorphic
measurements
were within normal
limits (50th
percentile 2SD);
fasting labs within
normal limits.
Patient is ‘still
convinced that his
choice to live as a
man was the right
one’ (p. 846).
De Vries et al.
(2011)
Prospective
follow-up to
compare
GD and
psychological
functioning
before and
after puberty
suppression.
N=70
Mean
age =13.6
(1.8) years
Race/ethnicity
N\not
reported
Not provided in
this paper.
Not
provided
in this
paper.
GnRHa, but no
drug name
given.
AFAB had
more anxiety
and anger
and had more
problem
behaviors
than AMAB.
GD was not
significantly
changed over
time.
Both AFAB and
AMAB showed
significant fewer
emotional and
behavior problems
over time. Both
also reported
decreases in
depressive
symptoms and
increases in global
functioning.
Khatchadourian
et al. (2014)
Retrospective
chart review;
describe
patient
characteristics,
treatment, &
response
N=84:
45 AFAB;
37 AMAB
2 undecided
natal males
Ages 11.4–
19.8 years.
Race/ethnicity
not
reported.
Screened by
mental health
professional.
Tanner 2 or +.
Diagnosis of
gender
dysphoria by
Utrecht Scale
or other scales.
Tanner
stage 2
GnRHa
14/15 FtM
transitioned to
testosterone (7
continued
GnRHa, 7
discont.
GnRHa).
GnRHa to 11 MtF
(5 rec’d
estrogen and 1
13 months =not
pursue change.
Drug name not
provided.
(continued)
©2020 Association for Child and Adolescent Mental Health
doi:10.1111/camh.12437 Review of puberty blockers 7

Table 2. (continued)
Author, date Purpose Sample
Prerequisites for
Drug Use
Tanner
Stage at
Initiation
Hormones or
Drugs Used
Risks or
Adverse
Outcomes Positive Outcomes
of these DC’d
GnRHa; 1
stopped due to
emotional
lability; 1
stopped due to
heavy smoking.
One MtF
stopped GnRHa
after
One stopped
GnRHa due to
mood swings &
emotional
lability.
Need long-term
follow-up
studies.
FtM patients
who undergo
mastectomy
have more
favorable post-
op outcomes.
Should be told
about fertility
preservation.
Klaver et al.
(2018)
Retrospective
design.
Examine how
body shape
and
composition
change during
treatment
with GnRHa
N=192:
71 AMAB
121 AFAB
Age 22 years.
3 Asian,
3 Black
American,
184 Caucasian
(96%)
Diagnosis of
gender
dysphoria.
Breast
stage 2
for girls
(age
14.5).
Gonad
stage 3
for boys
(age
15.3)
Sub-q GnRHa
3.75 for
4 weeks. No
drug name
provided.
Added cross-sex
hormones at
age 16.
Greater
changes in
body
composition
(>fat in MtF
and <fat in
FtM
compared to
cisgender).
Earlier treatment
associated with
closer resemblance
to desired sex
Nahata et al.
(2017)
Retrospective
medical record
review to
examine
mental health
diagnoses,
self-injurious
behaviors,
school
victimization,
and rates of
insurance for
hormone
therapy.
N=79:
n=28 AMAB
n=51 AFAB
Ages 9–
18 years
83.5% White
6.3% Black
6.3% biracial
2.5%
American
Indian
1.3% Hispanic
Diagnosis of
gender
dysphoria and
‘readiness’ for
hormone
treatment by
psychiatrist (p.
189)
Beginning
at Tanner
2–3
27 received
GnRHa but no
drug name was
given.
Cost of
GnRHa =up
to $25k per
year.
Only 8 of 27
had insurance
coverage
Not reported
Schagen et al.
(2016)
Prospective
observational
study to
evaluate
efficacy and
safety of
GnRHa
(triptorelin)
N=116:
49 AMAB
67 AFAB
Ages 11.1–
18.6 years.
Race/ethnicity
not
reported.
Diagnosis of
gender identity
disorder,
lifelong
extreme
gender
dysphoria,
psychologically
stable, living in
supportive
environments.
Median
Tanner
stage at
initiation
MtF- 4
FtM -
3.75 mg IM
Triptorelin
(GnRHa) every
4 weeks after
initial at 0, 2,
4 week dosing
Decreased
alkaline
phosphatase -
probably
related to
slowed
growth
velocity;
decrease in
lean body
mass % and
increase in fat
%; decreased
height
velocity.
All subjects had
suppressed
gonadotropin and
sex steroids;
testicular volume
decreased in MtF
and menses ceased
in FtM. No
sustained
creatinine or LFT
abnormalities
Schneider et al.
(2017)
Longitudinal
case report of
N=1
Age 11,
Diagnosis of
gender
Tanner
stage 2
Global IQ
decreased
(continued)
©2020 Association for Child and Adolescent Mental Health
8Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14

(Cohen-Kettenis et al., 2011; Schagen et al., 2016; Vlot
et al., 2017) and leuprorelin (Schneider et al., 2017). The
other five studies just used the term GnRHa but pro-
vided no specific drug name. Gender-affirming drugs
such as testosterone and estradiol were mentioned in
some studies as added later in the treatment protocols.
Risks/adverse outcomes
Known risks and adverse outcomes of using GnRHa in
children included mood swings and emotional lability
(Khatchadourian et al., 2014). Klaver et al. (2018)
reported different changes in body composition between
patients AMAB and patients AFAB after treatment; per-
sons AMAB had increased fat whereas AFAB persons
had decreased fat compared to cisgender peers. Nahata
et al. (2017) reported the cost of using GnRHa as an
adverse byproduct of this treatment in addition to the
lack of insurance coverage. Other adverse risks associ-
ated with use of these hormones included slow growth,
decrease in lean body mass, increased fat, and
decreased height velocity (Schagen et al., 2016); and
decrease in bone turnover markers (Vlot et al., 2017).
Positive outcomes associated with GnRHa
Positive outcomes associated with using GnRHa drugs
with adolescents included anthropomorphic measure-
ments returning to normal limits in adulthood (Cohen-
Kettenis et al. 2011); and better outcomes for patients
assigned female at birth who also underwent mastec-
tomy (Khatchadourian et al., 2014). Schagen et al.
(2016) reported positive changes in secondary sexual
characteristics along with the lack of sustained crea-
tinine or LFT abnormalities. Schneider et al. (2017)
reported the individual’s improvement in affective and
social life. Similarly, de Vries et al. (2011) found signifi-
cant improvements in general functioning, decreases in
depressive symptoms, and decreases in emotional and
behavioral problems. One study reported no positive
outcomes (Nahata et al., 2017). Importantly, when
Table 2. (continued)
Author, date Purpose Sample
Prerequisites for
Drug Use
Tanner
Stage at
Initiation
Hormones or
Drugs Used
Risks or
Adverse
Outcomes Positive Outcomes
effects of
puberty
suppression on
brain white
matter.
FMAB.
Race/ethnicity
not
reported.
dysphoria and
gender
incongruence.
Leuprorelin
3.75 mg. IM/
every 28 days
slightly, some
difficulty in
math and
exact sciences.
Improvement in
affective and social
life.
Turban et al.
(2020)
Cross-sectional
survey to
relate access to
puberty
blockers in
adolescence
and mental
health
outcomes in
adulthood.
N=89 who
received
puberty
blockers
between
ages 9 and
16. From
national
Transgender
Survey.
Not provided in
this paper.
Not
provided
in this
paper.
Not provided in
this paper.
None noted Decreased lifetime
suicidal ideation
and past-month
psychological
distress and binge
drinking. Reduced
lifetime illicit drug
use.
Vlot et al. (2017) Retrospective
study of bone
turnover
markers and
bone density
in adolescents
receiving
GnRHa and
later HRT
N=70:
28 AMAB
42 AFAB
Ages 11.5–
18.6.
Race/ethnicity
not
reported.
Diagnosis of
gender
dysphoria
FtM - start
at T2+;
MtF -
start
testicle
volume
at least 6
–8mlor
when T2-
3
Triptorelin
3.75 mg subcu-
taneously every
4 weeks
At 16 yo -
testosterone or
estradiol added.
Decrease in
bone
turnover
markers ICTP
and P1NP,
also coincides
with decrease
in BMAD Z
scores
primarily in
lumbar spine
(most
hormone
sensitive);
even after
HRT started,
in most,
pretreatment
Z scores were
not reached
even after
24 months on
HRT
Some recovery of
BMAD Z scores
after HRT started
Abbreviations: AFAB, males, assigned female at birth; AMAB, females, assigned male at birth; GD, gender dysphoria; GnRHa, gonadotro-
pin-releasing hormone agonist.
©2020 Association for Child and Adolescent Mental Health
doi:10.1111/camh.12437 Review of puberty blockers 9

compared to youth who did not receive pubertal sup-
pression, those who did showed lower lifetime rates of
suicidal ideation (Turban et al., 2020).
Quality
Table 3 is a summary of the quality checklists used to
determine quality in the four studies that were retro-
spective chart reviews. In sum, three of the studies were
deemed of fair quality with relatively high risk for bias.
These studies had quality scores that were 4 and 5 crite-
ria out of 10 that were met; one study was assessed as
good with a score of 7 out of 10 criteria met. The risk of
bias in the studies with fair quality was owing to such
things as not reporting how data abstractors were
trained and monitored, lack of standardized abstraction
forms, and lack of procedural manual or description of
data abstraction process in the study. None of the stud-
ies reviewed here reported having pilot tested the data
collection method or tools. All of these studies met the
criterion for addressing ethical and legal concerns.
The prospective studies by de Vries et al. (2011), and
Schagen et al. (2016), plus the cross-sectional study by
Turban et al. (2020), which were assessed using the JBI
checklist, earned ‘good’ratings as shown in Table 4. The
study by Cohen-Kettenis et al. (2011) was a single case
study, for which we used the JBI Critical Appraisal
Checklist for Case Reports (Joanna Briggs Institute,
2018), was rated excellent, having met all eight criteria
(100%). We also used the JBI Critical Appraisal Check-
list for Case Reports for the other single case study by
Schneider et al. (2017) and rated it good, with 7 of 8 crite-
ria met (87.5%). The checklists for these two case reports
are in Table 5.
Discussion
The studies identified and reviewed here are current
with publication dates ranging from 2011 to 2020. As
adolescents, their families, and healthcare providers
seek more guidance about using GnRHa drugs to sup-
press puberty, the findings from this critical review are
timely, unique, and useful. Given the relatively short
amount of time that GnRHa drugs have been used for
patients with GD, it is not unexpected that we found no
longitudinal empirical studies to guide practice in this
expanding population, although studies are currently
underway (Olson-Kennedy et al., 2019). At present, the
lack of longitudinal data remains a gap in the litera-
ture. From an exhaustive search of four databases,
however, we were able to answer our four research
questions with data from a total sample of N=702
youth described in a mere nine published articles. The
samples ranged not only in size (1–192) but also in age
(9–35). Although race/ethnicity was reported in <67%
of the studies, where it was, the vast majority of partici-
pants were Caucasian or White. Clearly, more studies
are needed to address the needs of this diverse and
expanding population.
Being screened by a mental health professional to
establish a diagnosis of gender dysphoria (GD) or gender
Table 3. Vassar & Holzmann’s quality checklist for retrospective chart reviews of articles in critical review of puberty-blocking drugs (by
first author)
Quality Question Khatchadourian Klaver Nahata Vlot
1. Are there well-defined and
clearly articulated research
questions?
a
Aim to describe
cohort in hospital
Yes =1
Aim to examine
changes and
compare
Yes =1
Goals to examine prevalence of
mental health diagnoses and
insurance coverage.
Yes =1
Objective to investigate course
of three bone turnover
markers during Rx.
Yes =1
2. Is there clear evidence of
an a priori sampling plan?
No =0 Yes =1 Yes =1 Yes =1
3. Were the variables
operationalized
adequately?
(e.g., age at first visit,
natal sex, Tanner at
first visit).
Yes =1
Yes =1 Yes =1 Yes =1
4. Were data abstractors
trained and monitored
throughout the study?
No =0 No/not
stated =0
Yes =1No=0
5. Was a standardized
abstraction form used?
No/uncertain =0 No/not
stated =0
Yes =1No=0
6. Was there a procedural
manual or description for
data abstraction?
No/uncertain =0 No/not
stated =0
No =0No=0
7. Were there explicit
inclusion and exclusion
criteria?
Yes =1 Yes =1 Yes =1 Yes =1
8. Were interrater/intrarater
reliability addressed?
No =0No=0No=0No=0
9. Was there a pilot test of
the data collection and
analysis?
No/uncertain =0No=0No=0No=0
10. Were ethical and legal
considerations addressed?
Yes =1 Yes =1 Yes =1 Yes =1
OVERALL ASSESSMENT Fair: 4/10 Fair: 5/10 Good: 7/10 Fair: 5/10
a
If there was a clear aim, objective, or goals for the study, and research questions could be inferred, we rated this criterion as ‘yes’.
©2020 Association for Child and Adolescent Mental Health
10 Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14

identity disorder (GID) was found as a prerequisite to
using puberty-blocking drugs in half of the studies. The
studies that included older samples, meaning that diag-
nostic prerequisites were met prior to publication of the
fifth edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM) (American Psychiatric Associa-
tion, 2013), reported using a diagnosis of gender identity
disorder (GID) rather than GD. Authors of all the studies
reviewed here noted that this diagnosis was an essential
starting point before considering the use of puberty sup-
pressors. All studies in this sample also included not ini-
tiating puberty suppressing drugs prior to the onset of
puberty. These recommendations are consistent with
guidelines published by WPATH (2011) and the Endo-
crine Society (2017), which note that hormonal therapies
should not be instituted prior to the onset of puberty.
They are also consistent with a gender-affirming concep-
tualization of care based on the premise that society
upholds diversity in gender development and expression
(Edwards-Leeper et al., 2016, p 165).
There was general agreement that gonadotropin-re-
leasing hormone analogue (GnRHa) drugs are preferred
for puberty suppression. Five of the papers reviewed
here described the use of triptorelin or leuprorelin (off-la-
bel), followed by sex-affirming hormones. The other four
papers did not give the name of the drugs used, but the
authors wrote that GnRHa drugs were administered.
These procedures follow the ‘Dutch protocol’outlined by
Delemarre-van de Waal and Cohen-Kettenis (2006) in
which 3.75 mg. of triptorelin is given every four weeks
intramuscularly or subcutaneously when adolescents
have reached Tanner stages 2–3 and have been diag-
nosed with gender dysphoria (previously gender identity
disorder).
As for positive outcomes, improved psychological
health was identified in this review (Turban et al., 2020;
de Vries et al., 2011). The most recent study by Turban
et al. (2020) was the first to demonstrate that access to
pubertal suppression during adolescence was associ-
ated with decreased lifetime suicidality among transgen-
der adults. In a prospective, longitudinal investigation,
de Vries et al. (2011) reported improvements in general
functioning as well as decreases in depressive symp-
toms and emotional and behavioral problems. The find-
ings of these two studies are further supported by a
recent longitudinal investigation that found youth aged
9–25 years who engaged in gender-affirming endocrine
treatment (i.e., puberty suppression or cross-sex hor-
mones) demonstrated improved mental health over
time (Achille et al., 2020). The chance to have more
time to consider medical transition was helpful to the
young person in one of the case study reports (Cohen-
Kettenis et al., 2011). Despite these psychosocial
improvements, most of the studies reviewed here
focused on biological outcomes rather than psychoso-
cial ones. Although the biological outcomes that affirm
the patient’s gender are critical to the success of using
puberty-blocking drugs, a more holistic view including
psychosocial outcomes are equally important to ensure
all needs of patients are being met. Such a holistic view
highlights both the physical and mental health implica-
tions of access to puberty suppression. As the Endo-
crine Society (2017) indicate, transgender individuals
in puberty should be cared for by a multi-disciplinary
team that can address both mental and physical health
concerns simultaneously.
As other studies have shown, risks and adverse out-
comes described in these studies included emotional
lability, changes in body composition (e.g., fat deposits),
Table 4. Joanna Briggs Institute’s critical appraisal checklist for cross-sectional and prospective observational studies
de Vries
et al. (2011)
Schagen
et al. (2016)
Turban
et al. (2020)
1. Were the criteria for inclusion in the sample clearly defined? Y Y Y
2. Were the study subjects and the setting described in detail? Y Y NA
3. Was the exposure measured in a valid and reliable way? U Y Y
4. Were objective, standard criteria used for measurement of the condition? Y Y Y
5. Were confoundingfactors identified? N U Y
6. Were strategies to deal with confounding factors stated? N U Y
7. Were the outcomes measured in a valid and reliable way? Y Y U
8. Was appropriate statistical analysis used? Y Y Y
TOTAL PERCENTS 62.5% 75% 85.7%%
Legend: Y =yes; N =no; U =unclear; NA =not applicable. Denominator does not include items judged ‘NA’.
Table 5. Joanna Briggs institute’s critical appraisal checklist for case report reports
Criteria Cohen-Kettenis et al. (2011) Schneider et al. (2017)
1. Were patient’s demographic characteristics clearly described and presented? Yes Yes
2. Was the patient’s history clearly described and presented as a timeline? Yes Yes
3. Was the current clinical condition of the patient on presentation clearly described? Yes Yes
4. Were diagnostic tests or assessment methods and the results clearly described? Yes Yes
5. Was the intervention(s) or treatment procedure(s) clearly described? Yes Yes
6. Was the postintervention clinical condition clearly described? Yes No
7. Were adverse events (harms) or unanticipated events identified and described Yes Yes
8. Does the case report provide takeaway lessons? Yes Yes
TOTAL criteria met 8/8 =100% 7/8 =87.5%
©2020 Association for Child and Adolescent Mental Health
doi:10.1111/camh.12437 Review of puberty blockers 11

decreased height velocity, decreased bone turnover,
decreased bone mineral density, high cost of these
drugs, and inadequate insurance coverage. These find-
ings raise issues with important policy implications and
beg for further study.
We need more studies that address the potential posi-
tive and negative outcomes related to the use of puberty-
blocker therapies not only as they affect the individual
but also as they affect the family. Families with health
insurance policies that do not support all the services
described in the WPATH standards of care for transgen-
der adolescents may suffer financial hardships that
could be prevented with additional research demonstrat-
ing long-term benefits of this treatment (Padula & Baker,
2017). Families may also need counseling and support
groups to deal with issues such as stigma, uncertainty
about the future (Gray, Sweeney, Randazzo, & Levitt,
2016), grief and family conflict as youth begin to con-
sider seriously pursuing puberty suppression (Ashley,
2019). Research confirms that TGD youth who lack fam-
ily and other forms of social support bear a heavy burden
of psychological distress (McConnell, Birkett, & Mustan-
ski, 2016).
The quality of the studies reviewed was modest but
promising. In all the studies reviewed, the primary risk
for bias was selection of the samples, but this may be
unavoidable given that the population in each case is
already self-selected. Nearly half (44%) of the studies
reviewed were retrospective chart reviews and only one
of these was rated as ‘good’, which meant that it had a
relatively low risk for bias compared to the others.
Because the other three studies omitted important crite-
ria for retrospective chart reviews, they reflected fairly
large risks for bias, particularly concerning the inexact
methods by which data were extracted from the patients’
records. Although the remaining studies were deemed
‘good’or ‘excellent’in terms of meeting more criteria for
their respective study designs, these designs provided
low-level evidence: case reports, prospective observa-
tional, and cross-sectional studies. Case studies are
considered to be the weakest of designs or lowest form of
evidence, containing threats to internal validity includ-
ing history, maturation, and mortality (Campbell &
Stanley, 1963; Cochrane, n.d.). These findings suggest
the need for additional studies to be conducted using
more rigorous designs with fewer threats to internal
validity.
The findings from this review support the position
taken by Reisner et al. (2016) that we need more longitu-
dinal studies on youth who have taken puberty-blocking
drugs in adolescence. Such studies as well as studies
using mixed methods designs could document both bio-
logical and psychosocial changes over time and are able
to provide a more holistic and comprehensive view of
how the use of such agents affects the lives of individuals
as they explore this critical time of development. More-
over, qualitative studies are needed to document the
first-person experiences of TGD youth, as Vrouenraets
et al. (2016) have also suggested.
Additional research can lend more strength to current
clinical guidelines and assist clinicians in caring for
these patients and their families especially as questions
arise during treatment. Underscoring the need for ongo-
ing research, access to puberty blockers, and the poten-
tial benefits that they provide, is not universal and varies
greatly by geography, insurance status, health-
care provider availability among other factors (Kimberly
et al., 2018). An increase in high-quality longitudinal
data should lend additional support to what health-
care providers are witnessing clinically: improvements
in short- and long-term health outcomes of these very
vulnerable youth. With additional research should come
increased access to these treatment modalities and
improvements in mental health outcomes.
Limitations
This study was limited to a review of papers published in
English, thus we may have missed important findings
published in other languages and other countries. This
study was also limited to only four databases. Other
databases may have included studies that we missed.
Our specific research questions also may have limited
our inclusion criteria. Despite these limitations, the find-
ings are strengthened by our adherence to a critical and
systematic review process, including the extensive
search assistance from an experienced science librarian
(last author), and the relatively large number of total par-
ticipants in the nine studies reviewed.
Implications
The implications for multidisciplinary teams of health-
care professionals working with this population are that
this body of research supports the use of puberty sup-
pression in early adolescents who are carefully screened
for gender dysphoria and who have reached an early
stage of pubertal development.
Conclusion
Despite a recent increase in the number of TGD youth
seeking healthcare services for their gender dysphoria,
there exists a relatively small amount of research regard-
ing the positive and negative short- and long-term effects
of using GnRHa drugs to suppress puberty and to allow
more time for gender identity exploration. The need for
additional well-designed longitudinal and mixed meth-
ods studies is critical to support and even improve cur-
rent practice for this very vulnerable population.
Although large long-term studies with diverse and multi-
cultural populations have not been done, the evidence to
date supports the finding of few serious adverse out-
comes and several potential positive outcomes. This lit-
erature suggests the need for TGD youth to be cared for
in a manner that not only affirms their gender identities
but that also minimizes the negative physical and psy-
chosocial outcomes that could be associated with puber-
tal development.
Acknowledgements
There was no funding source for this study. The authors have
declared that they have no competing or potential conflicts of
interest.
Ethical approval
No ethical approval was required for this review article.
Correspondence
©2020 Association for Child and Adolescent Mental Health
12 Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14

Lynn Rew, School of Nursing, The University of Texas at
Austin, 1710 Red River, Austin, TX 78712, USA; Email:
ellerew@mail.utexas.edu
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©2020 Association for Child and Adolescent Mental Health
14 Lynn Rew et al. Child Adolesc Ment Health 2021; 26(1): 3–14