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Health considerations for gender non-conforming children and transgender adolescents

Primary authors: Johanna Olson-Kennedy, MD; Stephen M. Rosenthal, MD; Jennifer Hastings, MD; Linda Wesp, MSN, NP-C

Introduction

Care for transgender and gender non-conforming (TGNC) youth is a rapidly expanding field of medicine, and lends itself to controversy among professionals. It stands to reason that transgender adults started as transgender youth, and if identified in childhood or adolescence may benefit from early access to hormone blockers and/or gender-affirming hormones. While sparse data exist regarding the impact of puberty suppression and gender-affirming hormones administered during adolescence, there have been promising results from the Netherlands indicating that this approach in adolescents results in improved quality of life and diminished gender dysphoria.[1] The principle challenge in determining best practice for transgender youth lies in the fact that development is different for each individual. While there are standard ranges of pubertal initiation in children,[2] the age at which children begin to articulate their experience of gender dysphoria or assert a gender identity that is distinct from their assigned sex at birth is highly variable. Providers of transgender youth care should be skilled at meeting the needs of young people presenting for care at any stage in their process. The care of transgender youth does not need to be limited to pediatric endocrinologists. General pediatricians, specialists in adolescent medicine, family medicine, medicine/pediatrics, as well as nurse practitioners, physician assistants and others are all potentially qualified to provide high quality care for transgender youth.

Creating affirming spaces for youth

Cultural sensitivity and awareness begins with front office staff, and other staff that are initial points of contact for parents and patients. Staff and provider inquiry about, and consistent use of appropriate pronouns and name is the first, and potentially most important step toward creating a culturally sensitive and welcoming environment. Professionals can model appropriate use of names and pronouns in the presence of parents and caregivers.

Increasing numbers of young people are presenting with nonbinary or gender queer identities, preferring gender-neutral pronouns as a more accurate way to be described. It is not uncommon for providers, parents, friends and family members to struggle with gender-neutral pronouns, and inadvertently invalidate nonbinary identities. Regardless of whether nonbinary identities are a stepping stone to a more binary identity, or are landing spots, they are valid and need to be honored.

Mental health support

Mental health professionals have a critical role in the care of TGNC youth. Even prior to disclosure of an authentic gender identity that differs from assigned sex at birth, transgender youth commonly experience symptoms of depression, anxiety, social isolation, behavioral problems, school struggles, and suicidal ideation.[3] Often young people are engaged in mental health services long before presenting for care related to phenotypic gender transition. Unfortunately, because so few mental health providers are experienced in the care of TGNC youth, inaccurate recommendations are not uncommon. Mental health support should not be sought in order to convince TGNC youth into accepting a gender identity that aligns with their assigned sex at birth, but rather, to provide a safe and welcoming space for young people to discuss and explore their gender, and any mental health challenges that may exist. While historically mental health professionals have been charged with authenticating the gender of their TGNC clients, this approach is rapidly falling out of favor, and is being replaced by a support model, rather than a gatekeeper model of accessing care.[4] Mental health professionals play an important role in helping youth learn to articulate their gender experience, and identify their needs around a gender that is not aligned with their sex assigned at birth. Therapists should spend time with young people gathering historic information from youth about their experience of their gender, and how that has been handled by the young person's support system. Additionally, therapists can help youth develop strategies around disclosure, self-acceptance, integration of transgender identity, intimate partnerships, and social transition if that is desirable. Therapists can help youth clarify what they are hoping to gain from pubertal suppression, gender-affirming hormones, and/or surgery.

Mental health providers also play a major role in educating parents, family members, schools and others about the needs of TGNC youth, as well as advocating for the young person across multiple domains. Therapists also can work closely with parents to help them understand what their child is experiencing, and will likely need from their parents and/or caregivers. Many TGNC adolescents, like most people of any age undergoing a significant life change, will benefit from ongoing therapy during both pubertal suppression, and the first few years of gender-affirming hormone administration, and perhaps, beyond. Despite increasing visibility and acceptance, TGNC youth are likely to experience transphobia and its negative consequences, and may benefit from ongoing support. Requiring participation in therapy in order to access medical care related to physical gender transition is neither successful, nor does it promote honest communication between young people and therapists. Therapy should be strongly recommended, and discussed routinely with youth, though due to an ongoing lack of skilled gender mental health professionals it is not always feasible, financially or geographically, for TGNC youth or families to access this resource. Increasingly, therapists skilled in supporting TGNC youth are offering online or telephonic therapy to assist in these difficult situations. Additionally, youth are often accessing mental health care for reasons not related to gender, such as social anxiety, depression, self-harm, and others. While these symptoms overlap with gender dysphoria, there are plenty of mental health professionals who are familiar with these particular challenges. Issues addressed by mental health providers can also be addressed by medical providers who are experienced, comfortable and have the time to have such discussions with youth. This is often necessary in geographic locations without available or accessible mental health professionals.

Pre-pubertal gender non-conforming (GNC) children

Over the past five years, it has become increasingly common for families with young children to request advice about the best way to approach their gender non-conforming child. Children as young as 18 months old have articulated information about their gender identity and gender expression preferences. Most parents are at a loss as to how to best help their child, and may seek the advice of a professional; commonly a psychiatrist or pediatrician. At this stage of development, no medical intervention is warranted or necessary. For young children, decisions must be made to create safe environments that promote healthy growth and development. For some children this may include a social transition - changing of external appearance (clothing, hairstyle) and possibly name and pronouns to match one's internal gender.

While there still exists uncertainty as to which GNC children will continue into adolescence and adulthood with transgender identities and/or gender dysphoria and which will not, it is been noted in prior studies that increased intensity of gender dysphoria is a predictor of a future transgender identity. This finding is subject to confounding, as youth who repress gender dysphoria due to safety or lack of basic language to express ones feelings may be no less likely to persist into adulthood, yet not present at an early age. Clinical experience has shown that it is those children who are the most dysphoric who seek social transition - the opportunity to live and be seen as a gender other than their assigned sex. Social transition has become more common, and a recent research endeavor reported good mental health among transgender children supported in their asserted gender.[5] Social transition for children can be logistically complicated and is best facilitated by a support team that includes the family, medical providers, mental health therapists and even lawyers. This team can work together to advocate for the child in school, sports, and other places so that GNC children can participate safely in these activities. Mental health therapists can play a significant role in the education of parents and other family members about GNC children, and their need for support and love.

Medical care for transgender youth

The approach to care may be simplified by defining two distinct cohorts of youth: those in the peri-pubertal, or early pubertal stages of development (Tanner 2-3), and those who are well along, in the final stages of, or completed with pubertal development (Tanner 4-5). These two cohorts often require different medical interventions; suppression of endogenous puberty, and/or the use of gender-affirming hormones for the development of masculinizing or feminizing features.

Suppression of endogenous puberty in early pubertal youth

Youth with gender dysphoria often experience significant trauma at the onset of their endogenous pubertal process.[6] Not uncommonly, gender dysphoria first emerges with the onset of puberty. The development of secondary sexual characteristics can be the solidification of an undesired physical developmental process for those with a gender identity that is incongruent with their assigned sex at birth. With the high frequency among transgender youth of mental health challenges including anxiety, depression, social isolation, self-harm, drug and alcohol misuse, many providers view early treatment as life-saving.

For those youth on a transmasculine spectrum, puberty begins with the development of breast buds at approximately age 10, though a large cross-sectional study demonstrated that 10% of caucasians, 23% of black non-Hispanics, and nearly 15% of hispanics had Tanner 2 breast development by 7 years of age.[7] For those youth who identify on the transfeminine spectrum, the first sign of puberty is enlargement of the testicles to beyond 4 mL in volume, with an approximate average age of onset of 11 years. Development of undesired secondary sex characteristics related to natal puberty can have profound negative psychosocial effects and for many, are a source of great distress.

A team of experts in the Netherlands at the Gender Identity Clinic at the VU University Medical Center in Amsterdam was the first to develop a protocol that presented the possibility of delaying, or avoiding altogether, the development of undesired secondary sex characteristics resulting from an unwanted endogenous pubertal process.[8] This model of care includes the use of gonadotropin releasing hormone (GnRH) analogues, most commonly in the United States, leuprolide acetate or histrelin, medications that have been used for decades to delay pubertal development in children with central precocious puberty.[9] GnRH analogues offer a reversible intervention that allows youth temporary relief from an undesired, and potentially traumatic endogenous puberty. While data are sparse, preliminary results from the Netherlands indicate that behavioral problems and general psychological functioning improve while youth (age 12 and older) are undergoing puberty suppression.[10]

In order to avoid the development of undesired secondary sexual characteristics, GnRH analogues ideally are initiated at the earliest stages of puberty (Tanner 2-3).[11] There is a role for using GnRH analogues in youth who are in the later stages of pubertal development, either for induction of amenorrhea, or to halt ongoing development of undesired secondary sex characteristics. In addition, GnRH analogues are an effective complement to estrogen treatment in transfeminine youth, given that estrogen alone, at physiologic doses, is typically insufficient to adequately suppress testosterone production (see below). Youth cannot remain on GnRH analogues alone indefinitely, as bone mineralization relies on the presence of sex steroids. While clinically becoming increasingly common, the impact of GnRH analogues administered to transgender youth in early puberty and <12 years of age has not been published. While rare, reported side effects from the use GnRH analogues may include diminished bone mineral density acquisition, weight gain, abscesses at the site of injection (if injectable form is used), irregular vaginal bleeding, and emotional lability.

Obtaining consent for treatment

Additional challenges arise when parents have discordant opinions about their TGNC child, or if a youth is in the custody of the courts. If both parents maintain medical decision-making for the youth then it becomes the task of the medical and mental health providers to help both parents understand the necessity of medical interventions. This process is not always straightforward, can take a lot of time, and sometimes necessitates involvement of legal assistance. For youth in the child welfare system, judges can order that medical intervention, including the administration of gender-affirming hormones, be undertaken.

Dosing of GnRH analogs

Leuprolide acetate can be delivered via injection anywhere from daily, to every 3 to 4 months.[12] Histrelin is delivered via a time-release implant that is surgically inserted in the underside of the upper arm. The implant lasts between 12 and 36 months.

The physical exam for children beginning an unwanted puberty can be extremely stressful. Providers should work on developing clinical rapport with children in order to foster trust prior to carrying out to a genital exam. Providers should discuss the importance of genital exams (for those with testicles) and chest exams (for those with ovaries) in assessing pubertal progress. Using techniques to distract children during these exams with phones, devices, books and other things can make the exam tolerable. Significant genital and chest dysphoria are common among youth, and aversion to an examination of secondary sex characteristics should not be a barrier to moving forward with suppression of puberty. In fact, the provider should consider deferring a genital or chest exam until a follow-up visit, after a positive rapport has hopefully been established. In extreme cases, providers should consider creative approaches such as obtaining labs first to confirm initiation of puberty, and following up with the genital and/or chest exam after the relationship is better established.

Monitoring youth on GnRH analogues

Blood tests to determine if the hypothalamic-pituitary-gonadal axis is suppressed with GnRH analogues should occur 6-8 weeks after starting monthly doses, or 8 weeks after starting the 3-month dosing. For those with implants, blood levels assessing efficacy should be obtained 8 weeks after the implant is placed. Blood tests include ultrasensitive LH/FSH/total testosterone (in those with testes) or estradiol (in those with ovaries). There is some evidence that LH/FSH levels are not necessarily reliable indicators of suppression in those with GnRH analogue implants, therefore more accurate assessment of adequate suppression might require gonadotropin response to a subcutaneous leuprolide acetate stimulation test.[13] ] While current guidelines recommend laboratory tests every three months to assess adequate suppression of the hypothalamic-pituitary-gonadal (HPG) axis,[11] repeated blood draws can be expensive and traumatizing for TGNC children. Suppression of the hypothalamic-pituitary-gonadal (HPG) axis should be assessed with clinical evaluation including height and weight, every three to four months, with blood serum ultrasensitive LH, FSH, estradiol/testosterone levels, renal and liver function, lipids, glucose, insulin, glycosylated hemoglobin considered annually, as clinically deemed appropriate while patients are on GnRH analogues. If there are clinical concerns regarding the efficacy of the puberty blocker, ultrasensitive pediatric FSH/LH, and sex steroid levels may be considered more frequently. More comprehensive and frequent laboratory tests will occur if the child is involved in a clinical or research trial.

There are potential benefits of baseline information about bone density, although no consensus about the necessity of obtaining bone densitometry prior to, and during GnRH analogue administration exists. If there is a family history of non-traumatic bone fractures, or osteoporosis, baseline screening is recommended. To optimize bone health, providers should ensure adequate dietary intake of calcium and should monitor vitamin D levels (25-OH) and supplement if indicated. Weight-bearing activity should also be encouraged. Physical changes of puberty should be assessed at follow up visits.

Follow-up conversation with youth who are undergoing pubertal suppression should include an assessment of an ongoing desire for endogenous puberty suppression. While extraordinarily rare, some youth may want to discontinue GnRH analogues and experience their endogenous puberty. For young people who remain gender dysphoric, and are interested in moving forward with masculinization or feminization, gender-affirming hormones can be added to GnRH analogues.

Gender-affirming hormones

Gender-affirming hormones may be added to GnRH analogues to assist in the development of feminizing or masculinizing features in transgender youth. While the current Endocrine Society guidelines recommend starting gender-affirming hormones at about age 16,[11] some specialty clinics and experts now recommend the decision to initiate gender-affirming hormones be individually determined, based more on state of development rather than a specific chronological age. (Grading: X C S).[12] Factors which support consideration of hormone initiation prior to age 16 include:

  1. Length of time on GnRH analogues - for those youth whose endogenous puberty is suppressed in the earliest stages of puberty, waiting until age 16 to add hormones means a potential 5-7 year gap, during which bone mineral density is only accruing at a pre-pubertal rate. This could potentially impact peak bone mineral density, and place youth at risk for relative osteopenia/osteoporosis.
  2. Experiencing puberty in the last years of high school or early college years presents multiple potential challenges. The emotional upheaval that occurs for youth undergoing puberty happens normally at 11 or 12 years of age. For those youth who struggle with emotional lability at that age, they do so in a relatively protected environment, regulated by parents/caregivers, and without access to potential dangers such as motor vehicles, drugs, alcohol and adult (or almost adult) peers and sexual partners. Having the physical appearance of a sexually immature 11 year old in high school can present emotional and social challenges that are amplified by gender dysphoria.
  3. Available data from the Netherlands indicates that those youth who reach adolescence with gender dysphoria are unlikely to revert to a gender identity that is congruent with their assigned sex at birth.[10]

Awareness of one's gender identity does not require cognitive capacity acquired in adolescence or early adulthood, nor does it require a fully myelinated frontal lobe. Gender studies in non-transgender participants have found that children are aware of their gender by the age of five or six, and often earlier.[14]

Induction of amenorrhea in post-pubertal youth

Commonly, trans-masculine youth are either not yet ready for, or are not yet at an appropriate age to begin testosterone therapy, but are interested in induction of amenorrhea. GnRH analogues may be used in this situation, however access is often difficult for financial and other reasons, and these medications cannot be used without hormone replacement indefinitely. Other mechanisms for inducing amenorrhea include continuous administration of oral contraceptive pills, and progestagen-only long acting reversible contraceptives (LARC) such as depo-medroxyprogesterone acetate injections, a levonorgestrel intrauterine device (IUD), or etonorgestrel rod implants (Grading: NT R M). Progesterone releasing intrauterine devices may result in amenorrhea in approximately half of all users.[15] Note that some trans-masculine youth are uncomfortable using "female" hormones, even for induction of amenorrhea. Youth can be informed that the administration of progestagens alone have little if any feminizing effect. Careful consideration of the individual's needs is critical in this decision making process.

Preparing for gender-affirming hormone use in transgender youth

Prior to the initiation of gender-affirming hormones, providers should review the expectations that patients have about the use of hormones in their phenotypic gender transition. It is important for young people to have realistic expectations about gender-affirming hormones, and have an understanding about what hormones can and cannot achieve. Both GnRH analogue and gender-affirming hormone administration require parental/legal guardian consent if a youth is under the age of 18. Side effects, risks, and benefits should be reviewed during the consent process, as well as addressing the possibility of unknown long-term risks. The consent process for hormones should include a conversation about fertility. While options are being explored to preserve future fertility for transgender youth, the current reality is that cryopreservation is very expensive, in many cases prohibitively so for those with ovaries. For youth whose pubertal process has been suspended in the earliest stages, followed by administration of gender-affirming hormones, development of mature sperm or eggs is unlikely at the present time, although it is noteworthy that there is active research developing gametes in vitro from the field of juvenile oncology. The issue of future infertility is often far more problematic for parents and family members than for youth, especially at the beginning stages of discussing moving forward with gender-affirming hormones. Youth who determine that future genetic contribution to offspring is more important than avoiding the development of unmatched secondary sex characteristics can choose to stop GnRH analogues, and progress through endogenous puberty in order to cryopreserve sperm, or harvest eggs.

Administration of gender-affirming hormones in youth undergoing concurrent GnRH analogue puberty suppression

For those youth who are on GnRH analogues for puberty suppression, providers have the opportunity to create a more natural puberty with exogenous hormones. Because there is no need to use exogenous sex hormones to suppress endogenous secretion of sex hormones, an escalating dose of either testosterone (for transmasculine youth) or estradiol (for transfeminine youth) can be used.

Transmasculine youth - hormone therapy with GnRH analogs

For those youth assigned female at birth who identify on the transmasculine spectrum, testosterone is used for the development of masculine secondary sexual characteristics. Testosterone can be delivered by injection, or topically via gel, compounded cream or a patch. Most adolescents are not enthusiastic about using gels or patches for a variety of reasons including necessity of daily application, potential of absorption for others in close proximity, and high incidence of local skin irritation in when a patch is used. Although injectable testosterone has historically been given intramuscularly, many practices have moved toward the less painful, and equally effective subcutaneous delivery mechanism.[16] Some patients note a surge of hormone with subcutaneous dosing, as serum testosterone levels may rise rapidly. Subcutaneous dosing must be weekly as the testosterone level decreases significantly by a weeks' time, whereas intramuscular testosterone lasts longer and may be dosed either weekly or every other week.

Subcutaneous dosing of testosterone with concurrent GnRH analogue use: Dosing schedules may start with 12.5 mg SC weekly for 8-12 weeks, increase to 25 mg SC weekly. Check levels after three months and adjust in 12.5 mg intervals accordingly. Practitioners may decide to mimic total testosterone levels that correspond to Tanner stages, and increase at 6-month intervals. Most patients achieve a normal male range of total testosterone and good clinical results at 50-75mg of testosterone delivered subcutaneously each week. Providing or prescribing 1 mL syringes for achieving these small doses is helpful. Providers should also prescribe 18 gauge 1-inch needles for drawing up medication, and 25 gauge 5/8-inch needles for injecting subcutaneously. Youth can learn to self-inject into the subcutaneous space in the flank or thigh, switching sides each week. A common side effect is induration in the area of injection that can be minimized if the area is massaged liberally after injection.

Intramuscular dosing of testosterone with concurrent GnRH analogue use: Intramuscular dosing of testosterone weekly or bi-weekly with an escalating schedule that is similar; 25 mg IM every week for 8 weeks, then increase to 50 mg IM every week. If dosing is every two weeks, the dose is doubled, but it is not uncommon for patients to experience fatigue, irritability and overall lack of energy toward the end of the second week of the cycle; weekly injections helps minimize these issues. Dosing is adjusted in 25 mg increments as guided by hormone level monitoring. Most patients do well on a final dose 50-100mg IM every week, or 100-200 mg every two weeks. Practitioners should provide or prescribe 1 mL syringes, 18 g 1-inch needles for drawing medication, and 21, 22, 23 or 25 g 1-inch needles (most commonly 23 or 25 gauge) for injecting intramuscularly. Youth can be taught to self-inject into the thigh, switching sides each time.

Injectable testosterone is suspended in oil, commercially in cottonseed oil, but often compounded for a less expensive form in sesame oil. Clinicians should be aware that some youth may have an allergic reaction to either of these oils, and usually switching to another oil is successful in alleviating the problem.

Topical dosing of testosterone with concurrent GnRH analog use: Occasionally there are youth who prefer testosterone delivery be topical, rather than injectable. Testosterone is available as a patch, gel or cream. Testosterone patches and gel are commercially available, cream can be compounded by specialty pharmacies. Testosterone patches come in 2mg and 4mg strengths, testosterone gel is available in 1% and 1.62% concentrations. There are no consensus dosing schedules for testosterone patches or testosterone gel in the induction of male puberty, only cited case examples of hypogonadal cisgender boys who's puberty was induced by topical testosterone.[17] Testosterone patches only come in two strengths and are difficult to titrate because of this, but testosterone pumps make titration a more feasible option.[18]

Monitoring

Monitoring for safety of testosterone is outlined elsewhere in these guidelines (link to testosterone administration), and the Endocrine Society have also published guidelines for testosterone administration.[11] Dosing adjustments should be made according to clinical response, and testosterone levels. Depending on the patient's age, providers may want to aim for testosterone levels that correspond to Tanner stages as doses are escalated.

Transfeminine youth - hormone therapy with GnRH analogs

For those youth assigned male at birth who identify on the transfeminine spectrum, 17β-estradiol is used for induction of feminizing secondary sex characteristics: breast development, fat distribution in the hip and chest area, and softening of the facial features. Estradiol will also help suppress the production of testosterone, which is unnecessary if youth are on GnRH analogues. Estrogen alone is not typically sufficient to fully inhibit testosterone production, and a second agent-either a GnRH analog or an antiandrogen such as spironolactone should be used (see below). As outlined in a recent review by Rosenthal [12] escalation of estrogen can be achieved in the following manner:

  1. Transdermal: twice weekly patches (6.25μg [achieved by cutting a 25-μg patch] with gradual increase to full adult dose of 400μg);
  2. Oral/sublingual: daily (0.25 mg with gradual increase to full adult dose of 6 - 8 mg/d);
  3. Parenteral IM (synthetic esters of 17β-estradiol): estradiol valerate (5-20 mg up to 30 - 40 mg/2 wk) or estradiol cypionate (2-10 mg/wk).

Monitoring for safety of estradiol is outlined elsewhere in these guidelines (link to testosterone administration), and the Endocrine Society have also published guidelines for estrogen administration.[11] Dosing adjustments should be made according to clinical response, and safety.

Timing for discontinuation of GnRH analogues

No consensus exists on the length of time GnRH analogues should continue after youth begin gender-affirming hormones. The Dutch Model follows a protocol in which simultaneous GnRH analogues and gender-affirming hormones continues until transgender individuals have their gonads removed. This model is appropriate in the Netherlands, where gonadectomy is easier to access at the age of 18 years old, and both gonadectomy as well as GnRH analogs are paid for by health insurance. In the United States, genital surgeries related to phenotypic gender transition are often not covered by insurance, and pose significant access issues. Additionally, gonadectomy is not necessarily desirable for all transgender persons, especially if future fertility is desired. Continuation of GnRH analogs in tandem with gender-affirming hormones into late adolescence or even early adulthood may be beneficial. Continued suppression of the HPG axis will permit use of lower doses of estradiol, and antiandrogens may not be necessary.

Administration of gender-affirming hormones without concurrent GnRH analogue administration

Many transgender youth accessing services are well beyond the early stages of puberty, and many are not able to get GnRH analogues covered by insurance. Because the cost of GnRH analogues is prohibitive for most families, gender-affirming hormones (in combination with other agents such as hormone blockers) are used to both suppress endogenous hormone production and masculinize or feminize bodies.

Hormone dosing in youth will vary based on the age, health, and other factors specific to the young person. In order to achieve amenorrhea with testosterone alone, masculinization will likely occur, which may or may not be desirable. In these cases, there may be a role for using other methods of suppressing menstruation such as continuous delivery of combined or progestin-only oral contraceptives, injected depo-medroxyprogesterone acetate, levonorgestrel containing-IUD, or etonorgestrel rod implants.

Transmasculine youth - hormone therapy without GnRH analogues

Similar to those transmasculine patients on GnRH analogues, testosterone is used for the induction of masculinizing features including body and facial hair growth, increased muscle mass, deepened voice, and body fat redistribution. Testosterone can be delivered via injections (subcutaneous or intramuscular), or topical (via gels, compounded creams or patches) for those youth not using GnRH analogues to suppress the HPG axis.

Subcutaneous dosing: Dosing schedules may start with 25 mg SC weekly for 8-12 weeks, increase to 50 mg SC weekly. Check levels after three months and adjust in 25 mg intervals accordingly. Practitioners may decide to mimic total testosterone levels that correspond to Tanner stages, and increase at 3-6-month intervals. Most patients will experience normal male ranges of total testosterone and good clinical response at 50-75 mg delivered subcutaneously each week. Providing or prescribing 1 mL syringes for achieving these small doses is helpful. Providers should also prescribe 18 gauge 1-inch needles for drawing up medication, and 25 gauge 5/8-inch needles for injecting. Youth can learn to self-inject into the subcutaneous space in the flank or thigh, switching sides each week. A common side effect is induration in the area of injection that can be minimized if the area is massaged liberally after injection.

Intramuscular dosing: If intramuscular dosing is preferential, some experts recommend doubling the above doses for IM administration. Intramuscular dosing can be done every one or two weeks with an escalating schedule that is similar; 25 mg IM every week, or 50 mg IM every two weeks for 8-12 weeks, then increase to 50 mg every week or 100 mg IM every two weeks. Check levels, and adjust in 25 mg increments accordingly. Most patients do well on a final dose 50-100mg IM every week, or 100-200 mg every two weeks. It is not uncommon for patients to experience fatigue, irritability and overall lack of energy toward the end of the second week of the cycle. Some patients prefer to dose at other intervals such as every 10 days with adjusting of the dose. Practitioners should provide or prescribe 1 mL syringes, 18 g 1-inch needles for drawing medication, and 21, 22, 23 or 25 g 1-inch needles for injecting intramuscularly. Youth can be taught to self-inject into the thigh, switching sides each time.

It is noted that for older youth who are well past endogenous puberty, the value of a very slow escalation is unclear, and may cause undue distress if masculinization takes years to achieve.

Regardless of technique used, injectable testosterone cypionate is suspended in oil, commercially in cottonseed oil. Clinicians should be aware that some youth may have an allergic reaction to either of these oils, and usually switching to another oil is successful in alleviating the problem. For those youth that are allergic to cottonseed oil, testosterone enanthate is suspended commercially in sesame oil. Additionally, some compounding pharmacies suspend testosterone cypionate in sesame oil for a less expensive option.

Transfeminine youth - hormone therapy without GnRH analogues

17β-estradiol is used for induction of feminizing secondary sex characteristics: breast development, fat distribution in the hip and chest area, and softening of the facial features. Estradiol will also help suppress the production of testosterone, but usually is administered in conjunction with an antiandrogen such as spironolactone. Estradiol is available in oral, injectable and topical delivery via patch and compounded creams.

Approaches for estrogen delivery vary based on the age of the young person. Slower escalation of estradiol may be beneficial for breast development, although is often unbearably slow for patients. For younger patients, smaller starting doses may be more advisable. As outlined in a recent review by Rosenthal [12] escalation of estrogen can be achieved in the following manner:

  1. Transdermal: twice weekly patches (6.25μg [achieved by cutting a 25-μg patch] with gradual increase to full adult dose of 400μg);
  2. Oral/sublingual: daily (0.25 mg with gradual increase to full adult dose of 6 - 8 mg/d);
  3. Parenteral IM (synthetic esters of 17β-estradiol): estradiol valerate (5-20 mg up to 30 - 40 mg/2 wk) or estradiol cypionate (2-10 mg/wk).

Because there is no concomitant use of GnRH analogues, dosing may need to be started higher than the schedule outlined above. Initial doses and escalation of dosing quantity should be individually tailored to each young person. For example, a youth who has experienced endogenous male puberty and enters care at age 16 or 17 may follow a dosing schedule such as:

  • Oral 17β-estradiol: start at 2 mg/day for 4-8 weeks, and increase by 1 mg increments depending on clinical response.
  • Parenteral IM (synthetic esters of 17β-estradiol): estradiol valerate 10-15 mg IM Q 14 days for 8-12 weeks, then increase by 5 mg as needed based on clinical and monitoring results.

It is noted that for older youth who are well past endogenous puberty, the value of a very slow escalation is unclear, and may cause undue distress if feminization takes years to achieve.

The utility of escalating doses of spironolactone (to decrease side effects including blood pressure instability or dizziness) is unclear, but because of the diuretic effect, it may be useful to start at 25 mg bid and taper up each week to a final dose of 200 mg BID.

The use of progesterone in transfeminine individuals does not have consensus among providers. It may be advisable when using progesterone to choose bio-identical micronized progesterone, as some experts have concerns of side effects with synthetic progesterone such as exacerbation of underlying depression or weight gain. A detailed discussion on the role and dosing of progestagens are included in the adult guidelines.

Surgical interventions for transgender youth

Transmasculine youth who have undergone endogenous puberty commonly experience significant chest dysphoria, and may engage in inappropriate methods of chest binding. Binding with duct tape, ace bandages and plastic wrap can all lead to serious medical complications. Even well fitted chest binders are hot, uncomfortable and make exercising difficult. Male chest reconstruction is a medically necessary part of phenotypic gender transition for many trans-masculine individuals. While increasing numbers of insurance companies are covering the cost of male chest reconstruction, there are often arbitrary barriers to surgery citing that youth need to be at least 18 years of age prior to undergoing this procedure. Providers should participate in appeal processes so that patients can undergo chest surgery. There are currently no available data that report the positive impact of male chest reconstruction in minors, although a study is underway now.

Despite advances in youth care that include the use of puberty blockers and hormones in adolescence, many transgender youth (particularly transfeminine youth) often experience genital dysphoria that results in significant anxiety and depression, and has been reported by many youth as a barrier to quality of life. The ability to develop skills and experience in social relationships is negatively impacted in those youth with genitals that do not correspond to their gender. High school is a time when young people begin to explore intimacy, as well as experience their own, and each other's physical bodies. For transgender adolescents, the very idea of sharing intimate space with a potential partner is often overwhelmingly terrifying, since their transgender status can be disclosed in an instant if their bodies are inadvertently exposed. For many transgender women, this disclosure has resulted in physical assault and all too often, death, at the hands of an angry partner. For many youth, social situations and dating are foregone, and the opportunity to learn necessary social skills during this stage of development is lost. Both the Endocrine Society Guidelines and the World Professional Association of Transgender Health (WPATH) Standards of Care version 7.0 recommend deferring genital surgery for both transmasculine and transfeminine youth until the age of 18 years. As youth are transitioning at increasingly younger ages, genital surgery is being performed on a case-by-case basis more frequently in minors, in order to address the issues mentioned above.

Editor's note:

Gender-affirming care for transgender youth is a young and rapidly evolving field. In the absence of solid evidence, providers often must rely on the expert opinions of innovators and thought leaders in the field; many of these expert opinions are expressed in this youth guideline. The four primary authors for this youth protocol represent many years of expertise in clinical care and research, in both academic and community practice settings, and within the disciplines of adolescent medicine, pediatric endocrinology, family medicine, and advanced practice nursing.

References

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