Transgender and gender-diverse children and adolescents: Approach to gender-affirming care

INTRODUCTION — 

Children are generally assigned a sex at birth based on their genital anatomy or chromosomes. For most children, sex assignment correlates with gender identity (ie, the innate sense of self as male, female, a blend of both, or neither). However, some children have a gender identity that is not congruent with their assigned sex at birth. These children are described as transgender or gender-diverse (TGD) youth. The table provides additional important terms (table 1). (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Terminology'.)

For many TGD children and adolescents, the incongruity between gender identity and sex assigned at birth causes distress. When distress emerges with the onset of puberty or has been present since childhood and intensifies with the onset of puberty, it rarely subsides.

This topic will provide an approach to gender-affirming care for TGD children and adolescents. The information provided is intended to allow primary care providers to educate and support patients and families/caregivers of TGD youth, coordinate care, provide referrals, and monitor patients who are receiving hormonal care.

Approaches to care should always be informed by the evidence available. Clinicians should be aware that high-quality data (eg, randomized trials) are lacking, and supporting data consist of observational studies [1]. The optimal approach to care is uncertain and should be tailored to the individual patient. (See 'Rationale for providing gender-affirming care' below.)

The American Academy of Pediatrics (AAP), Endocrine Society, American Academy of Child and Adolescent Psychiatry, Canadian Paediatric Society, and World Professional Association for Transgender Health (WPATH) have outlined patient-centered approaches to the care of TGD children and adolescents. Our approach is generally consistent with the recommendations in these guidelines. (See 'Society guideline links' below.)

Regional variations in gender-affirming care exist worldwide. Clinicians should be aware of local laws regarding the care of TGD youth.

Gender development and the clinical presentation of gender diversity in children and adolescents are discussed separately. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Referral'.)

OVERVIEW — 

Evidence to guide the management of gender diversity in children and adolescents has increased with the growing numbers of multidisciplinary centers providing treatment for transgender or gender-diverse (TGD) youth [2-5]. These data supplement the experience from case series of adults who underwent gender-affirming surgery.

The safety and wellbeing of the youth and their family members/caregivers is foremost. Family/caregiver acceptance and other affirming environments that create space for youth to express and grow into their authentic self are critical for healthy development [6-8]. Other treatment decisions must consider the potential for decreased sense of self-worth, depression, self-harm, suicidality, verbal victimization, physical victimization, etc.

Care for TGD youth is determined according to the individual's gender development, needs, and goals. Given the spectrum and fluidity of gender identity, it is important for health care providers to elicit and understand the specific needs of individual patients [9]. The degree and type of mental health, medical support, and interventions may vary. Not all TGD youth desire phenotypic transition, hormones, or surgeries.

Clinicians who are neither comfortable nor willing to become sufficiently knowledgeable to treat TGD patients should refer them to more experienced colleagues.

Given that TGD persons are increasingly visible and continue to seek medical and psychosocial resources, providers have increasing responsibility to be inclusive and to know about issues relevant to TGD patients. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Epidemiology'.)

Clinicians should be aware of transgender care-related legislation in their state, province, or country. Some states in the United States have legislative bans on gender-affirming care that may result in penalties for clinicians and/or caregivers [10].

TREATMENT SETTING — 

Supportive and affirming care for children and adolescents can be provided in a variety of settings.

Specialized centers with multidisciplinary teams offer coordinated services and may be involved in research that will add to the growing body of evidence regarding outcomes [11]. However, multidisciplinary centers are available in a limited number of cities, making it difficult for most TGD adolescents and their families/caregivers to receive care in a specialized center [12-15].

When gender specialty centers are not available, the World Professional Association for Transgender Health (WPATH) Standards of Care recommend that clinicians who provide affirming hormonal treatment be well-versed in the relevant medical and psychological aspects of treatment [16]. This care is often provided by board-certified adolescent medicine specialists, family medicine physicians, internal medicine physicians, or endocrinologists. Nonetheless, many primary care providers and clinicians with other medical backgrounds are receiving training on adolescent gender and sexual health and are adept at working with TGD youth [17].

Clinicians who are not comfortable with managing the care of TGD patients or are not sufficiently knowledgeable should refer patients to more experienced colleagues. More TGD individuals are seeking medical and psychosocial resources. Providers have an increasing responsibility to be inclusive in their care and to be familiar with issues relevant to TGD patients. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Epidemiology'.)

Telehealth presents an opportunity to expand access to care for patients who live a long distance from gender-affirming hormone (GAH) providers or do not have access to transportation. In one study, more than one-half of teens reported that they would be likely or very likely to use telehealth for future confidential care [18]. Yet, many participants also expressed concern about finding a private space to speak confidentially with the provider without being overheard by family members/caregivers.

GENERAL MEASURES FOR ALL PATIENTS

Affirmation of gender identity and expression — The authors of this topic use an affirming approach to children and adolescents who demonstrate any form of gender diversity. This approach, which is recommended by many professional organizations, promotes the exploration of gender identity, identity development, and self-definition within a safe setting [12,17,19,20]. (See 'Society guideline links' below.)

Family/caregiver acceptance and other affirming environments that create space for youth to express and grow into their authentic selves are essential for healthy development [6-8,21].

Affirming approaches put emphasis on understanding gender identity and gender expression from the child's perspective. They provide support for the child to evolve into their authentic self regardless of their age. These approaches also underscore that gender diversity is not a mental illness, so it is inappropriate to pathologize a child or adolescent's gender expression and behaviors.

The authors of this topic do not endorse the wait-and-see approach, redirection, or reparative therapy because these approaches are potentially harmful [20] and may cause a decreased sense of self-worth, depression, self-harm, and suicidality.

The wait-and-see approach (also called watchful waiting) involves waiting to see if the child's asserted gender identity will revert back to match the sex assigned at birth. The American Academy of Pediatrics (AAP) discourages pediatric providers from taking this approach because it is outdated and harmful, and it denies children the resources they need to explore gender identity. Wait-and-see is distinguished from following the child's lead, which is an affirming approach that allows the child to present in the gender role that feels correct and moves at a pace determined by the child.

The use of positive or negative reinforcement to try to "redirect" children toward behavior that is more typical of their sex assigned at birth or less gender-specific is not recommended. The goal of redirection is to eliminate gender-diverse desires and expressions over time [22]. This approach, which shames the child for gender-diverse expression, has substantial negative mental and social health consequences [19].

Reparative therapy (also called conversion therapy) claims to be able to "cure" a transgender identity. It is still practiced in some religious and conservative communities. This approach was initially used in the 1970s [23,24]. Reparative therapy is considered unhelpful and potentially harmful by most professional organizations, including the American Academy of Child and Adolescent Psychiatry, the AAP, and the Society for Adolescent Health and Medicine [16,20,25-31]. In the United States, several states, counties, and cities ban reparative therapy. The Movement Advancement Project provides a map of these localities.

Social transition — "Social transition" is an affirming, reversible intervention in which a child lives partially or completely in their asserted gender role by adapting their hairstyle, clothing, and pronouns as well as possibly using a chosen name. A social transition may be undertaken at any age or pubertal stage. However, not all prepubertal children will desire a social transition, and some children, adolescents, and young adults may prefer to wait until they have initiated gender-affirming hormones (GAH).

Social transition may include wearing makeup and using clothing modifications to hide the effects of puberty (eg, wearing a binder to hide breast development, tucking the penis and testicles so they are not visible). Transmasculine youth may wear prostheses or packers to simulate body parts or use devices that permit urination while standing.

Patients and families/caregivers may decide to have a "trial run" to allow the child to see how a social transition feels and to observe how the child responds. Patients and families/caregivers determine the extent of the changes they will make (eg, clothing, pronouns, name), whether and to whom they disclose their gender identity, and how to handle common potential challenges (eg, bathrooms, locker rooms, sleepovers).

Decisions about social transition are individualized after considering the potential benefits (eg, alleviation of psychological distress) and risks [12]. The safety of the child or adolescent and the likelihood of acceptance in the community are important considerations. While some communities are supportive, in others, a fully disclosed social transition may be hazardous to the young person's wellbeing.

Social transition and affirmation benefit many children, including prepubertal children who have persistent and strongly diverse gender identities [7,32]. This is particularly true for children who have difficulty functioning at home and in social and educational domains without being allowed to express their authentic gender identity. The potential risks of social transition must be balanced against the risk of the child becoming incapacitated by not living authentically. Most medical and mental health professionals agree that all children are more likely to have a healthy self-image, positive self-esteem, and general wellbeing when their authentic identity is recognized, supported, and loved [33].

Studies of the effects of social transition on future physical and mental health are ongoing. Among socially affirmed children, caregiver- and child-reported rates of depression are similar to rates in cisgender (ie, gender identity is aligned with the gender assigned at birth) age- and gender-matched controls as well as cisgender sibling controls, while rates of anxiety are only slightly higher [6,7,34]. The levels of depression and anxiety symptoms in these studies were substantially lower than those reported in previous studies of children with gender diversity who did not socially transition [35-38].

Although social transition benefits many TGD youth, it is not a prerequisite for initiating gender-affirming medical interventions. Some children and adolescents fear they will be harassed, bullied, or suffer physical violence if they make changes to their gender presentation before they develop the corresponding secondary sex characteristics. Consequently, youth who decide to wait on a social transition until after starting GAH should not have their affirming medical care delayed.

Health care providers can assist youth and their families/caregivers with making positive and successful social transition plans by:

●Helping them plan for disclosure to family/caregivers, friends, and social contacts

●Educating staff and students within the child's school system

●Creating plans for safety, responses to bullying, and other forms of social discrimination

Additional suggestions for education and support are provided separately. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Education and support'.)

Families/caregivers can contact a number of local or national social and advocacy agencies to assist in making a safety assessment or in facilitating social transition in school and other settings. These agencies work with schools, teachers, and students to assist in developing plans for bathroom and locker room accommodations, registration questions, and overall education about gender-related issues. (See 'Resources' below.)

Mental health support — Many TGD children and adolescents benefit from the support of a mental health provider to cope with gender dysphoria, nonaccepting parents/caregivers, or serious interpersonal conflicts with peers (eg, bullying) [17,39]. Importantly, not all children with gender incongruity require mental health support, especially those who are supported at home, at school, and by their peers. Additional details about the role of the mental health provider are discussed separately. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Role of the mental health provider'.)

ASSESSMENT OF PUBERTAL STAGE — 

Options for hormonal interventions vary depending on the patient's pubertal stage at the time of their initial presentation for medical care. Pubertal stages are typically categorized using the Tanner staging system, where Tanner stage 1 represents prepuberty and Tanner stage 5 represents completed puberty. Tanner stages 2, 3, and 4 represent the pubertal changes that occur during puberty (figure 1 and figure 2 and figure 3).

The onset of puberty is signaled by the development of breast buds or testicular enlargement (4 cc or larger) on physical examination. Levels of ultrasensitive luteinizing hormone, follicle-stimulating hormone, and estradiol or testosterone that are above the laboratory's prepubertal ranges provide further evidence of the onset of puberty. Additional details about determining a child's pubertal stage are discussed separately. (See "Normal puberty", section on 'Secondary sex characteristics (Tanner stages)'.)

PREPUBERTAL PATIENTS — 

Hormonal interventions are neither indicated nor appropriate for prepubertal children. Even so, many prepubertal children can benefit from gender affirmation, social transition, and/or mental health support. (See 'General measures for all patients' above.)

Some families/caregivers request a consultation prior to the child's pubertal onset due to their increasing anxiety about approaching puberty. These consultations provide an opportunity to educate about puberty, expected timing, pace, and options for suppression. We let prepubertal children and their families/caregivers know that starting pubertal suppression as soon as possible after puberty commences is an option, which usually provides some relief. These consultations also provide an opportunity to build relationships with patients who may be very anxious about discussing puberty, undergoing a pubertal staging examination, or having medication injections and/or blood tests.

RATIONALE FOR PROVIDING GENDER-AFFIRMING CARE — 

The rationale for providing gender-affirming care includes:

●Gender dysphoria rarely subsides – When the distress caused by the incongruity between sex assigned at birth and gender identity (ie, gender dysphoria) emerges with the onset of puberty or has been present since childhood and intensifies with the onset of puberty, it rarely subsides [40,41].

●Adverse psychosocial outcomes due to gender dysphoria – Youth with intense feelings of gender dysphoria are at risk for adverse psychosocial outcomes [12]. Severe gender dysphoria can cause depression, anxiety, nonsuicidal self-harm, and suicidality [12].

●Gender-affirming care improves psychosocial outcomes – Longitudinal studies suggest that symptoms of anxiety and depression in transgender and gender-diverse (TGD) adolescents improve with the initiation of gender-affirming hormone (GAH) therapy [42-45]. Access to GAH therapy in cross-sectional studies is associated with lower rates of anxiety, depression, and suicidality.

Long-term follow-up studies are limited but suggest that gender dysphoric adolescents who undergo pubertal suppression followed by GAH will be able to maintain relatively good functioning in their adult years. In one Dutch study (55 participants), initiation of pubertal suppression (mean age 13.6 years) followed by GAH therapy (introduced at a mean age of 16.7 years) and gender-affirming surgery (mean age 19.2 years) was associated with alleviation of gender dysphoria in young adulthood (mean age 20.7 years) [46]. Furthermore, the wellbeing of the participants was similar to or better than that of young adults from the general population.

A growing body of evidence on short- and medium-term outcomes suggests that most individuals are more satisfied with their lives and experience more comfort living in their bodies following the initiation of hormone therapy [47-50]. Other studies have demonstrated improvement in body dissatisfaction, improvement in emotional health, and improvement in transgender congruence after GAH [42,45,51]. In an anonymous survey sent to 941 current or former patients of a large pediatric gender clinic, participants were provided with a list of 13 emotions and asked to select all of the emotions they had experienced related to their gender-affirming care [47]. Of the 141 participants (ages 15 to 28 years, mean 18.6 years) who completed the survey and had ever received hormones, 74 (52 percent) selected only positive emotions, and most (88 percent) selected at least one positive emotion.

●Reidentification with the sex assigned at birth is rare – Reidentification with the sex assigned at birth rarely occurs after the initiation of GAH interventions. A retrospective cohort study was conducted over a seven-year period (2014 to 2020) to determine the reason why patients stopped attending a clinic providing gender-affirming medical services [41]. Of the 548 youth (aged 10 to 19 years) identified, 29 (5.3 percent) stopped attending due to reidentification with their assigned sex at birth. However, only 2 of the 29 had initiated any gender-affirming medical care (one received only pubertal suppression, and one received GAH). In another study, <0.5 percent of 1050 patients who had been receiving GAH for >6 months discontinued their hormones because they reidentified with their sex assigned at birth [52].

●Regret is very rare – When patients discontinue hormone therapy, they do so for a variety of reasons, including satisfaction with the current changes to their bodies, no desire for additional changes, or obstacles to accessing GAH [47,52,53]. Obstacles include no longer having financial resources to pay for hormone care, forgetfulness, and difficulty administering injections. Some individuals discontinue hormones for a while and then restart [52]. Only a small subset of this group has regret about having started hormone therapy. In the study of the 1050 patients who discontinued hormones, of the five patients who did so, one had regret, another denied regret, and regret was not documented in the charts of the other three [52].

●Limitations of the data – Randomized trials evaluating the benefits of gender-affirming care of TGD youth are lacking. There are many challenges to conducting randomized trials on gender-affirming care [1]. One challenge is the difficulty in maintaining participant blinding because it would quickly become apparent to participants to which group they were assigned. Another challenge is that once the adolescent and their parent/caregiver realized they were randomized to receive a placebo, unequal attrition between trial arms would be likely, which would undermine data validity. Consequently, the best data available on the outcomes of gender-affirming care come from observational studies.

EARLY-TO-MID PUBERTY

Endogenous pubertal suppression

Timing — Both the World Professional Association for Transgender Health (WPATH) Standards of Care Version 8 (SOC 8) and the Endocrine Society Guidelines endorse the use of puberty blockers in early puberty (Tanner stage 2+), if appropriate. Some families/caregivers choose to start pubertal suppression as soon as the child is eligible while others wait. The potential benefits and risks associated with starting pubertal suppression as soon as possible are discussed below. (See 'Assent/consent' below and 'Fertility considerations' below.)

Assent/consent — As with any medical intervention, the consent process for pubertal suppression involves a discussion about the benefits and risks.

The patient and parent/caregiver should be given ample opportunity to ask questions and have their questions answered to their satisfaction. Only after doing so should the parent/caregiver be asked to provide their consent for the child's treatment. Children and adolescents who are minors should also be asked to provide their assent for treatment. Some experts obtain consent verbally, while others document the process with the patient's and parent/caregiver's signatures on a consent form.

Although a parent/caregiver is typically required to provide consent for their minor child in the United States, most transgender and gender-diverse (TGD) adolescents have the capacity to provide informed consent. In a cross-sectional study of 74 transgender adolescents (age 10 to 18 years), 90 percent were assessed as competent to consent to pubertal suppression by the MacArthur Competence Assessment Tool for Treatment, a decision-making assessment tool with empiric support [54,55].

Benefits, risks, and fertility considerations

●Benefits

•The major benefit of pubertal suppression is the relief of psychological distress experienced by patients who are developing what feel like the wrong secondary sex characteristics [56,57]. The distress may be so severe that it interferes with a young person's mental health and daily functioning. Suppression of endogenous puberty helps to alleviate psychosocial distress and decrease these adverse effects [57-62]. In a cross-sectional survey of >20,000 TGD adults (age 18 to 36 years), wanting and receiving pubertal suppression during adolescence was associated with decreased rates of self-reported suicidality [63].

•Avoiding the development of unwanted secondary sex characteristics early in puberty may prevent the need for future medical and surgical interventions to manage unwanted, irreversible secondary sex characteristics. This allows for an easier, less costly physical affirmation process with improved physical outcomes for patients who decide to proceed with gender-affirming hormone (GAH) therapy and/or surgery [64].

•Pubertal suppression "buys time" for youth to more fully explore their gender identity without the distress caused by the progression of secondary sex characteristic development. For younger adolescents, it provides time to develop the maturity necessary to make a thorough and informed decision about partially reversible interventions (ie, GAH) [65]. This is often done in conjunction with the support and assistance of a trained mental health professional.

•Caregivers may also need additional time to learn more about gender diversity and affirming care before making any decisions about GAH. They may also need time to come to terms with a different future for their child than the one they may have envisioned [65,66].

●Risks

•Bone health – Because bone mineral accrual is suspended during pubertal suppression monotherapy, decreased peak bone mass is a possible risk of endogenous pubertal suppression. Although bone mineral accrual resumes when a gender-affirming hormone is added or pubertal suppression is discontinued, it is not clear whether bone mineral density (BMD) eventually catches up to where it would have been without endogenous pubertal suppression.

There is limited information about long-term bone health among TGD youth who are treated with pubertal suppression monotherapy followed by the addition of GAH. Likewise, there is limited information about whether maintaining physiologic levels of GAH in adolescence and early adulthood is associated with improved BMD.

The best data come from one cohort study that assessed lumbar spine, femoral neck, and total hip BMD z-scores of 75 participants (25 assigned female at birth, 50 assigned male at birth) at three time points: start of pubertal suppression; start of GAH therapy; and follow-up at least nine years after initiation of GAH therapy [67]. Most of the mean BMD z-scores returned to baseline at the long-term follow-up visit. The only exception was the mean lumbar spine z-score in participants assigned male at birth. The mean serum estradiol level of these participants at follow-up was 59 pg/mL, which is below the Endocrine Society guideline target levels (100 to 200 pg/mL) and may be insufficient for optimal bone accrual [56].

In other observational studies of TGD youth, the addition of GAH was associated with increased BMD at short-term follow-up, partially compensating for decreased accrual during pubertal suppression monotherapy [68-71]. In children who receive pubertal suppression therapy for precocious puberty, bone mass is regained after cessation of treatment, and peak bone mass is unaffected. (See "Treatment of precocious puberty", section on 'Monitoring'.)

Another concern is that baseline BMD (ie, prior to any intervention) of TGD youth is frequently lower than reference standards for sex assigned at birth, particularly for transgender girls [72-74], and this may compound any lack of return to baseline BMD at the lumbar spine [67].

•Future gender-affirming surgeries (transgender women) – When pubertal suppression is begun in early puberty and is followed by GAH, a transwoman who decides to have vaginoplasty surgery later in life may not have adequate scrotal and penile tissue for traditional penile inversion vulvovaginoplasty. However, newer surgical techniques, including peritoneal pull-through to create a viable vaginal canal, have been developed [75,76].

•Mood effects – Mood disruptions rarely occur when pubertal suppression is started in early puberty. However, if started during Tanner stage 3 or later, mood disruptions (eg, irritability, moodiness, and/or depression) can occur shortly after the initiation of pubertal suppression; mood disruptions often resolve within one to two months but may persist.

•Other short-term effects – If pubertal suppression is initiated at or after Tanner stage 3, patients may experience hot flashes and loss of libido; transmasculine patients may also experience withdrawal bleeding during the first four weeks after gonadotropin-releasing hormone (GnRH) agonist initiation.

●Fertility considerations – Endogenous pubertal suppression has no lasting effect on fertility if GAH (ie, testosterone or estrogen) are not added. If a decision is made to discontinue pubertal suppression, endogenous puberty will likely resume after 6 to 12 months. Once the gonads are mature, they will produce sperm or oocytes as they would have without treatment with GnRH agonists [77].

If GAH therapy is started after early pubertal suppression, when the gonads are still immature, the effect on future fertility is unknown. This is discussed in more detail below. (See 'Fertility considerations' below.)

Pubertal suppression regimens — Suppression of puberty can be achieved with the use of GnRH analogs, antiandrogens, antiestrogens, and medroxyprogesterone acetate (MPA) [56,58,78,79]. GnRH analogs, often referred to as "puberty blockers," are usually preferred because of their efficacy, safety profile, and clinical experience in treating children with precocious puberty [79-82]. (See "Treatment of precocious puberty", section on 'GnRH agonist therapy'.)

Nevertheless, in the United States (where pubertal suppression is not a labeled indication for puberty blocker medications, as with other pediatric formulary indications), pubertal suppression with GnRH analogs may be cost-prohibitive in states where they are not covered by insurance [83].

GnRH analogs may be administered in a variety of forms, including injections and implants (table 2). In our experience, most adolescents start with the histrelin implant (effective for two years or longer [84]) or with intramuscular or subcutaneous leuprolide or triptorelin injections every three to six months. The dose of the injection may be titrated, if needed, to adequately suppress puberty based on patient report, physical examination, and/or laboratory values. (See 'Monitoring' below.)

Medication regimens are not standardized. The protocol suggested in the Endocrine Society Clinical Practice Guideline was developed by the Center of Expertise on Gender Dysphoria (formerly the Amsterdam Gender Clinic) and is endorsed by the Australasian Paediatric Endocrine Group [39,56,68,85]. In small cohorts of patients, this protocol and others adapted from it have demonstrated successful suppression of puberty without adverse effects [3,4,57,86].

Monitoring — Monitoring youth during pubertal suppression includes assessments of mental and physical health, inquiry about potential adverse effects, and continued discussions of the affirmation plan with youth and their families/caregivers.

We monitor the following parameters:

●Growth (height, weight) – Pubertal suppression alters the timing of the pubertal growth spurt and delays fusion of the growth plates, which may affect adult height [58,68].

Monitoring height (including height velocity and height curves) every three to six months during pubertal suppression may inform interventions that help achieve the youth's height goals (eg, prevention of excessively tall stature for transfeminine patients; maximization of height for transmasculine patients). However, in a small retrospective study, receipt of early pubertal suppression followed by GAH at age 16 years in both transfeminine and transmasculine youth did not significantly alter final adult height based on pretreatment predictions [87]. The mean maternal and paternal height, adjusted for sex assigned at birth, remains the best predictor of final height.

We do not monitor bone age (eg, radiograph of the left hand). However, some experts obtain bone age annually in youth who are concerned about final height. In addition to following growth curves, serial bone age radiographs can help determine where the youth is in their growth trajectory.

●Pubertal progression – Asking patients and their parent(s)/caregiver(s) whether puberty is progressing or seems to have halted is the most important way to monitor the effectiveness of pubertal suppression therapy.

Some providers measure endogenous sex hormone and gonadotropin levels (using ultrasensitive estradiol or testosterone assays and luteinizing hormone assays) every six months to ensure adequate suppression into the prepubertal range or to reassure patients that suppression is effective. Sex hormone levels are the best indicator of suppression.

Measurement of endogenous sex hormone levels and gonadotropin levels is also warranted if patients report symptoms of pubertal progression. If these levels are not completely suppressed, the interval between GnRH analog injections may need to be shortened or the dose increased.

●Bone health – The Endocrine Society and WPATH recommend monitoring bone density annually for youth receiving GnRH analogs. Although data are lacking on the impact of monitoring BMD on prevention of future fractures in adulthood, TGD youth with restrictive eating disorders, chronic glucocorticoid use, or other risk factors for decreased BMD or osteoporosis may benefit most from BMD monitoring over time. This is particularly relevant for youth who receive GnRH analogs for ≥2 years without the addition of GAH. The addition of GAH may be warranted sooner than planned if bone density z-scores decrease substantially. However, this needs to be weighed against other important factors in the decision to initiate GAH. (See 'Timing of hormone initiation' below.)

Vitamin D and calcium supplementation are often recommended for youth on GnRH analogs [88]. Practice regarding vitamin D monitoring varies. Some providers recommend supplementation for all patients, and some monitor and maintain vitamin D levels >30 ng/mL. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

●Mental health and other effects related to hormonal changes – The mental health of patients undergoing pubertal suppression should be monitored regularly. Patients who develop concerning mental health issues (eg, depression) should be referred to a mental health specialist for additional care. Additional concerns reported by the family/caregivers should also be addressed.

LATE PUBERTY AND COMPLETED PUBERTY

Gender-affirming hormones ± pubertal suppression

Hormone effects and risks — An essential component of the assent/consent process is a review of the anticipated effects and possible risks of gender-affirming hormones (GAH). (See 'Assent/consent' above.)

●Expected effects – The average time from hormone initiation to onset and maximization of each hormone effect is presented in the tables (table 3 and table 4).

The degree of reversibility of each effect is as follows [12,56]:

•Estrogen

-Development of breasts (irreversible after six months)

-Female fat distribution pattern (reversible)

-Decrease in muscle mass and strength (reversible)

-Softening of the skin (reversible)

-Maintenance of a higher-pitched voice, if puberty was blocked prior to initiation of estrogen (reversible)

-Decrease in testicular size, which may make it easier to tuck the testicles into the inguinal canal (unknown if reversible)

-Decreased sperm production (unknown if reversible)

-Avoidance of masculine skeletal changes that occur during puberty (reversible)

-Prevention or reduced progression of facial and body hair growth (reversible)

-Decreased sexual desire (reversible)

-Decreased erections; for some patients, this may not be desired (reversible)

•Testosterone

-Clitoral enlargement (irreversible)

-Deepening of the voice (irreversible)

-Scalp hair loss (determined by genetics; irreversible)

-Facial and body hair growth (partially reversible)

-Skin oiliness and acne (reversible)

-Cessation of menses (reversible)

-Increase in lean muscle mass and strength (reversible)

-Male fat distribution pattern (reversible)

-Vaginal atrophy (reversible)

Irreversible and partially reversible effects of GAH occur gradually, giving providers and patients the ability to periodically review how the changes impact the patient's gender identity and feelings of dysphoria.

Additional details about the expected effects of GAH are discussed separately. (See "Transgender women: Evaluation and management", section on 'Feminizing effects' and "Transgender men: Evaluation and management", section on 'Masculinizing effects'.)

●Benefits – In addition to the desired effects described above, estrogen may have a beneficial effect on blood pressure and lipid levels (except for triglycerides). Many patients experience improved mental health and overall wellbeing.

Testosterone often suppresses menses, which has a beneficial effect on iron deficiency and anemia, heavy uterine bleeding, and dysmenorrhea. One study demonstrated that 85 percent of participants had ceased menstrual bleeding within six months after initiating subcutaneous testosterone injections, with an average time to menstrual cessation of 2.9 months [89].

●Risks – The possible risks of hormone therapy include:

•Estrogen – The risks of estrogen therapy in adults, including venous thromboembolism (VTE), are discussed separately. (See "Transgender women: Evaluation and management", section on 'Adverse events'.)

Some of the risks in adults may apply to adolescents to a lesser degree. At present, limited information exists about the frequency of adverse effects among adolescents receiving estrogen therapy.

In several small case series and a multicenter analysis of adolescent electronic health records, receiving gender-affirming estradiol therapy was not associated with serious adverse reactions or metabolic abnormalities [90-93]. These included hypertension; increased body mass index (BMI); electrolyte disturbances; and elevations in creatinine, liver enzymes, lipids, hemoglobin/hematocrit, and hemoglobin A1c (HbA1c).

However, in a longitudinal study of transgender youth, the prevalence of obesity at age 22 years was higher among transfeminine youth treated with GnRH analogs at age 15 years followed by GAH at age 17 years compared with cisgender peers (9.9 percent versus 2.2 percent) [92].

•Testosterone – The risks of testosterone therapy in adults, including erythrocytosis, are discussed separately. (See "Transgender men: Evaluation and management", section on 'Adverse events'.)

Some of the risks in adults may apply to adolescents to a lesser degree. However, as with estrogen therapy, little information exists about the frequency of adverse effects among adolescents receiving testosterone therapy.

In a case series of transmasculine adolescents, adverse effects of testosterone were generally mild and did not lead to permanent discontinuation of therapy [91,94]. Adverse effects included acne, male pattern baldness, mild dyslipidemia, mood swings, increased BMI, increased hemoglobin/hematocrit, and decreased high-density lipoprotein levels [95,96].

In other case series, gender-affirming testosterone therapy was not associated with changes in blood pressure, electrolytes, liver function tests, or HbA1c [58,97].

In a longitudinal study of transgender youth, the prevalence of obesity at age 22 years was higher among transmasculine youth treated with GnRH analogs at age 15 years followed by GAH at age 17 years compared with cisgender peers (6.6 percent versus 3 percent) [92].

Fertility considerations

●Early endogenous pubertal suppression followed by GAH – If GAH is introduced following early pubertal suppression, it is unclear what effect the addition of testosterone or estrogen will have on future fertility. In one case report, a transgender girl who had been receiving GnRH agonists (initiated at Tanner stage 2) for four years and estradiol for three years, had spermatogenesis [98]. She underwent sperm extraction without pausing her GnRH agonist or estradiol. Another case report described a transgender boy who received GnRH analogs at Tanner Stage 2 and underwent a rapid induction with successful harvesting of ovarian follicles [99,100].

●GAH initiated after gonads are mature – It is also unclear whether initiation of GAH after the gonads have fully matured will impair future fertility and, if so, to what degree. There are reports of transgender men pausing their testosterone, conceiving, and carrying a pregnancy to term as well as reports of egg retrieval, in vitro fertilization, and successful pregnancy with the assistance of a surrogate [101,102]. There are little data about the effect of GAH on the future fertility of transgender women. In one small study of nine transgender women who paused their estrogen and antiandrogen therapy, all had a return of spermatogenesis; three of the four who wanted to conceive a pregnancy with their partner were able to do so [103].

●Fertility preservation – Transgender persons who wish to optimize their potential for genetically related children should consult with a reproductive endocrinologist or urologist regarding their options for fertility preservation (eg, oocyte or sperm cryopreservation, cryopreservation of ovarian or testicular tissue) [104-108]. Although children with immature gonads generally do not have sperm or oocytes that can be cryopreserved [104], there are case reports of successful fertility preservation using alternative techniques in transmasculine individuals [99,109]. Notably, cost and infrequent insurance coverage limit the use of fertility preservation by adolescents. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Fertility preservation: Cryopreservation options".)

●Need for contraception – Although GAH has an uncertain effect on fertility, vaginal intercourse with someone who produces sperm may result in pregnancy, even after amenorrhea has been achieved [101,110]. Consequently, contraceptive methods are recommended for TGD persons who wish to avoid pregnancy [111]. Many transmasculine persons prefer contraceptive methods that do not have estrogen. As with all gender-affirmative care, the critical aspect of decision-making is very personal. Long-acting reversible contraception (eg, intrauterine device [IUD], etonogestrel implant) has superior efficacy and may have desirable side effects such as amenorrhea [112]. These and other contraceptive methods are discussed separately. (See "Contraception: Overview of issues specific to adolescents", section on 'Contraceptive options'.)

Adolescents are generally able to weigh the pros and cons of hormone therapy, including the uncertain impact on future fertility. In the authors' experience, many transgender youth report that their desire to express their gender authentically supersedes their desire for fertility. They clearly articulate plans to parent children, but they want to do so in their identified gender and use resources such as adoption or reproductive technologies. Surveys of TGD adolescents support the authors' experience, with only 20 to 36 percent expressing interest in biologic parenthood [113-115].

Timing of hormone initiation — For patients who have reached late puberty or completed puberty (ie, Tanner stages 4 or 5), initiation of GAH therapy is often appropriate. Similarly, as adolescents who received early pubertal suppression mature, initiation of GAH therapy is often appropriate.

As might be expected with the very individual and personal nature of gender identity goals and timing, the optimal age for initiating GAH therapy is uncertain, and evidence from long-term studies is limited. Protocols from the Netherlands recommend initiation of GAH at age 16 years, which is the legal age of consent in the Netherlands and several other European countries [2,3,12,56,68]. However, the guidelines from the Endocrine Society and WPATH acknowledge that there may be compelling reasons to initiate GAH before age 16 years [16,56]. Additionally, the gender-affirmative model supports an approach that relies on careful and thorough listening and respecting the patient experience, along with tailoring care to their individual needs.

For adolescents who underwent pubertal suppression in early-to-mid puberty (ie, Tanner stage 2 or 3), initiation of GAH that is more congruent with peer average age of puberty (ie, age 12 to 13 years for females and age 13 to 14 years for males) is desirable. Given the importance of peer congruence during the high school years, it is reasonable to assume that a 16-year-old with the sexual development of a 10-year-old may suffer psychological distress. However, this has not been formally evaluated in clinical studies. Observational studies of cisgender adolescents suggest that constitutional delay of growth and puberty may be associated with adverse psychosocial effects, including incompetence, vulnerability, impaired self-esteem, reluctance to participate in athletic activities, social isolation, impaired academic performance, substance use, and disruptive and suicidal behavior [116]. Earlier initiation of GAH therapy might also prevent a prolonged period during which bones have no exposure to sex steroids, a potential risk factor for decreased peak bone mass [16]. (See 'Assent/consent' above.)

Adolescents with gender dysphoria who have not undergone pubertal suppression may begin GAH therapy if they would benefit from GAH, demonstrate the capacity to assent, have a healthy and safe affirmation plan, and are ready to begin their second puberty [2,12]. (See 'Pretreatment considerations for GAH' below.)

Initiation of pubertal suppression with GnRH analogs in late puberty may offer limited benefit because most irreversible secondary sex characteristics are already well developed (eg, breasts, Adam's apple, voice-deepening). However, if initiation of GAH will be delayed, patients in late puberty may opt to initiate pubertal suppression—a safe and completely reversible option—to prevent any remaining pubertal changes. This may be particularly helpful for transfeminine adolescents who continue to grow new facial and body hair and experience facial bone masculinization late in puberty. This may be a useful first step for parents/caregivers who are struggling to support their TGD child.

The initiation of pubertal suppression with GnRH analogs is rarely indicated once an individual has completed puberty.

Pretreatment considerations for GAH — Pretreatment considerations before initiating GAH therapy include ensuring that the adolescent [16,56]:

●Has adequate psychosocial support – If gender dysphoria impairs self-esteem and function (eg, activities of daily living), hormonal treatment requires ongoing close collaboration with mental health providers.

●Assents to treatment, understanding the expected outcomes and the risks and benefits of GAH. (See 'Assent/consent' above.)

●Has the support of a mental health provider – Some providers require a letter from a mental health provider who has determined that the youth would benefit from GAH therapy; other providers do not.

●Has no contraindications to GAH – Most contraindications and precautions for hormone therapy are uncommon in adolescents and are as follows:

•Transfeminine individuals – Estrogen therapy is contraindicated for transfeminine individuals who have an estrogen-sensitive tumor.

Coexisting medical problems that increase the baseline risk of VTE are not usually considered contraindications to estradiol use because there are no other medication options to achieve the development of female secondary sex characteristics. The potential (but unquantifiable) risk of VTE must be balanced with the known risks of negative health outcomes (eg, self-harm, depression, and suicidality) in transgender individuals who cannot access GAH. Treatment plans should focus on efforts to minimize other VTE risk factors (see 'Transfeminine adolescents' below). Nonoral estradiol poses a smaller risk for VTE.

Severe liver dysfunction is a relative contraindication to oral estrogen therapy because oral estrogen is metabolized in the liver.

•Transmasculine individuals – Testosterone therapy is contraindicated for transmasculine individuals who have preexisting problematic or symptomatic polycythemia. As gender hormones are metabolized hepatically, caution is advised regarding starting estradiol or testosterone in a person with liver failure or severe liver dysfunction.

●Has baseline laboratory tests drawn – Baseline laboratory tests for transmasculine adolescents may include hemoglobin, hematocrit, lipids, and testosterone level, and for transfeminine adolescents, prolactin and estradiol.

Hormone regimens

Transfeminine adolescents — Regimens to induce and maintain gender-affirming secondary sex characteristics are available from the Endocrine Society, WPATH, and centers of excellence for transgender care [16,56,117,118]. These are also discussed separately. (See "Transgender women: Evaluation and management", section on 'Estrogen therapy'.)

When pubertal suppression is initiated in early or mid-puberty, it can be continued concurrently with the addition of GAH until young adults can make a decision about whether to undergo a gonadectomy [56]. Pubertal suppression is often discontinued earlier once estrogen achieves hypothalamic-pituitary-gonadal axis suppression. Prolonged suppressive therapy with GnRH analogs is expensive, may not be covered by insurance, and may be unaffordable or unavailable for patients [83,119].

The concomitant use of GnRH analogs, whether continued as pubertal suppression or initiated with GAH, provides a continuous but reversible blockade to GnRH stimulation of ovaries independent of the estradiol dose. A gradual increase in the estradiol dose allows the adolescent to progress through puberty at the same pace as their cisgender peers. It may also prevent the development of striae and abnormal breast shape, regardless of GnRH analog use.

Alternatively, the addition of androgen blockers (eg, spironolactone, bicalutamide, or finasteride) may be used to reduce testosterone activity at the androgen skin and hair receptors, which reduces testosterone and dihydrotesterone stimulation of male-pattern hair growth. Use of progesterone with estradiol may also be associated with generally lower testosterone levels [120]. (See "Transgender women: Evaluation and management", section on 'Androgen suppression'.)

The daily 17-beta estradiol tablet administered sublingually and the transdermal estradiol patch are the most commonly used forms of estrogen in adolescents [121,122]. We present all of the available options to youth and their parents/caregivers and make a decision based on the patients' values and preferences. Details about specific dosing regimens are discussed separately. (See "Transgender women: Evaluation and management", section on 'Estrogen therapy'.)

In general, transdermal estradiol is recommended rather than sublingual or oral estradiol in patients who have had a previous VTE.

In a review of 28 adolescents who received gender-affirming pubertal induction with 17-beta estradiol, breast development started within three months in 15 of 18 transgender girls for whom data were available, and 12 of 14 individuals achieved Tanner stage 4 to 5 breast development within three years [90].

Transmasculine adolescents — Regimens to induce and maintain gender-affirming secondary sex characteristics are available from the Endocrine Society, WPATH, and centers of excellence for transgender care [16,56,117,118]. These are also discussed separately. (See "Transgender men: Evaluation and management", section on 'Testosterone therapy'.)

Pubertal suppression that was initiated in early or mid-puberty is ideally continued when testosterone GAH is started to maintain suppression of endogenous estrogen. In addition, as with estradiol, if GnRH analogs are discontinued before testosterone begins to fully suppress estrogen production, endogenous puberty may resume. A gradual increase in the testosterone dose is considered preferable because this allows the adolescent to progress through puberty (eg, facial and body hair growth) at the same pace as their cisgender peers.

Subcutaneous injections are the most commonly used form of testosterone in adolescents. Intramuscular injections and topical preparations are also used. Transdermal gel is absorbed within several hours so that, in most persons, it is not likely to transfer to sexual partners, close contacts, or pets. However, there are case reports of adult men receiving testosterone gel whose testosterone transferred to a close contact (hyperandrogenism in a female partner and precocious puberty in a child) [123-125].

Less commonly used formulations that may be preferable for patients with needle phobia, needle fatigue, or difficulty remembering their dose include weekly autoinjectable subcutaneous testosterone, deep intramuscular injections every two to three months, or subdermally implanted testosterone pellets.

Transmasculine individuals who are having receptive vaginal sex with people with penises (ie, sperm and egg sex) should be advised that testosterone administration will not reliably prevent pregnancy even if the patient is amenorrheic. (See 'Fertility considerations' above.)

Nonbinary adolescents — There are increasing numbers of youth presenting for gender services who endorse a gender identity that is neither male nor female but rather somewhere in between or something else. (See "Gender development and clinical presentation of gender diversity in children and adolescents", section on 'Terminology'.)

As with binary transgender children and adolescents, the goal for nonbinary adolescents is to develop a treatment plan that meets the young person's individual embodiment goals [9,126]. Given the spectrum and fluidity of gender identity, it is important for health care providers to elicit and understand the specific needs of the individual patient, including how they conceive of their internal gender identity as well as how they want to externally present their experienced gender to the outside world. As with transgender youth and adults, not all nonbinary youth desire a social transition, hormones, or surgeries. Thus, interventions will vary from one individual to another.

Depending upon the level of discomfort associated with the mismatch between gender identity and sex assigned at birth, nonbinary youth may or may not want to use GAH. Medical interventions for youth who prefer less feminization or less masculinization include short-term use of GAH and/or lower dosing (sometimes referred to as microdosing) strategies, which may result in slower changes and a more androgynous appearance [127,128]. The use of less conventional hormones such as the anabolic steroid nandrolone or selective estrogen-receptor modulators has also been suggested [129].

Clinicians who see large numbers of nonbinary youth who were assigned female at birth report an increase in patients who are interested only in male chest reconstruction or menstrual suppression [130].

Monitoring — We schedule follow-up visits approximately every three months initially to ensure that each patient's hormonal status is meeting desired goals, to assess whether they are having any undesired effects, and to discuss overall adolescent wellbeing. After the first year, if the patient's pubertal changes are progressing well and they are having no concerning side effects, we decrease the frequency of visits to every 6 to 12 months.

Ongoing monitoring may include height for persons whose growth plates have not closed. It may also include other vital sign measurements, although no clinically significant blood pressure changes have been observed in adult populations. Weight changes are common in puberty and, as noted, can also change in adolescents undergoing gender hormone treatment. Monitoring for weight changes in TGD adolescents is also important because they can be at higher risk for disordered eating.

Annual blood testing, including creatinine and potassium, for those using spironolactone is generally advised. Hormone levels are generally monitored annually or according to phenotypic response to and/or side effects from hormone therapy. Monitoring is discussed in detail separately. (See "Transgender women: Evaluation and management", section on 'Monitoring' and "Transgender men: Evaluation and management", section on 'Routine monitoring'.)

Menstrual suppression — Transmasculine patients who are not using a GnRH analog or have not initiated gender-affirming testosterone therapy may request menstrual suppression. Menstrual suppression is likely to improve mental health and quality of life for transmasculine individuals who experience mild-to-severe exacerbation of gender dysphoria during their menses.

As with their cisgender peers, TGD youth can achieve menstrual suppression with a progestin-only or combined estrogen-progestin method. Several progestin-only methods are available for TGD youth who are unable to take or not comfortable taking estrogen.

The option that is most appropriate for an individual patient will depend, in part, upon whether they also desire contraception:

●Patient cannot or does not want to use estrogen

•Contraception optional – These patients may use any of the available progestin-only options, including oral norethindrone acetate (NETA), norgestrel over-the-counter pill, or medroxyprogesterone acetate (MPA). Additional options include depot medroxyprogesterone acetate (DMPA) injections and the 52-mg levonorgestrel-releasing IUD (LNG-IUD) [131].

The contraceptive efficacy of oral NETA and MPA is not equivalent to progestin-only methods of birth control, and they should only be used for menstrual suppression or regulation. The typical starting dose of NETA or MPA is 5 mg daily and can be titrated to 10 mg daily. If a 10-mg daily dose of either progestin does not adequately suppress menses, a trial of the other is reasonable.

The pros and cons of using oral norethindrone, MPA injections, and the 52-mg LNG IUD are discussed separately [112,131]. (See "Contraception: Overview of issues specific to adolescents".)

•Contraception desired – Neither NETA nor MPA provides reliable contraception. However, the other progestin-only methods described above do provide contraception. The etonogestrel implant and the 52-mg LNG IUD provide exceptionally reliable contraception (<1 percent failure rate) [112,131].

●Patient is comfortable using estrogen and has no contraindications – Some transmasculine youth do not mind using estrogen and are open to using continuous oral contraceptive pills or the contraceptive intravaginal ring, which also provide contraception. The use of a combined oral contraceptive containing drospirenone may be less desirable because of its antiandrogenic properties [132].

Patients often prefer a progestin-only method, as described above, even if estrogen-containing methods are an option.

GnRH agonists are not generally used solely for long-term, ongoing menstrual suppression.

SURGICAL INTERVENTIONS — 

Many youth and caregivers have questions about gender-affirming surgical interventions for gender affirmation. It is important to respond to these questions, acknowledge the possibility of surgical intervention in the future, and make referrals as necessary when youth reach a stage when surgery may be appropriate. However, for children and most adolescents, we redirect the focus to social and medical interventions.

While most genital surgeries are performed after individuals reach the age of majority (the definition of which varies geographically), chest dysphoria (distress about a female chest contour) is debilitating for many transmasculine youth, and male chest reconstruction during adolescence is occasionally performed [133]. Masculinizing chest surgery has been demonstrated to substantially alleviate chest distress and has a very low regret rate [133-135].

Gender-affirming surgeries (formerly surgical sex reassignment) include:

●Male chest reconstruction (ie, removal of female breasts and construction of a more masculine-appearing chest)

●Breast augmentation

●Genital reconstruction surgery:

•Creation of a neophallus with testicular implants

•Vulvovaginoplasty and orchiectomy

In the United States, insurance preauthorization for gender-affirming surgery in adolescents <18 years of age typically requires substantial documentation of distress that impairs psychosocial functioning. However, authorization for surgery, especially for transmasculine persons with chest dysphoria, does occur.

Gender-affirming surgery is discussed in detail separately. (See "Gender-affirming surgery: Masculinizing procedures" and "Gender-affirming surgery: Feminizing procedures".)

RESOURCES — 

Resources for patients, families/caregivers, and providers include:

●American Academy of Pediatrics (AAP): A Pediatrician's Guide to an LGBTQ+ Friendly Practice

●Children's National Health System Gender Development Program

●Expert Consensus Guidelines for Parents and Caregivers: Navigating Early Childhood Gender Identity and Expression

●Gender Spectrum

●National Center for Education in Maternal and Child Health at Georgetown University

●TransActive

●TransYouth Family Allies

●University of California, San Francisco Center of Excellence for Transgender Health

●World Professional Association for Transgender Health (WPATH)

Books for children, adolescents, families/caregivers, and therapists are listed in the table (table 5).

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transgender health" and "Society guideline links: Adolescent sexual health and pregnancy".)

SUMMARY AND RECOMMENDATIONS

●General measures for all transgender and gender-diverse (TGD) patients

•Affirmation of gender identity and expression – Gender-affirming approaches promote the exploration of gender identity, identity development, and self-definition within a safe setting. Affirming approaches place emphasis on understanding gender identity and gender expression from the child's perspective, and they provide support for the child to evolve into their authentic self, regardless of their age. (See 'Affirmation of gender identity and expression' above.)

•Social transition – Social transition is a reversible intervention in which a child lives partially or completely in their asserted gender role by adapting their hairstyle, clothing, and pronouns as well as possibly using a chosen name. (See 'Social transition' above.)

•Mental health support – Many TGD youth utilize mental health support to cope with gender dysphoria, nonaccepting parents/caregivers, or serious interpersonal conflicts with peers (eg, bullying). (See 'Mental health support' above.)

●Prepubertal children – Hormonal interventions are neither needed nor appropriate for prepubertal children. However, many prepubertal children benefit from gender affirmation, social transition, and/or mental health support. (See 'Prepubertal patients' above.)

●Early-to-mid puberty – Once a child with gender dysphoria enters puberty, they are eligible to consider pubertal suppression.

•Assent/consent – Parental/caregiver consent and patient assent are required before initiating pubertal suppression. This involves a discussion about the benefits and risks of pubertal suppression. (See 'Assent/consent' above.)

•Benefits – The primary benefit is relief of psychological distress experienced by youth who are developing what feel like the wrong secondary sex characteristics. (See 'Assent/consent' above.)

Avoiding the development of unwanted secondary sex characteristics early in puberty may prevent the need for future medical and surgical interventions.

Pubertal suppression allows youth to focus on gender identity exploration without the distress from ongoing secondary sex characteristic development.

•Risks – Bone mineral accrual is suspended during pubertal suppression monotherapy and resumes with the addition of a gender-affirming hormone (GAH) or discontinuation of pubertal suppression. It is not clear whether bone mineral density (BMD) eventually catches up to where it would have been without endogenous pubertal suppression. (See 'Assent/consent' above.)

When pubertal suppression begun in early puberty is followed by GAH, a transwoman who desires vaginoplasty later in life may not be eligible for a traditional penile inversion vulvovaginoplasty procedure.

Mood disruptions (including irritability, moodiness, and/or depression) may occur shortly after the initiation of pubertal suppression. These often resolve within one to two months but may persist.

•Fertility considerations – Endogenous pubertal suppression has no lasting effect on fertility if GAH are not added. (See 'Assent/consent' above.)

•Pubertal suppression regimens – Gonadotropin-releasing hormone (GnRH) agonists are the most commonly used agents for pubertal suppression in children and adolescents with gender dysphoria. (See 'Pubertal suppression regimens' above and "Treatment of precocious puberty", section on 'GnRH agonist therapy'.)

●Late puberty and completed puberty – Patients with gender dysphoria who have reached late puberty or completed puberty have the option to initiate GAH therapy. The following points also apply to adolescents who received early pubertal suppression and have gained the maturity to consider GAH therapy. (See 'Gender-affirming hormones ± pubertal suppression' above.)

•Pretreatment considerations – Pretreatment considerations for the initiation of GAH include ensuring that the adolescent has adequate psychosocial support; understands the expected outcomes, risks, and benefits of GAH; provides informed consent or assent; and has been assessed by a mental health provider. (See 'Pretreatment considerations for GAH' above.)

•Hormone effects – The tables present the anticipated effects of testosterone and estrogen (table 4 and table 3). (See 'Hormone effects and risks' above.)

•Hormone risks – Limited information exists about the frequency of adverse effects among adolescents receiving estrogen or testosterone therapy. The risks of estrogen therapy in adults include venous thromboembolism (VTE), but this risk is likely to be lower in adolescents. The risks of testosterone therapy in adults include erythrocytosis. (See 'Hormone effects and risks' above.)

•Fertility considerations – It is unclear what effect the addition of estrogen or testosterone will have on future fertility. This is the case whether GAH is introduced following early pubertal suppression or after the gonads are mature. (See 'Fertility considerations' above.)

•Regimens – 17-beta estradiol is used to induce secondary sex characteristics in transfeminine adolescents. A daily sublingual tablet and biweekly transdermal patch are the most common forms of estrogen used in adolescents. Weekly subcutaneous injections are the most common form of testosterone used to induce secondary sex characteristics in transmasculine adolescents. (See 'Hormone regimens' above and "Transgender women: Evaluation and management", section on 'Estrogen therapy' and "Transgender men: Evaluation and management", section on 'Testosterone therapy'.)

•Monitoring – Monitoring occurs approximately every three months for the first year of treatment. If the patient is progressing well, providers may decrease the frequency to every six months or yearly thereafter. (See 'Monitoring' above.)

●Rationale for providing gender-affirming care – Randomized trials are lacking and are challenging to conduct. The best data available on the outcomes of gender-affirming care come from observational studies. (See 'Rationale for providing gender-affirming care' above.)

•When distress caused by the incongruity between sex assigned at birth and gender identity emerges with the onset of puberty or has been present since childhood and intensifies with the onset of puberty, it rarely subsides.

•A growing body of evidence on short- and medium-term outcomes suggests that most individuals are more satisfied with their lives and experience more comfort living in their bodies following the initiation of hormone therapy.

•Long-term follow-up studies are limited but suggest that gender dysphoric adolescents who undergo pubertal suppression followed by GAH will maintain good functioning in their adult years.

•Reidentification with the sex assigned at birth rarely occurs after the initiation of GAH interventions.

•When patients discontinue hormone therapy, they do so for a variety of reasons, including satisfaction with the current changes to their bodies, no desire for additional changes, or obstacles to accessing GAH. Only a small subset of this group regrets having started hormone therapy.