Kuper 2014 Puberty Blockers Clinical Research Review PDF
Kuper 2014 Puberty Blockers Clinical Research Review PDF
Kuper 2014 Puberty Blockers Clinical Research Review PDF
2
3
Gender affirming medical care is receive gender affirming medical care assessment process with a
considered medically necessary of any kind. Increasingly, transgender multidisciplinary team and
treatment for transgender individuals individuals are requesting care at adolescents are tracked over time
who experience physical dysphoria earlier ages due to larger social shifts and provided with support during the
(i.e., distress associated with physical in visibility and acceptance that have transition period [5, 6].
sex characteristics) [1, 2]. While not all resulted in earlier ages of “coming
individuals who experience a out.” As a result, gender clinics The following report provides
discrepancy between their gender specializing in the medical treatment an overview of puberty blockers
identity and sex assigned at birth of transgender individuals are offering including how they work, how
experience physical dysphoria, many cross-sex hormone therapy at they are prescribed, and what
do. Forms of gender affirming medical younger ages (16-18 years old) [3, 4]. research exists to support their
care include use of hormones and In addition, a number of doctors are
use.
gender affirmation surgeries (e.g., “top” now prescribing puberty blockers to
surgeries, “bottom” surgeries, facial adolescents with strong physical
feminization, and laser hair removal). dysphoria that persists or emerges
Historically, transgender individuals with the onset of puberty. Puberty
were required to wait until age 18 to blockers are prescribed after an
Disclaimer: This publication is not able to provide medical care recommendations or advice specific to any one individual. If your child is
expressing a strong desire for medical gender transition (e.g., hormones, puberty blockers) it is important to connect with supportive
professionals. A number of organizations now exist to support transgender children and their families, including, but not limited to:
Gender Spectrum, TransYouth Family Allies, Trans Youth Equality Foundation, TransActive, Gender Odyssey
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review IMPACT LGBT Health and Development Program
Lorem Ipsum What Changes During Puberty?
Puberty involves changes in body structures, body functions, and physical appearance. Differences
between the sexes are often divided into primary and secondary sex characteristics. Primary sex
characteristics include egg (ova) production in female bodied individuals and sperm production in male
bodied individuals. These processes are referred to as primary because they are most closely linked to
sexual reproduction. While females are born with eggs already produced, these eggs do not fully mature
until menstruation begins. In contrast, males do not start producing sperm until they begin to ejaculate
during puberty. Secondary sex characteristics include fat distribution, muscle mass, breast tissue, voice,
body hair, height, and body frame. During puberty, both males and females also experience a growth spurt
and change in bone density. Cognitive development (i.e., changes in the brain) also occurs during puberty.
At the start of puberty, the connections between brain cells rapidly increase, particularly in the part of the
brain that controls problem solving and planning. Several years after this burst in connections, connections
that are not used are “pruned.” A process called myelination also speeds up the communication between
brain cells. Both pruning and myelination continue throughout the teen years to make the brain efficient and
specialized. Most adolescents also experience an increase in sexual attraction and interest sex, sexuality,
and dating, although not all individuals report these experiences (e.g., asexual identified youth).
Tanner Staging:
Doctors often describe the changes associated with puberty using the Tanner staging system. Individuals at
Tanner stage I are pre-pubertal, meaning they have not yet experienced any pubertal changes. Tanner
stage II reflects the start of puberty while stage III and IV reflect continued pubertal changes. By Tanner
stage V, sex characteristics have reached adult development. Tanner stages are typically assessed via
examination of breast size, testicular volume and penis size, and pubic hair. Tanner stage also can be
confirmed by a blood test that identifies the level of testosterone or estradiol circulating throughout the body.
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual.
What Changes During Puberty? (cont.) 3
The timing of puberty varies across individuals. However, changes typically start with increases in
testicular volume followed by pubic hair development and a growth spurt for male bodied individuals (age
10-16). Puberty typically starts earlier with pubic hair development and breast development for female
bodied individuals (age 8-14). Sperm production (age 12-14) and menstruation (age 10-16.5) occur
somewhat later. Without medical intervention, the vast majority of individuals who are transgender or gender
non-conforming progress through the puberty typical of their birth sex. However, a small minority of
individuals may experience puberty unusually early (precocious puberty) or late (delayed puberty). In
addition, intersex conditions, or differences of sex development, are sometimes first identified when puberty
does not progress as expected. These differences in sex development occur in approximately 1% of the
population, but are not typically the cause of physical dysphoria or transgender identification. Within
countries such as the US, the average age of puberty has been decreasing but the causes of this change
are not fully understood. In addition, research suggests that, on average, African American individuals begin
puberty at earlier ages than white individuals. Finally, genetics also plays a role. Research shows that
individuals tend to progress through the stages of puberty at similar ages as biological siblings and parents.
The changes that occur during puberty are driven by changes in hormone production. Prior to
puberty, male and female-bodied individuals have similar levels of testosterone (an androgen) and estradiol
(an estrogen) hormones. During puberty, testosterone levels steadily increase in male-bodied individuals
while estradiol levels steadily increase in female-bodied individuals. Testosterone also increases slightly in
females and estradiol in males, although not nearly as much. In both sexes, this process is started by
changes in the pattern of gonadotropin releasing hormone (GnRH) production in the hypothalamus (a region
of the brain involved in the development and regulation of hormones). Depending on the amount and
frequency of GnRH released, two additional hormones (luteinizing hormone, follicle-stimulating hormone)
are secreted from the pituitary gland. These hormones then stimulate the testes or ovaries to produce
testosterone or estradiol.
GnRH analogues (puberty blockers) are a synthetic form of the human body’s GnRH hormone. When taken regularly
GnRH analogues work by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone. These are
the two hormones that stimulate the testes to produce testosterone and the ovaries to produce estradiol. Testosterone
and estradiol are responsible for the changes that occur during puberty. GnRH analogues can be taken in the form of
injections monthly or every three months, or small implants that are placed under the skin for up to 12 months
[4, 7]. Treatment of transgender adolescents with puberty blockers is fairly recent. As a result, they have not been
approved by the US Food and Drug Administration (FDA) for use in this population. However, for approximately the past
30 years, these same medications have been successfully used to treat precocious puberty with few “side effects”
identified. A number of studies have been conducted that have tracked these patients over time [7, 8, 9, 10, 11, 12].
Several small studies also have been conducted on transgender adolescents [4, 6]. Together, these studies provide
information on the impact that puberty blockers have on development.
Fertility Considerations:
If puberty blockers are taken for a period of time but then discontinued, they do not appear to impact future fertility (i.e.,
ability to conceive a child) [1, 8-12]. However, for transgender individuals who go on to take cross-sex hormones, future
fertility may be extremely difficult if not impossible. Some transgender adults are able to conceive after discontinuing
cross-sex hormone therapy for a period of at least several months (and remaining off of hormones for the course of the
pregnancy, if carrying the child). Even in these cases, fertility may be difficult or not possible due to the prior effects of
cross-sex hormones. Some transgender individuals choose to undergo procedures to harvest and store their sperm or
eggs prior to starting cross-sex hormones. However, in both of these cases, individuals had already gone through the
puberty associated with their birth sex. Individuals who go on puberty blockers during adolescence followed by cross sex
hormones can stop hormone use during adulthood. These individuals would then experience many of the physical
changes associated with the puberty of their birth sex (some of which would be irreversible such as facial hair growth).
However, due to the lack of research in this area, it is not clear that going through this process would allow the individual
to become fertile. It is important to factor this uncertainty regarding future fertility into the decision-making process. It
may also be helpful to explore resources on alternate parenting options such as adoption [13, 14].
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review, IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual
Use of Puberty Blocking Medication with Transgender 5
Adolescents: Review of the Research Literature
In order to better understand the research conducted on transgender adolescents, it is helpful to know what
research has been conducted on transgender adults receiving gender affirming procedures (such as hormones,
“top” surgery, “bottom” surgery). First, it is important to note that as a group, transgender individuals are
diverse in their gender identities, gender expression, and desired physical appearance [15, 16]. Many
transgender-identified individuals do not experience physical dysphoria strong enough to seek gender affirming
procedures. For those that do, research has consistently found that gender affirming procedures are
effective at eliminating or significantly reducing physical dysphoria. A recent meta-analysis combined data
from 23 studies of clients receiving gender affirmation surgeries along with cross sex hormones [17].
Approximately 80% of these clients reported a decrease in gender dysphoria, improvement in sexual function,
and an increase in quality of life. While a minority of adults receiving gender affirming procedures do report some
dissatisfaction with surgical outcomes (e.g., difficulty with sexual intercourse, dissatisfaction with chest scarring)
(7-13%), rates of regret are very low (about 1.5%) [18, 19, 20].
Just as with adults, much variation exists in the gender related experiences of children and adolescents.
Many children and adolescents express cross-gender interests (e.g., enjoying toys and activities typically
associated with the other sex). Some may also adopt cross-sex roles in pretend play and/or experiment with
cross-sex clothing or dress up activities. Even among those children and adolescents who are consistently
gender non-conforming in their interests and activities; research suggests that most will not go on to adopt a
cross-sex identity that persists through adulthood [14, 15]. However, these gender nonconforming individuals
may continue to prefer clothing, hairstyles, and nicknames that are typically associated with the other sex or are
gender neutral. Some of these gender nonconforming individuals will affirm gender identities such as
genderqueer or androgynous. In contrast, research suggests most adolescents who consistently assert a cross-
sex identity in adolescence maintain this identity throughout adulthood [2, 21, 22]. These differences in gender-
related trajectories were demonstrated in a small interview based study of adolescents who initially presented in
childhood for evaluation at a specialized gender clinic in the Netherlands [23]. Steensma and colleagues found
that, at the time interviewed (age 14 to 18), those who persisted in their cross-sex identity described this identity
as stable by age 10. At the onset of puberty, physical dysphoria also intensified within this group,
particularly in response to pubertal changes. Many also described a growing desire to live “full time” as
their affirmed gender (e.g. most commonly by changing name/pronouns but also included growing out hair
and/or changing clothing for affirmed females). In contrast, at the time of interview, those that did not persist in
their cross-sex identity also did not report significant physical dysphoria or strong dislike of being referred to by
their assigned sex. When reflecting on their childhood, these youth described being “boyish” girls or “girlish” boys
who wished they were, or thought it would be easier to be, the other sex. In contrast, youth who affirmed a cross-
sex identity described feeling as if they were truly this affirmed gender. It is important to note that in early
childhood, youth from both groups reported not thinking much about gender or experiencing physical dysphoria.
Further, during both early and middle childhood, youth from both groups described shared experiences of being
gender non-conforming in their interests as well as desired clothing (particularly for those assigned female who
had greater ability to dress as desired) [23].
Participants from this previous study who persisted in their cross-sex identity were part of a larger cohort of 111
adolescents who were the first to receive puberty blockers between 2000 and 2008 at the Amsterdam
gender identity clinic in the Netherlands [24]. During this time, 29 adolescents between the ages of 16 and 18
also were prescribed cross-sex hormones but had progressed too far into puberty for blockers. Neither puberty
blockers nor cross sex hormones was deemed to be appropriate for an additional 56 adolescents (29%). deVries
and colleagues reported on outcome data for the first 70 of these adolescents to receive puberty blockers. These
adolescents were assessed just before start of puberty suppression and again just before the start of cross-sex
hormone therapy (an average of 2 years later). All but one of these adolescents socially transitioned during the
assessment process (e.g., change in pronouns and name across settings), and all 70 adolescents continued with
cross-sex hormone therapy. Between these time points, general functioning improved while depression,
behavioral, and emotional difficulties decreased (ratings of anxiety and anger remained similar). However,
approximately one third of these adolescents and their families required ongoing counseling to address co-
occurring social, emotional, and relational concerns such as oppositional behavior, depression, and family
conflict. The average assessment period of 6 to 12 months was often prolonged in these cases [25].
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review, IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual
Use of Puberty Blocking Medication with Transgender
Lorem Ipsum
Regular meetings with all members of the multidisciplinary team assists in the monitoring of each
adolescent’s gender identity development, physical dysphoria, and overall functioning. By age 16
hormones are typically introduced, assuming that puberty blockers were helpful at reducing gender dysphoria
and that cross-sex hormones are desired. Typically, hormone levels are then gradually increased every 6
months for about 2 years until adult levels are reached. Follow up care continues throughout this process and
into adulthood although the frequency of visits may decrease over time [1-6, 26].
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review, IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual
Why not wait to see if gender dysphoria resolves during or after puberty?
Lorem Ipsum
Some doctors and clinicians have expressed concerns regarding providing gender-related medical interventions to
adolescents because this is a time when identity development is typically taking place. They worry that these adolescents’
gender identities or physical dysphoria may change during or following puberty. For many gender non-conforming, gender
fluid, or gender diverse children, puberty blocking treatment is indeed not necessary or appropriate [14, 16]. However,
doctors and clinicians specializing in the care of transgender adolescents point out that there is no evidence that the
changes associated with puberty are helpful at resolving strong and consistent physical dysphoria. In contrast, preliminary
research suggests that when strong and consistent physical dysphoria is present, delaying treatment is linked to
higher rates of depression, anxiety, eating disorders, and sucidality. These mental health difficulties also can
negatively impact social and academic functioning and distract from identity development in other areas [3, 4, 5, 14].
In addition, it is more difficult to align the body with one’s affirmed gender once physical changes in secondary sex
characteristics occur, especially for male-bodied individuals. Changes in facial structure, facial hair, Adams apple, and
voice will not reverse with hormone treatment once puberty is complete, which can make it very difficult for some affirmed
females to have their gender correctly identified and respected. In addition, the medical procedures associated with altering
these features are often expensive, painful, and time consuming (e.g., electrolysis, facial feminization). For both affirmed
males and females, puberty blockers followed by cross-sex hormones helps to prevent the need for “top” surgery and
produces a final height and body frame more in line with affirmed gender. These outcomes cannot be accomplished by only
using cross-sex hormones. Additionally, while research suggests that rates of post-surgical regret are generally very low,
those who do experience regret were more likely to have received care at older age. Regrets also appear to be more
common among those who experience complications during surgery as well as those who experience difficulty “passing” as
their affirmed gender, most likely due to higher rates of experiencing discrimination and violence [18, 19, 20, 28]
In light of the irreversible changes that occur during puberty, specialists who work with transgender adolescents
emphasize that “wait and see” approaches are not neutral responses to persistent gender dysphoria. That being
said, in a minority of cases, adolescents and/or families may initially express unrealistically high expectations for puberty
blockers. It is important to note that while extremely helpful in many cases, co-occurring mental health difficulties may
persist even after treatment. Transgender individuals also are likely to continue to face unique adjustment-related
challenges throughout adolescence and adulthood (e.g., navigating social stigma, managing disclosure). For these reasons,
providers also emphasize the importance of building and maintaining supportive social and professional networks for the
adolescent as well as their family [3, 4, 5, 6]
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review, IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual
CITED Research
[1] Hembree, W. C., Cohen-Kettenis, P., Delemarre-van de Waal, H. A., Gooren, L. J., Meyer III, W. J., Spack, N. P., ... & Montori,
V. M. (2009). Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. Journal of Clinical
Endocrinology & Metabolism, 94(9), 3132-3154.
[2] Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P.,... & Zucker, K. (2012). Standards of care for the health of
transsexual, transgender, and gender-nonconforming people, version 7.International Journal of Transgenderism, 13(4), 165-232.
[3] Cohen‐Kettenis, P. T., Delemarre‐van de Waal, H. A., & Gooren, L. J. (2008). The treatment of adolescent transsexuals:
Changing insights. The Journal of Sexual Medicine, 5(8), 1892-1897.
[4] Olson, J., Forbes, C., & Belzer, M. (2011). Management of the transgender adolescent. Archives of Pediatrics & Adolescent
Medicine, 165(2), 171-176.
[5] Delemarre-van de Waal, H. A. (2014). Early medical intervention in adolescents with gender dysphoria. In Gender Dysphoria
and Disorders of Sex Development (pp. 193-203). Springer US.
[6] Spack, N. P., Edwards-Leeper, L., Feldman, H. A., Leibowitz, S., Mandel, F., Diamond, D. A., & Vance, S. R. (2012). Children
and adolescents with gender identity disorder referred to a pediatric medical center. Pediatrics, 129(3), 418-425.
[7] Mul, D., & Hughes, I. A. (2008). The use of GnRH agonists in precocious puberty. European Journal of
Endocrinology, 159(suppl 1), S3-S8.
[8] Heger, S., Partsch, C. J., & Sippell, W. G. (1999). Long-term outcome after depot gonadotropin-releasing hormone agonist
treatment of central precocious puberty: Final height, body proportions, body composition, bone mineral density, and reproductive
function. Journal of Clinical Endocrinology & Metabolism, 84(12), 4583-4590.
[9] van der Sluis, I. M., Boot, A. M., Krenning, E. P., Drop, S. L., & de Muinck Keizer-Schrama, S. M. (2002). Longitudinal follow-up
of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH
agonist therapy. Journal of Clinical Endocrinology & Metabolism, 87(2), 506-512.
[10] Pasquino, A. M., Pucarelli, I., Accardo, F., Demiraj, V., Segni, M., & Di Nardo, R. (2008). Long-term observation of 87 girls with
idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass
index, bone mineral content, and reproductive function. Journal of Clinical Endocrinology & Metabolism, 93(1), 190-195.
[11] Bertelloni, S., & Mul, D. (2008). Treatment of central precocious puberty by GnRH analogs: long‐term outcome in men. Asian
Journal of Andrology, 10(4), 525-534.
[12] Tanaka, T., Niimi, H., Matsuo, N., Fujieda, K., Tachibana, K., Ohyama, K., ... & Kugu, K. (2005). Results of long-term follow-up
after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of
gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. Journal of Clinical Endocrinology &
Metabolism, 90(3), 1371-1376.
[13] De Sutter, P. (2007). Reproduction and fertility issues for transpeople. Principles of transgender medicine and surgery, 209-
222.
[14] Brill, S., & Pepper, R. (2013). The transgender child: A handbook for families and professionals. Cleis Press.
[15] Lev, A. I. (2004). Transgender emergence. Binghamton, NY: Haworth Press.
[16] Kuper, L. E., Nussbaum, R., & Mustanski, B. (2012). Exploring the diversity of gender and sexual orientation identities in an
online sample of transgender individuals. Journal of sex research, 49(2-3), 244-254.
[17] Murad, M. H., Elamin, M. B., Garcia, M. Z., Mullan, R. J., Murad, A., Erwin, P. J., & Montori, V. M. (2010). Hormonal therapy
and sex reassignment: a systematic review and meta‐analysis of quality of life and psychosocial outcomes. Clinical
Endocrinology, 72(2), 214-231.
[18] Smith, Y. L., Van Goozen, S. H., Kuiper, A. J., & Cohen-Kettenis, P. T. (2005). Sex reassignment: Outcomes and predictors of
treatment for adolescent and adult transsexuals. Psychological Medicine, 35(1), 89-99.
[19] Lawrence, A. A. (2003). Factors associated with satisfaction or regret following male-to-female sex reassignment
surgery. Archives of Sexual Behavior, 32(4), 299-315.
[20] De Cuypere, G., Elaut, E., Heylens, G., Van Maele, G., Selvaggi, G., T’Sjoen, G., ... & Monstrey, S. (2006). Long-term follow-
up: Psychosocial outcome of Belgian transsexuals after sex reassignment surgery. Sexologies, 15(2), 126-133.
[21] Delemarre-van de Waal, H. A., & Cohen-Kettenis, P. T. (2006). Clinical management of gender identity disorder in adolescents:
A protocol on psychological and paediatric endocrinology aspects. European Journal of Endocrinology, 155(suppl 1), S131-S137.
[22] Smith, Y. L., van Goozen, S. H., & Cohen-Kettenis, P. T. (2001). Adolescents with gender identity disorder who were accepted
or rejected for sex reassignment surgery: A prospective follow-up study. Journal of the American Academy of Child & Adolescent
Psychiatry, 40(4), 472-481.
[23] Steensma, T. D., Biemond, R., de Boer, F., & Cohen-Kettenis, P. T. (2011). Desisting and persisting gender dysphoria after
childhood: A qualitative follow-up study. Clinical Child Psychology and Psychiatry, 16(4), 499-516.
[24] de Vries, A. L., Steensma, T. D., Doreleijers, T. A., & Cohen‐Kettenis, P. T. (2011). Puberty suppression in adolescents with
gender identity disorder: A prospective follow‐up study. The Journal of Sexual Medicine, 8(8), 2276-2283.
[25] de Vries, A. L., McGuire, JK, Steensma, T. D., Wagenaar, E. C., Doreleijers, T. A., & Cohen‐Kettenis, P. T. (2014). Young
adult psychological outcome after puberty suppression and gender reassignment. Pediatrics, 134(4), 1-9.
[26] Zucker, K. J., Bradley, S. J., Owen-Anderson, A., Singh, D., Blanchard, R., & Bain, J. (2010). Puberty-blocking hormonal
therapy for adolescents with gender identity disorder: A descriptive clinical study. Journal of Gay & Lesbian Mental Health, 15(1),
58-82.
[27] Cohen-Kettenis, P. T., & van Goozen, S. H. (1997). Sex reassignment of adolescent transsexuals: A follow-up study. Journal of
the American Academy of Child & Adolescent Psychiatry, 36(2), 263-271.
[28] Grant, J. M., Mottet, L. A., Tanis, J., Herman, J. L., Harrison, J., & Keisling, M. (2010). National Transgender Discrimination
Survey Report on health and health care. National Center for Transgender Equality and National Gay and Lesbian Task Force.
Washington, DC, 1-23.
AUTHOR INFORMATION
Laura Kuper, MA
lakuper@gmail.com
Research website: aboutLGBTQ.org
PHOTOGRAPHY PROVIDED BY
Lindsay Morris
lindsaycmorris.com
Kuper, L.E. (2014) Puberty Blocking Medications: Clinical Research Review, IMPACT LGBT Health and Development Program
This publication is not able to provide medical care recommendations or advice specific to any one individual