Pediatric Annals

CME 

The Peripubertal Gender-Dysphoric Child: Puberty Suppression and Treatment Paradigms

Johanna Olson, MD; Robert Garofalo, MD, MPH

Abstract

Gender-nonconforming youth are emerging at increasingly younger ages, and those experiencing gender dysphoria are seeking medical care at, or sometimes even before, the onset of puberty. Youth with gender dysphoria are at high risk for depression, anxiety, isolation, self-harm, and suicidality at the onset of a puberty that feels wrong. Medical providers would benefit from understanding interventions that help gender-nonconforming children and youth thrive. The use of gonadotropin-releasing hormone (GnRH) agonists to block the onset of an undesired puberty in youth with gender dysphoria is a relatively new practice, particularly in the United States. These medications shut down the hypothalamic-pituitary-gonadal axis (HPG), and the production of either testosterone or estrogen is temporarily halted. Puberty blocking allows a young person to explore gender and participate more fully in the mental health therapy process without being consumed by the fear of an impending developmental process that will result in the acquisition of undesired secondary sexual characteristics. GnRH agonists have been used safely for decades in children with other medical conditions, including central precocious puberty. Potential side effects of GnRH agonists include diminished bone density, injection site problems, emotional instability, and weight gain. Preliminary data have shown GnRH agonists to be very helpful in improving behavioral and overall functioning outcomes. Puberty suppression should ideally begin in the first stages of pubertal development and can be given via intramuscular or subcutaneous injections, or via an implant that is inserted in the upper arm. Monitoring to assure suppression of the HPG axis should occur regularly. Gender-nonconforming youth who remain gender dysphoric can go on to receive cross-sex hormones for phenotypic gender transition when they are older. GnRH agonists have changed the landscape of medical intervention for youth with gender dysphoria and are rapidly becoming the standard of practice.

[Pediatr Ann. 2014; 43(6):e132–e137.]

Abstract

Gender-nonconforming youth are emerging at increasingly younger ages, and those experiencing gender dysphoria are seeking medical care at, or sometimes even before, the onset of puberty. Youth with gender dysphoria are at high risk for depression, anxiety, isolation, self-harm, and suicidality at the onset of a puberty that feels wrong. Medical providers would benefit from understanding interventions that help gender-nonconforming children and youth thrive. The use of gonadotropin-releasing hormone (GnRH) agonists to block the onset of an undesired puberty in youth with gender dysphoria is a relatively new practice, particularly in the United States. These medications shut down the hypothalamic-pituitary-gonadal axis (HPG), and the production of either testosterone or estrogen is temporarily halted. Puberty blocking allows a young person to explore gender and participate more fully in the mental health therapy process without being consumed by the fear of an impending developmental process that will result in the acquisition of undesired secondary sexual characteristics. GnRH agonists have been used safely for decades in children with other medical conditions, including central precocious puberty. Potential side effects of GnRH agonists include diminished bone density, injection site problems, emotional instability, and weight gain. Preliminary data have shown GnRH agonists to be very helpful in improving behavioral and overall functioning outcomes. Puberty suppression should ideally begin in the first stages of pubertal development and can be given via intramuscular or subcutaneous injections, or via an implant that is inserted in the upper arm. Monitoring to assure suppression of the HPG axis should occur regularly. Gender-nonconforming youth who remain gender dysphoric can go on to receive cross-sex hormones for phenotypic gender transition when they are older. GnRH agonists have changed the landscape of medical intervention for youth with gender dysphoria and are rapidly becoming the standard of practice.

[Pediatr Ann. 2014; 43(6):e132–e137.]

Most transgender individuals seeking medical interventions (hormones and/or surgery) for gender transition have, and still continue to access, care in adulthood. The past decade has shown increasing numbers of transgender youth presenting for care at gender centers throughout the world, with the average age of referral getting younger each year.1 This vast groundswell of gender-nonconforming children and adolescents seeking care at increasingly younger ages is likely due in part to improved access to information about other transgender or gender-nonconforming youth via the internet, or through exposure to transgender characters portrayed increasingly in popular media. Additionally, conversation that parents have with their children has changed in the past few decades, resulting in an increased openness to exploring the feelings of a child expressing an alternative gender. Treatment of gender-nonconforming youth has evolved tremendously during the past decade, but available data and information regarding the complexities of medical interventions remain sparse.

Prepubertal Gender-Nonconforming Children

Although the numbers are increasing, it is still rare that transgender individuals are able to articulate and assert an alternative gender in early childhood. There is, however, a small cohort of children who simply state that they are boys, as opposed to girls, or vice versa. Some children articulate an experience of being neither, or both genders. Those who are able to talk about having a gender other than the one they were assigned at birth based upon anatomy often experience intense gender dysphoria: the persistent distress about the incongruence between one’s assigned gender and one’s internal experience of gender.2 These children may benefit from undergoing a social, or non-medical, transition, the reversible changes of one’s external presentation that allows them to live in the gender role that corresponds with their internal gender identity. This might include a change in clothing, hairstyles, and even a name and gender pronoun change. Due to the lack of evidence-based data, there is no consensus of opinion about social transition in childhood, but clinically many children who do undergo social transition seem to show improved functioning across multiple life domains. A recent study published by Steensma et al.3 found that children who were socially transitioned (living in their asserted gender role) in childhood were five times more likely to have persistent transgender identity in adolescence. Social transitioning in childhood has become increasingly common in North America and Western Europe. This phenomenon has led to an increasing need for medical and mental health professionals to understand the experiences, trajectories, and potential interventions to help gender-nonconforming children and youth thrive.

Gender-nonconforming children who have not started puberty do not require medical intervention and primarily need the adults surrounding them to create supportive and safe environments for them to explore gender, and potentially facilitate them living in their authentic gender role. Gender-nonconforming children who are presenting to clinics prior to starting puberty may benefit from learning about the process of puberty, including knowledge of the first physical or clinical signs. Often, gender-nonconforming children have genital and/or chest dysphoria, which leads to increased need for body privacy and, subsequently, challenges for parents trying to monitor pubertal development. Gender-nonconforming children should be given the opportunity to participate in mental health therapy to help develop and improve resiliency skills, as well as assess the child for any mental health challenges they might be facing.

Peripubertal Youth

The first sign of puberty in assigned females is the development of breast buds, and in assigned males, increased testicular volume. Assigned females who are asserting a male gender identity may experience significant distress when breast buds begin to become noticeable. The onset of either female or male endogenous puberty for many gender-nonconforming youth is a painful and sometimes traumatic experience. The development of an adult version of a body that the young person experiences as “wrong” may represent the permanence of gender incongruence and can trigger some of the negative psychosocial outcomes that are well-known challenges for gender-nonconforming youth, including depression, anxiety, social isolation, self-harming behaviors, illicit drug use, high-risk sexual behavior, suicidality, and other maladaptive coping mechanisms.4 Gender dysphoria may also emerge for the first time at the onset of puberty, when youth begin to experience the development of undesirable secondary sexual characteristics.

Clinicians should recognize that gender dysphoria may present in other ways at the start of puberty, including declining academic and social functioning, behavioral problems, depression, suicidality, anxiety, impulse-control problems, drug use, social isolation, and disordered eating. The symptoms of gender dysphoria may closely resemble those of depression, anxiety, and other mood disorders. It is not uncommon for adolescents to be evaluated, diagnosed, and treated by psychiatrists for such symptoms. Many gender-dysphoric youth present for care already taking one or more psychotropic medications. During this tenuous period of pubertal development, it is critical that providers understand the use of medications that suppress puberty as a strategy to address gender dysphoria.

Puberty Suppression

The development of adult male (larnyngeal prominence, deepening of the voice, tall stature, etc.) or adult female (chest, menstruation, and short stature) secondary sexual characteristics often triggers specific body dysphoria for many transgender adolescents and adults. The use of medications for the purpose of suppressing endogenous puberty, and thus potentially bypassing the development of undesired secondary sexual characteristics altogether, is a relatively new strategy in the approach to treating gender-nonconforming youth. Primarily pioneered by a team of gender specialists in the Netherlands, suppression of puberty is becoming increasingly common in many gender clinics around the world.5 The purpose of suppressing puberty in youth with gender dysphoria is not simply to delay and/or potentially avoid altogether the development of undesired secondary sexual characteristics. It also allows the young person the opportunity to explore gender without having to experience the anxiety of an impending undesired developmental process that occurs with the onset of puberty consistent with their natal sex. For families who have only recently become alerted to a young person’s transgender identity, an additional advantage of puberty blockers is further time and opportunity to integrate this new information into their own experience and develop skills to support their child’s authentic self. It is often the case that parents need an adjustment period to gather information, seek emotional support, and prepare for an altered future trajectory for their child. It is critical that parents of gender-nonconforming children support and love their children and leave space for them to explore their gender in a safe environment.6 A final benefit of puberty suppression is making obsolete some gender-confirmation surgeries, including facial feminization, tracheal shave, male chest reconstruction, and vocal cord alteration that would be required if an initial “incorrect” puberty had been undergone and completed.

Puberty-Suppressing Medications

At the start of puberty, gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile manner from the hypothalamus, triggering the pituitary gland to release leutinizing hormone and follicle stimulating hormone, which both activate the respective gonads to produce appropriate sex steroids. There are multiple medications that can be used to suppress an individual’s endogenous puberty, but the most effective are the GnRH agonists, which include triptorelin, busarelin, nafarelin, deslorelin, histrelin, goserelin, and leuprolide. GnRH agonists were developed nearly three decades ago for the treatment of precocious puberty, endometriosis, prostate cancer, and other medical conditions exacerbated by the secretion of sex steroids. GnRH agonists shut down the production of sex steroids from the gonads by supplying the brain with a steady-state delivery of a GnRH synthetic peptide that ultimately desensitizes the receptors on the hypothalamus and the pituitary gland in the brain.7 After 3 to 4 weeks, the gonads stop producing sex hormones, and the patient is eventually returned to a prepubertal physiologic state. Regression of secondary sexual characteristics may occur if medication is administered early enough. Puberty suppression with GnRH agonists is essentially a reversible intervention. If the medication were discontinued, the young person would continue their endogenous puberty where they left off. Additionally, youth continue to experience growth in all other domains that are not specifically dependent on sex steroids. For example, linear growth and cognitive development continue during GnRH agonist administration.

Timing of Puberty Suppression

The first research-driven protocol describing the use of puberty blockers in gender-dysphoric adolescents was published in the Netherlands in 2006. The Dutch protocol calls for the use of GnRH agonists for the purpose of suspending pubertal development in appropriately diagnosed and assessed gender-dysphoric youth as early as 12 years of age, with the addition of cross-sex hormones for the development of desired secondary sexual characteristics when youth reach the age of 16 years. The early success of this protocol led to the inclusion of its concepts into the Endocrine Society’s Clinical Practice Guideline: “Endocrine Treatment of Transsexual Persons.”8 The guidelines recognize the inconsistency of starting puberty suppression at age 12 with the intent of avoiding the development of undesired secondary sexual characteristics and instead make the recommendation to initiate puberty suppression at the earliest stages of puberty (Tanner stage 2 or 3), regardless of chronological age. This is important because the mean age of beginning breast development in females is between 8 and 11.9 In addition to the Endocrine Society’s Clinical Practice Guidelines, The World Professional Association of Transgender Health (WPATH) has published standards of care (SOC) that are consistently revised. The latest version, SOC 7, was released in 2011. The SOC 7 also recommends suppression of puberty in its earliest stages for gender-dysphoric youth. Both organizations recommend that children and adolescents be assessed prior to initiation of puberty suppression by mental health providers who are trained in child psychology with skills in addressing gender-related issues. The WPATH SOC addresses a broad definition of the expectations for mental health professionals working with gender-nonconforming children and transgender adolescents.10

Dosing/Types of GnRH Agonists

The most commonly used GnRH agonists in the United States for puberty suppression in gender-dysphoric youth are leuprolide and histrelin. Leuprolide is an injectable GnRH agonist that has been very effective clinically at suppressing the hypothalamic/pituitary/gonadal (HPG) axis in gender-dysphoric youth. Leuprolide is administered via injection and can be given daily, monthly, or even every 3 months. Histrelin is delivered via an implantable device that is inserted in the inside of the upper arm, positioned subcutaneously between the triceps and the biceps muscles. The implant is marketed for children with precocious puberty but has been successfully used in gender-dysphoric youth as well. The implant secretes 65 mcg of histrelin daily and adequately suppresses the HPG axis. The implant can be placed easily in an outpatient office or surgical suite and does not require sedation. The implant is effective for more than a year and can be removed and replaced again when necessary at the same visit. Dosing of GnRH analogues can be adjusted based on adequate suppression of the HPG axis. Types of GnRH agonists and dosing are displayed in Table 1.

Gonadotropin-Releasing Hormone Agonists and Dosinga

Table 1.

Gonadotropin-Releasing Hormone Agonists and Dosing

Side Effects and Monitoring of Youth on GnRH Agonists

During the first 4 weeks following administration of GnRH agonists, there will be an initial surge of gonadal hormones that may worsen symptoms or induce a menstrual cycle. Some providers give an additional dose of injectable leuprolide 2 weeks after the initial dose to counter this effect. The primary concern when using GnRH agonists for prolonged periods of time is the potential decrease in bone mineral density. In adult men using GnRH agonists for prostate cancer, bone mineral decreases after 1 year of treatment.11 In youth who are administered GnRH agonists, bone mineral accrual should occur at a prepubertal rate, slower than if endogenous puberty had not been blocked. Early data from the Netherlands indicate that in the first cohort of youth treated with puberty blockers, bone mineral density stayed the same during the first 2 years of treatment and increased appropriately when cross-sex hormones were added to the regimen.5 The Endocrine Clinical Guidelines recommend yearly monitoring of bone density during the period of puberty suppression. A recent study of gender-nonconforming youth being treated at a clinic in British Columbia reported one patient who experienced injection site abscesses, leg pain, headaches, weight gain, and emotional lability while being administered GnRH agonists for puberty suppression.12 Other side effects reported by the manufacturers of Lupron Depot (leuprolide acetate for depot suspension, AbbVie, Inc.) include injection site reactions (pain, swelling, and abscess), rash, vaginal discharge or bleeding, and hot flushes/sweating. Youth should be assessed for adequate suppression 1 to 2 months following the first monthly injection or insertion of histrelin implant with luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either testosterone (assigned males) or estradiol (assigned females) levels, and 2 to 3 months following the first 3-month injection. Adequate suppression can also be assessed using a GnRH stimulation test. Other laboratory monitoring is recommended to screen for rare side effects of GnRH agonists.8 Monitoring during GnRH agonist treatment is shown in Table 2.

Monitoring Intervals During Puberty Suppression

Table 2.

Monitoring Intervals During Puberty Suppression

The Endocrine Society Clinical Guidelines recommend continuing gender-dysphoric youth on GnRH agonists with the addition of cross-sex hormones when appropriate until they are able to have their gonads removed. This recommendation necessitates modification, however, under several common circumstances. One major concern about the plan outlined in the guidelines is the time gap between initiating puberty suppression and the addition of cross-sex hormones. Studies have demonstrated that girls who start puberty later have decreased bone mineral content compared with their peers who started earlier.13,14 If children will potentially have their puberty suppressed at age 9, or even younger in some exceptional circumstances, and then wait until the age of 16 to start cross-sex hormones, bone density development could be negatively impacted. For this reason, among others, starting cross-sex hormones earlier than age 16 is considered by some to be advantageous for the health of the youth. Research is sorely needed on the short- and long-term outcomes on these medical interventions on U.S. children and adolescents.

All youth who are started on GnRH agonists should understand that if they continue on to cross-sex hormones, their ability to produce genetic material for future offspring will be compromised. In most cases, youth would have to undergo significant pubertal maturation after discontinuing GnRH agonists in order to cryopreserve adequate reproductive material for biological offspring. Open and honest discussion about youth’s desire for children in the future is a critical portion of the consent process for both puberty suppression and cross-sex hormone initiation, and additional research in this area, including developing options for fertility, is sorely needed.

Impact of Blocking Puberty

There are very limited published data outlining the impact of GnRH agonist use in gender-nonconforming youth. Early results from the first 70 gender-dysphoric youth undergoing puberty suppression with GnRH agonists showed a decrease in behavioral and emotional problems, as well as a decrease in depressive symptoms. Improved general functioning for these youth was also reported.15 Important to note is that gender dsyphoria was not improved with the use of GnRH agonists. This is likely because GnRH agonists simply suspend the progress of the “incorrect” puberty, they do not induce the development of desired secondary sex characteristics as do cross-sex hormones. A study examining the physiologic impact of puberty suppression with GnRH agonists reported that the first 21 patients undergoing this treatment had adequate suppression of their pituitary gonadal axis and no progression of their endogenous puberty. While on GnRH agonists, bone density remained in the same range for patients experiencing suppression. Compared with age-matched peers, bone density z-scores went down while patients were being suppressed.5 Of note is that to date, there has been only one report of a single youth who started puberty suppression and did not continue on to use cross-sex hormones for gender transition. 12

Role of GnRH Agonists in Older Adolescents

There are benefits to using GnRH agonists for transgender youth who have already undergone the development of undesired secondary sexual characteristics. From a physiologic perspective, blocking further progress of the later developments of puberty can be extremely useful while adolescents are navigating gender identity and the impact of gender transition. Induction of amenorrhea is extremely beneficial for assigned females, as is halting further development of skeletal changes for assigned males. For transgender minors with parents who are unwilling to consent to the use of cross-sex hormones, GnRH agonists may provide a neutral compromise. Some youth may be attending single-gender schools and cannot pursue acquisition of alternative secondary sex characteristics until graduating or leaving. Consideration should be given to the use of GnRH agonists for those youth with non-binary gender identities (both male and female, neither male nor female, or other gender identity). Because GnRH agonists shut down the production of endogenous sex steroids, minimal masculinization or feminization can occur with smaller doses of cross-sex hormones.

Conclusion

Medical care for gender dysphoria and transgender youth has changed rapidly during the past few years. The ability to suppress unwanted puberty has changed the trajectory of patients’ lives, making possible a nearly seamless phenotypic gender transition. Puberty blockers afford youth the opportunity to undergo a single, correct pubertal process and avoid many of the surgical interventions previously necessary for assimilation into an authentic gender role. Pediatricians, endocrinologists, family physicians, and other providers of general medicine are fully equipped to advocate for, prescribe, and monitor GnRH agonists. This essentially reversible intervention is simple and has the capacity to improve health outcomes and save lives.

References

  1. De Vries ALC, Cohen-Kettenis PT. Clinical management of gender dysphoria in children and adolescents: the Dutch approach. J Homosexual. 2012;59(3):301–320. doi:10.1080/00918369.2012.653300 [CrossRef]
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
  3. Steensma TD, McGuire JK, Kreukels BP, Beekman AJ, Cohen-Kettenis PT. Factors associated with desistence and persistence of childhood gender dysphoria: a quantitative follow-up study. J Am Acad Child Adolesc Psychiatry. 2013;52(6):582–590. doi:10.1016/j.jaac.2013.03.016 [CrossRef]
  4. Olson J, Forbes C, Belzer M. Management of the transgender adolescent. Arch Pediat Adol Med. 2011;165(2):171–176. doi:10.1001/archpediatrics.2010.275 [CrossRef]
  5. Delemarre-van de Waal HA, Cohen-Kettenis PT. Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects. Eur J Endocrinol. 2006;155(suppl 1):S131–S137. doi:10.1530/eje.1.02231 [CrossRef]
  6. Malpas J. Between pink and blue: a multi-dimensional family approach to gender nonconforming children and their families. Fam Process. 2011;50(4):453–470. doi:10.1111/j.1545-5300.2011.01371.x [CrossRef]
  7. Magon N. Gonadotropin releasing hormone agonists: expanding vistas. Indian J Endocrinol Metab. 2011;15(4):261–267. doi:10.4103/2230-8210.85575 [CrossRef]
  8. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine Treatment of Transsexual Persons: an Endocrine Society clinical practice guideline. J Clin Endocr Metab. 2009;94(9):3132–3154. doi:10.1210/jc.2009-0345 [CrossRef]
  9. Slyper AH. The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty. Clin Endocrinol. 2006;65(1):1–8. doi:10.1111/j.1365-2265.2006.02539.x [CrossRef]
  10. Coleman E BW, Botzer M, et al. Standards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7. Int J Transgenderism. 2011;13:165–232. doi:10.1080/15532739.2011.700873 [CrossRef]
  11. Mittan D, Lee S, Miller E, et al. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab. 2002;87(8):3656–3661. doi:10.1210/jcem.87.8.8782 [CrossRef]
  12. Khatchadourian K, Amed S, Metzger DL. Clinical management of youth with gender dysphoria in Vancouver. J Pediatr. 2014;164(4):906–911. doi:10.1016/j.jpeds.2013.10.068 [CrossRef]
  13. Gilsanz V, Chalfant J, Kalkwarf H, et al. Age at onset of puberty predicts bone mass in young adulthood. J Pediatr. 2011;158(1):100–105, 105.e1–105.e2. doi:10.1016/j.jpeds.2010.06.054 [CrossRef]
  14. Jackowski SA, Erlandson MC, Mirwald RL, et al. Effect of maturational timing on bone mineral content accrual from childhood to adulthood: evidence from 15 years of longitudinal data. Bone. 2011;48(5):1178–1185. doi:10.1016/j.bone.2011.02.010 [CrossRef]
  15. De Vries AL, Steensma TD, Doreleijers TA, Cohen-Kettenis PT. Puberty suppression in adolescents with gender identity disorder: a prospective follow-up study. J Sex Med. 2011;8(8):2276–2283. doi:10.1111/j.1743-6109.2010.01943.x [CrossRef]
  16. Medscape. Leuprolide (Rx). Available at: http://reference.medscape.com/drug/lupron-leuprolide-342221#0. Accessed April 24, 2014.

Gonadotropin-Releasing Hormone Agonists and Dosinga

Type/Weight Dose Frequency
Lupron Depot-Ped (monthly)
  < 25 kg 7.5 mg IM Monthly
  > 25 kg to 37.5 kg 11.25 mg IM Monthly
  37.5 kg 15 mg IM Monthly
Lupron Depot-Ped (3-month)b
11.25 mg IM Every 3 months
30 mg IM Every 3 months
Leuprolide acetate 50 mcg/kg subcutaneous Daily
Histrelin implant (50 mg) 65 mcg/day Every 12 to 24 months

Monitoring Intervals During Puberty Suppression

Measurement Drug Manufacturer Recommendation Endocrine Society Clinical Guidelines
Bone density 6 to 12 months Annually
Height/weight 6 to 12 months Every 3 months
Bone age 6 to 12 months Annually
Luteinizing hormone/follicle-stimulating hormone 6 months Every 3 months
Testosterone/estradiol 6 months Every 3 months
Liver function tests No recommendation Annually
Renal function No recommendation Annually
Lipids No recommendation Annually
Glucose No recommendation Annually
Insulin No recommendation Annually
Glycosylated hemoglobin No recommendation Annually
Authors

Johanna Olson, MD, is Medical Director, Center for Transyouth Health and Development, Children’s Hospital Los Angeles, and Assistant Professor of Clinical Pediatrics, University of Southern California, Keck School of Medicine. Robert Garofalo, MD, MPH, is Division Head of Adolescent Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, and Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine.

Address correspondence to: Johanna Olson, MD, 5000 Sunset Boulevard, 4th Floor, Los Angeles, CA 90027; email: jolson@chla.usc.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00904481-20140522-08

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