INTRODUCTION

Transgender and gender diverse (TGD) adolescents (those whose gender identity differs from their sex assigned at birth) contributemakeup up to 2% of the adolescent population in the United States.¹ Gender, an innate internal sense of self, related to cultural conceptions of gender identity, is diverse.² Additional terminology relevant to this chapter is seen in Table 1. Diverse genders have been known in cultures throughout the world for centuries, and the prevalence of gender diversity worldwide will likely be influenced by how communities and cultures identify gender, as well as how accepting a community is of diverse genders, which can influence the number of people living openly in their gender.^1,3,4,5,6 Many TGD individuals experience stigma and trauma in the community and medical settings.^2,7 As such, it is not uncommon for TGD individuals to not disclose their identity, to not be “out” to clinicians, further influencing our perceived prevalence of TGD individuals in health care.^2,8

It is important to offer medical care in a gender-inclusive way so that patients feel safe to disclose sensitive information and have their comprehensive medical needs met.^9,10 This chapter will review key considerations in providing welcoming care for TGD adolescents and areas of care specific to TGD adolescents that that clinicians may encounter or be asked to provide.

TGD ADOLESCENT HEALTH DISPARITIES

Transgender individuals face numerous health care disparities. These disparities are often rooted in health care inequities, including stigma and discrimination both inside and outside the medical system.¹¹ In the United States, TGD youth have an increased risk of poor mental health, experienced violence, and high-risk behaviors.¹ Global data shows similar patterns of disparities for transgender individuals worldwide, including greater challenges with mental health and higher rates of HIV and substance use and violence and abuse compared to cisgender peers.^12,13,14 Some of the most common health care barriers described by transgender individuals include the inability to find a knowledgeable provider, having to teach their provider about gender and gender-affirming care in order to receive competent care, and experiencing one or more negative interactions with a health care provider, including being refused treatment or harassment due to gender identity.² This is particularly true in women's health, where many gynecologists do not feel comfortable or prepared to care for transgender individuals.^9,15 Despite this, transgender individuals also have great resilience, and many more in recent years are reporting improvements in quality of life and health.¹⁶ Increased social awareness and inclusion of diverse genders due to global transgender advocacy and visibility have resulted in numerous strides for the transgender community.¹⁷ However, significant gaps remain, and closing these gaps requires collective action and individual. One of the goals of this chapter is to help empower clinicians to care for TGD adolescents and begin closing those gaps.

This chapter first addresses key ways to improve the health of TGD adolescents by creating a welcoming, inclusive clinical space for patients of all genders. Transgender adolescents, just like their cisgender peers, need primary and preventative services as they grow and thrive in adolescence and beyond. They also may need specialty services such as appendicitis or a broken wrist. While the treatment of these is no different than for cisgender peers, there are necessary clinical considerations to ensure the environment in which this care is being provided, and the clinical approach are both gender-inclusive.

Additionally, TGD adolescents may have specialty health goals beyond those common to all adolescents, such as gender-affirming mental health, hormones, or surgeries. We will also address those in this chapter as they relate to TGD adolescents. Certain specific transgender health considerations only relevant in adulthood (e.g., breast cancer screening) will not be addressed here.

INCLUSIVE CARE

Regardless of the medical specialty or clinical environment, clinicians can do several universally applicable things to ensure they are welcoming for adolescents of all genders. First, clinicians should consider their current clinical space.¹⁸ Clinicians should identify posters, pictures, flyers, handouts, or other reading materials, which are present and visible to patients and ensure that at least some are welcoming to TGD adolescents. Optimal signage should be welcoming to all patients; this includes having gender-inclusive bathroom signs when available. Single stall bathrooms should be converted to "all-gender" bathrooms. Some clinics may use gendered terminology in their titles (e.g., "women's health").⁷ Clinics with this signage where patients of all genders are seen should reflect on how they can improve this to reflect the patient population(s) they serve more accurately.

Global training is essential for all staff. Every interaction is an opportunity for a positive experience and an opportunity for misgendering or discrimination. Transgender adolescents not only interact with clinicians but with receptionists, phlebotomists, and all allied health professional staff.

The check-in process should be interrogated and evaluated for gender inclusivity. Intake forms should have places for a patient's legal name and name in use and pronouns. Some transgender patients may use a different name from the one on their legal documents.¹⁹ While the legal name must be recorded for legal purposes, including billing and insurance, the name in use should be used in all patient communication. Pronouns should also be respected. Pronouns are historically assumed based on gender expression. However, this is an inaccurate way to provide care and will often lead to increased frequencies of misgendering patients, which is often cited as a cornerstone of negative interactions with health care providers by transgender patients.² In English, pronouns include she/her, he/him, they/them, as well as others. They as a singular pronoun has long been an acceptable form in the English language.²⁰ Other languages have different pronouns, which may be used. Clinical processes should then ensure that the information about names and pronouns are relayed throughout the patient clinical experience to prevent instances where the wrong name or pronoun is used with the patient. Where available, clinicians should advocate for this information to be included in electronic medical records. Specifically, clinicians should ask all adolescent patients about their name use and pronouns in private. Some adolescents may not be "out" to their families or guardians but may feel comfortable with their clinicians.²¹ In these instances, it is also important for clinicians to ascertain when and how the patient wants the clinician and staff members to use their legal name versus name in use and which pronouns to use with whom. Transgender adolescents should be allowed to drive decisions about if and when they come out to other people as transgender. Clinicians can help facilitate this with families, but adolescents should direct this process. Adolescents who are not yet ready to come out to their families should be respected and supported, particularly concerning safety. Transgender teens are at high risk for violence and make up a significant percentage of adolescents experiencing homelessness and involvement in the child welfare system.^1,22

Taking a history from and performing a physical exam with a TGD adolescent is generally no different from a cisgender adolescent, with a few exceptions. TGD adolescents may experience dysphoria or distress related to certain aspects of the history and physical exam, particularly when discussing body parts related to sex traits such as the chest (or breasts), hair growth, genitals, or menses.^23,24 A few considerations can improve the care experience and clinical outcomes of TGD adolescents. First, clinicians should explain the reasons for their questions, or need for examination of the genitalia with patients. Transgender patients have been subject to inappropriate medical examinations and intrusive questions, and the explanations can help ensure patients understand the reasons for the care approach.²⁵ Second, clinicians can improve this experience for patients by asking them if there are terms they use to describe certain body parts or processes which may not be anatomic terms (such as front hole instead of vagina).²⁶ Clinicians should clarify as needed to ensure they are discussing the same part or process, but then should aim to mirror patient language about their body. As patients may undergo procedures that alter their genital anatomy, an anatomic inventory (Table 2) is recommended to use with all patients to ensure clinicians are aware of the relevant structures that are present, structures that were removed, and whether those present are native or neo (surgically created).

TGD adolescents should be asked about gender-affirming therapies and surgeries when taking a complete history. Clinicians seeing patients for preventative health care or annual visits should also ask about any desired therapies or surgeries. In adolescence, transgender individuals may desire these therapies or surgeries but have not yet initiated them. By asking, clinicians can acquire a history and identify areas where they can assist in care coordination. See the section below for more about hormone therapies and gender-affirming surgeries.

In sexual histories, clinicians should ask open-ended questions to patients. It is important not to assume that sexuality and sexual activity are synonymous.²⁷ Sexuality is often identified based on gender, so a transmasculine person who identifies as straight may feel romantically and sexually interested in women. A transmasculine identified person who identifies as straight may still engage in intercourse with persons who have a penis (both cis men and trans women). Thus, asking about sexuality is insufficient to determine if a person is at risk for pregnancy.²⁸ Asking what body parts the persons have with whom the patient engages in intercourse can be a neutral, unbiased way to ascertain sexual activity and pregnancy risk.

Patients may be more reticent to undergo examinations of parts of their body where they experience dysphoria.²⁹ Clinicians should utilize a trauma-informed approach throughout the decision-making process regarding the history and physical exam, including if and when certain aspects of the exam occur.³⁰ Patient-centered approaches to the exam include addressing the need for an invasive pelvic exam and discussing noninvasive alternatives as first-line approaches (e.g., transabdominal ultrasounds and blind swabs). Patients should be asked what would make them feel comfortable and safe during exams, such as offering a mirror, having a support person in the room, or using headphones.

Gender- affirming therapies

The majority of gender- affirming care that clinicians provide TGD adolescents is the aforementioned welcoming and inclusive clinical environment for all patients of all genders. Some patients will additionally desire mental health, medical, or surgical gender-affirming care.³¹ This section reviews those aspects of care. As every gender journey is unique, not every patient will desire the same therapies or surgeries.² Utilization of hormones or undergoing procedures does not make someone "more or less transgender" than someone else. In adolescence, some patients may desire certain therapies or surgeries but may not presently be on them or have undergone them due to age, maturity, legal barriers in access, or need for parental/guardian consent. Regardless, when asking about gender-affirming therapies and procedures, clinicians should also elicit patients' goals regarding interest in medical therapies or surgeries clinicians as well as desire regarding timing both in relation to their life and life milestones as well as in relation to one another (e.g., desiring to start testosterone before having top surgery).

The primary international guideline for the initiation or performance of gender-affirming therapies or surgeries is the World Professional Association for Transgender Health (WPATH) Standards of Care (SOC).³² The latest iteration at the time of the creation of this chapter was version 7; version 8 was in progress. The content below will be based on SOC 7. However, clinicians should always review the latest iteration of the SOC for the most up-to-date guidance. Additional guidelines we will reference that clinicians may also use include the Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline, which has robust guidance on the provision of gender-affirming puberty-blocking therapy and hormone therapy.³³

Gender- affirming mMental health

Supportive behavioral health can be a cornerstone of care for some TGD adolescents.³⁴ Adolescence is a common time when transgender individuals actively explore and express their gender to those around them.³⁵ It is also a time when there is a higher likelihood of the emergence of gender dysphoria, distress, or impairment in daily activities or functioning related to gender identity. This can be due to puberty and bodily changes, which may cause distress for transgender adolescents if they do not align with their internal sense of self, may be caused by changes in peer relationships, or maybe caused by other things. Not all transgender adolescents experience gender dysphoria, particularly in cultures and communities supportive of gender diversity.³⁶ Transgender identities are not themselves behavioral health concerns. Research supports that gender identity is innate and not externally changeable. Past efforts in psychological and psychiatric fields have resulted in harm to transgender individuals, and most major organizations oppose these practices, with some municipalities having banned the practice.^37,38

Some transgender adolescents will not experience gender dysphoria and instead experience gender euphoria.³⁶ Behavioral health support and needs should be tailored to the patient. For those who will benefit from behavioral health, clinicians should assist families in finding providers who are competent in caring for transgender adolescents. Additionally, adolescents seeking gender-affirming therapies or surgeries (see below) will typically require the involvement of behavioral health clinicians before therapies or surgeries are performed.³² As such, for any adolescent, even those not experiencing gender dysphoria, behavioral health involvement early on may be useful in helping to understand and navigate the adolescents' long-term gender goals.

Gender- affirming medical therapies

Gender-affirming therapies for TGD adolescents, including puberty blockers and gender-affirming hormones, have been shown to improve the well-being of transgender adolescents and decrease adverse health outcomes.^33,39 The initiation of gender-affirming puberty blockers or hormones should be performed by a clinician skilled in this care. Those clinicians arise from various fields, including pediatric and adult gynecology, endocrinology, and primary care.

For TGD adolescents (specifically minors), the WPATH SOC 7 recommends that a trained medical professional diagnose gender incongruence or gender dysphoria before initiation of puberty blockers or gender-affirming hormones.³² Ultimately, treatment readiness should be determined by the prescribing clinician and based on the patients' ability to assent/consent and the guardians' ability to provide consent where required depending on the municipality.

Per the WPATH SOC 7, for those who have reached the age of majority or are considered adults in their society, clinicians comfortable diagnosing persistent, well-documented gender incongruence or dysphoria do not need to have a separate mental health evaluation prior to therapy initiation.³² Ultimately, treatment readiness should be based on the patient's ability to consent to therapy. The pubertal suppression and gender- affirming hormone therapy medications reviewed below are all off label use.

PUBERTAL SUPPRESSION

Puberty blockers are medications whose primary goal is to delay pubertal progression.³³ They can be initiated as early as Tanner II-III development. They should not be initiated prior to the entrance of puberty. They are the first-line therapy offered for TGD youth entering adolescence to prevent additional permanent physical changes that occur with secondary sex characteristics that may not ultimately align with a patient's gender identity. Puberty suppression is relatively reversible. Their use aids transgender adolescents, their families, and clinicians in having a greater amount of time through childhood and early adolescent development to consider the patient's ultimate gender goals, such as the use of gender-affirming hormone therapies. Additional benefits of taking puberty-blocking medication include preventing the development of permanent unwanted secondary sex characteristics. This may decrease an adolescents' desire or need to undergo certain gender-affirming procedures in the future they may otherwise need to have if they had gone through their natal puberty.⁴⁰

As sex steroids are necessary for patients' long-term health, puberty blockers should not be used indefinitely, and eventual transition to gender-affirming hormones, or discontinuance of puberty blockers and allowance for endogenous hormone production, should occur. TGD adolescents who utilize pubertal suppression may continue to utilize it as they start gender-affirming hormone therapy to suppress endogenous hormonal production. Not all patients who start on puberty-blocking hormones will desire gender-affirming hormone therapies.⁴¹ However, as patients near the point where discussions of sex steroids are ready to commence, TGD adolescents are those whose gender identity is likely to persist and will likely continue to seek gender-affirming therapies and surgeries into adulthood.

Puberty blockers are generally safe and well-tolerated medications.^33,42,43 The primary medication used for this is GnRH analogs, which temporarily suppress puberty (suppressing luteinizing hormone and follicular stimulating hormone). They come in injectable and implantable versions. Leuprolide Acetate, the injectable form, is administered intramuscularly with a dosing of roughly 11.25 mg every 3three months. Some patients may require higher dosing if their gonadotropin levels are incompletely suppressed.³³ A histrelin implant is an alternative subcutaneous implant placed in the arm and will emit a slow release of GnRH analog. It will last anywhere from one to three years.³¹

While GnRHa is the mainstay of treatment, they are not universally accessible.⁴⁴ These medications are costly, require clinician administration for injections or implants, and are not universally covered by insurance. Menstrual suppression agents can also be used for those born with ovaries and uterus whose primary concern in pubertal suppression is menstrual suppression (see below).

Table 3 shows the appropriate clinical surveillance for a person on puberty blockers as recommended by the Endocrine Society.

MENSTRUAL SUPPRESSION

TGD adolescents with ovaries and uteri may seek menstrual suppression as a part of gender affirmation.^45,46 Menstruation is a source of dysphoria for many transgender adolescents.⁴⁷ Some transgender adolescents may use menstrual suppression as a stepping stone in gender care, given that it can provide relief from menstruation while adolescents are exploring pursuing subsequent androgen therapy.⁴⁶ No diagnosis of gender incongruence or participation with mental health is required to suppress menses.

The types of menstrual suppression available are predominately the same medications as those available for their cisgender peers (Table 4).⁴⁶ Some patients may have priorities regarding the choice of menstrual suppression that differ from their cisgender peers, such as avoidance of estrogen or desire to conceal the method.²⁸ Clinicians should not assume which methods a patient may prefer but offer all options and tailor choice to the patient's goals. In addition to medications commonly used for menstrual suppression, Danazol, a synthetic androgen-progestin, may also be offered as a form of menstrual suppression for TGD adolescents.⁴⁶ It produces high rates of amenorrhea in studies from the late 20th century when it was prominently used for endometriosis.^48,49 It also has weak androgen-like effects at higher doses, which some TGD adolescents may desire.

For those adolescents who use menstrual suppression, some will continue to utilize those as they initiate testosterone therapy. This is typically done to avoid any return of menses while androgen levels are increasing. Patients should be counseled that while this may limit the chance of not having any breakthrough bleeding, it is not an assurance. Just as with menstrual suppression alone, some patients will still experience breakthrough bleeding when using a concomitant menstrual suppression agent with testosterone⁴⁶ This is discussed further in the section on testosterone.

GENDER- AFFIRMING HORMONE THERAPIES

Testosterone

Gender- affirming hormone therapies typically fall into two camps: those that induce virilization and those that minimize and promote estrogenic features.

The mainstay of virilizing therapy is testosterone, which comes in various preparations (Table 3).³³ This includes injectables that can be administered subcutaneously or intramuscularly, with no difference seen in outcomes between them.⁵⁰ It also includes oral, transdermal gel and patch forms and subcutaneous pellets. Different preparations are available in different countries, so clinicians should familiarize themselves with local drug approval. Route choice is dependent on the patient. Most patients will begin with a non-subcutaneous pellet form, which is the longest-acting of the preparations. Other factors, which can influence the method, include comfort with injections and avoidance of topical products, which can cause contact transfer to other individuals. Topicals may also cause skin irritation. The goal is to have serum testosterone levels of 320–1000 ng/dlL and suppressed estrogen levels.³³ These testosterone levels are important to maintain during adulthood for sex steroid benefit, particularly for those who have undergone oophorectomy. Typical dosing approaches are seen in Table 5. For those who have previously been on puberty blockers, the approach may be modified to start at a lower dose (e.g., 25 mg/m² injectable testosterone every 2 weeks) and increase slowly (e.g., by 25 mg/m² every 6 months).

Testosterone increases facial/body hair, muscle mass, acne, libido, clitoral size, deepens the voice, and typically induces amenorrhea. It also can cause male-pattern balding and fat redistribution. The timing of each of these varies, and the degree of change seen is unique to the individual and influenced in part by genetics, duration, and serum level of testosterone. Most effects are maximally seen by two years following initiation.³² Patients should be counseled that everyone’s cadence of changes is different. Testosterone side effects include erythrocytosis, which increases the risk for cerebrovascular disease and thrombosis, lipid profile changes, vaginal dryness, and possible mild elevation of transaminases. However, no studies have shown any clinically significant changes because of this.³³ Patients on testosterone should be encouraged to avoid smoking and maintain a healthy diet and exercise due to the increased risk of cardiovascular disease in cisgender men that is thought to, in part, be androgen driven.

Contraindications to testosterone therapy for gender affirmation are few. Active polycythemia and unstable coronary artery diseases are two considerations and active pregnancy.³³ As testosterone stimulates erythropoiesis, for those who acquire polycythemia while on testosterone, a standard technique to manage this (e.g., blood donation) is recommended to maintain a hematocrit less than 55%. In patients with concerns for thromboembolic disease, serum hematocrit, hemoglobin, and total testosterone should be acquired to evaluate for underlying erythrocytosis or elevated testosterone. Testosterone has presently not been shown to increase the frequencies of reproductive cancers. It is not presently contraindicated in persons with a personal or familial history, though clinicians should inform patients of the minimal existing data and engage in shared decision making.^51,52,53 Some clinicians will offer aromatase inhibitors to minimize the conversion of exogenous testosterone to estrogens in these patients, though this has not been studied.

Different patients may have different goals regarding virilization and gender-affirming hormone therapy. Clinicians should ask about these goals and incorporate them into counseling. This may identify patients whose goals do not align with testosterone therapy. Some patients may seek slower changes or ask for less virilization. The communal term for this is “microdosing .”. This is simply starting at a lower dose of testosterone than typical protocols or going slower on increasing doses. This may allow patients a more gradual or subtle change. Microdosing is generally considered safe. However, if a patient has a uterus, they should be counseled that testosterone levels long term in the range of PCOS may place patients at risk of endometrial hyperplasia due to the persistence of endogenous estrogen and should be counseled on beginning a medication that can protect the uterine lining, similar to anovulatory hyperandrogenic patients with PCOS.⁵⁴ Patients should also be counseled that just as with standard dosing, changes on lower doses or slower increases cannot be predicted and for any given individual may still be prominent.

After initiating testosterone, patients are typically followed every 3three months for the first year and then every 6–12 months after that, depending on the type of testosterone used (pellets will require more frequent visits for administration) and any patient concerns. Clinical parameters assessed include a CBC at baseline, then a CBC and serum total testosterone every 3three months while initiating therapy and increasing dose, and yearly after that, or when changing doses.

FEMINIZING THERAPY

Feminizing therapy is typically dual, including estrogen and anti-androgens (Table 4).^31,32,33 Estrogen comes in various oral, injectable, and transdermal preparations. Anti-androgens include several different medications designed to either reduce the production of androgens or reduce their activity at the androgen receptor. Different medications are available in different countries, so clinicians should familiarize themselves with local drug approval. Estrogen route choice primarily depends on patient preference, which may be influenced by the comfort with injections or topical preparations and cost. Transdermal estrogen is less thrombogenic. This may be the preferred method of choice for transgender adolescents who have a higher personal risk of venous thromboembolism (VTE)VTE. Anti-androgen choice can also be determined by patient preference, influenced by route and access. Anti-androgens also have different side effects, which may influence choice. The goal is to suppress serum testosterone levels to cis female ranges (<50 ng/dl) and have serum estrogen levels of 100–200 pmg/ml. At lower doses of estrogen, anti-androgens are often needed to suppress testosterone levels. However, higher doses of estrogen may not require anti-androgens to suppress serum testosterone. Typical dosing approaches are seen in Table 6. For those who have previously been on puberty blockers dosing should start lower (5 μg/kg/day of oral estradiol or 6.25–12.5 μg/day of transdermal estradiol), increase the amount of the starting dose every 6six months until adult dosing ranges.

Estrogens in combination with anti-androgens will typically soften skin, increase breast development, reduce further production of facial/body hair (will not remove hair currently present), decrease muscle mass and alteration in fat distribution, and decrease libido and spontaneous erections. There is no effect on the bony structure or vocal cord changes, which may have previously occurred from endogenous androgens. The timing of each of these varies, and the degree of change seen is unique to the individual and influenced in part by genetics and duration of hormone use. Patients should be counseled that everyone's cadence of changes is different. Estrogen side effects include nausea, headaches, breast tenderness, dry skin, brittle nails, and increased appetite and weight gain. There is also a risk of increased prolactin levels. However, most prolactinomas found have been benign and asymptomatic, and routine surveillance has not been indicated. Estrogen has a risk for VTE.⁵⁵ Patients on estrogen should be encouraged to avoid smoking to decrease VTE risk. Estrogen also increases the risk for estrogen-sensitive cancers later on in life, though the absolute risk is still unknown. Breast cancer risk appears to be greater than for cisgender men but less than for cis women, though this likely has to do with the duration of estrogen exposure.^51,56,57 Risks of androgen blockers are specific to each medication.

Spironolactone is an aldosterone receptor antagonist diuretic and can lower blood pressure and induce hyperkalemia. Patients on spironolactone need to have potassium levels monitored and be counseled about possible increased urinary frequency and need for hydration. This may not be a good option for transgender adolescents who lack bathroom safety. Cyproterone acetate, a synthetic progestin, is used in some countries as it has a robust anti-androgen component. Patients should be counseled on the risk of prolactinemia, hyperlipidemia, and rare but serious risks of fulminant hepatitis and meningioma. Bicalutamide is rising in popularity as an anti-androgen. It is generally well-tolerated and has safety data from its use in oncology; it also has an incompletely understood and rare risk of liver dysfunction, including fulminant hepatitis.

Contraindications to feminizing therapy in transgender adolescents for gender affirmation are few.³³ Estrogen should not be started in someone with active estrogen-sensitive cancers. While not contraindications, patients who are smoking who have baseline increased risks for VTE may benefit from transdermal estrogen due to its less thrombogenic properties. Contraindications for spironolactone are renal insufficiency and preexisting hyperkalemia (>5.5 mEq/lL).

Different patients may have different goals regarding feminization and gender-affirming hormone therapy. Clinicians should ask about these goals and incorporate them into counseling. This may identify whether a patient would benefit from starting with just an anti-androgen or estrogen alone or which anti-androgen may be best for a patient. Some patients may seek slower changes. Using lower doses of feminizing hormones is generally considered safe in patients with intact gonads. Someone on GnRHa or who has undergone orchiectomy should be counseled on the benefits of staying on a minimum dose of exogenous estrogen to support their physiologic development, particularly bone. However, these doses are typically lower than standard gender-affirming estrogen doses. Patients should also be counseled that just as with standard dosing, changes on lower doses or slower increases cannot be predicted and for any given individual may still be prominent.

Some patients will desire additional progestins in feminizing therapy. Presently data does not strongly support or refute their use, and as such most clinicians engage in shared decision making regarding if and when to initiate. Anecdotal reports have documented improvements in breast development, mood, and libido. Concerns about progestins arise from an increased risk of breast cancer seen in cisgender postmenopausal women on combined estrogen/progesterone therapy. However, it is unclear how this translates to those on feminizing gender-affirming hormone therapy. The cisgender data was in persons on equine estrogens who had a baseline higher risk of breast cancer. The most common forms utilized in gender-affirming care are micronized bioidentical progesterone (100–200 mg daily) and oral medroxyprogesterone acetate (2.5–10 mg daily).

After initiating therapy, patients are typically followed every 3three months for the first year and then every 6–12 months after that, depending on the therapies used and patient concerns. Clinical parameters assessed include a complete metabolic panel at baseline, serum total testosterone, and estradiol during follow up are in Table X. Clinical parameters assessed include a CMP at baseline, then serum total testosterone and estradiol every 3three months while initiating therapy and increasing dose, and yearly after that, or when changing doses. A CMP should additionally be monitored alongside hormone levels if the patient is on spironolactone. If a patient shows symptoms of prolactinoma (e.g., headaches, vision changes, or galactorrhea), a prolactin level should be drawn.

FERTILITY AND GENDER- AFFIRMING CARE

Some gender-affirming therapies and surgeries will affect a patient's fertility potential.⁵⁸ As such, patients' fertility goals should be addressed prior to the initiation of gender-affirming therapies or surgeries thatwhich impact fertility. Fertility goals should be asked in the broader context of family-building goals, as not all families are genetically related. Patients should be asked if they see themselves having children in the future, if they would like to use their gametes (sperm or eggs) for these children, and if they would like to carry a pregnancy. Transgender adolescents have diverse fertility and family-building goals, which may change over time.⁵⁹ Clinicians should aid patients in having all the relevant information about the therapy or surgery they are interested in and the known and unknown effects it will have on fertility, to help the adolescent make the most informed decision. Data is unclear on how many transgender people regret decisions about fertility preservation they made as adolescents.^60,61 Transgender adolescents may not know the answers to questions about their future fertility desires or may influence their decisions based on the perceived or real barriers fertility preservation can possess, such as the need for invasive exams and procedures or delaying the initiation of hormone therapy.⁵⁹ Regardless, fertility preservation should be offered to all patients where therapies or surgeries may affect fertility, and appropriate referrals should be provided for those interested in fertility preservation.

Fertility preservation should be considered in the context of the known and unknown effects of gender-affirming therapies on fertility. For transgender adolescents who are prepubertal and desire pubertal suppression upon entrance into puberty, who desire to preserve fertility, the primary option is gonadal tissue preservation due to the immature gametes.⁵⁸ However, patients with ovaries on pubertal suppression should be counseled that there has been a report of oocyte retrieval while on GnRHa.⁶² For post-pubertal transgender adolescents with testes, feminizing hormone therapy has been shown to decrease fertility.⁵⁸ For these patients, the standard recommendation is to preserve sperm prior to beginning estrogen therapy. There have been a few cases of patients discontinuing estrogen and successfully retrieving sperm. However, this should not be considered a reliable possibility.⁶³ For transgender patients with ovaries and uteri, the historical thought was that testosterone rendered patients infertile. The growing body of data in this area shows that the reality is far more nuanced.^{28,52,53,64,65} Many transgender individuals with ovaries and uteri have discontinued testosterone and successfully carried pregnancies or preserved eggs.^64,66 Testosterone may impact fertility but not nearly to the degree it was previously thought to do. The standard of care for those who do not desire to have their fertility impacted by testosterone or want to preserve gametes prior to initiating testosterone is oocyte cryopreservation (or embryo cryopreservation if done with sperm). If a patient desires to undergo oocyte or embryo cryopreservation later on in life while on testosterone, most clinicians recommend discontinuing testosterone until the testosterone levels return to endogenous levels before ovulation induction. However, every clinic varies in its approach to the duration of time off testosterone. Moreover, there has been a report of successful oocyte retrieval while on testosterone.⁶⁷ Another aspect of fertility is the ability to carry a pregnancy. Reassuring data suggests that testosterone does not prevent a uterus from carrying a pregnancy, and reports have documented successful pregnancies following testosterone discontinuance. It is recommended to discontinue testosterone prior to pregnancy due to the risk of virilization of a fetusfoetus with two X chromosomes in utero, which has the greatest impact in the first trimester. It is unknown how restarting testosterone prior to completion of the pregnancy after the first trimester would affect the fetusfoetus.²⁸ Lastly, while fertility conversations about pregnancy traditionally focused on those born with a uterus, advances in uterine transplant could offer those not born with a uterus the chance to carry a pregnancy in the future.⁶⁸ As such, asking all patients about pregnancy desires during fertility conversations allows for identifying patients who may seek this in the future.

Fertility preservation should also be addressed before a patient undergoes a sterilizing procedure such as an orchiectomy, typically included in a vaginoplasty but may also be done in isolation, or a hysterectomy or metoidioplasty or phalloplasty, which may require a hysterectomy as a prerequisite. Hysterectomies done for gender affirmation, including those as a prerequisite for masculinizing genital surgeries, do not require oophorectomies.⁶⁹ For those who may not be sure if they want to use their ovaries in the future but who desire gender- affirming hysterectomy or masculinizing genital surgeries requiring hysterectomy, they can leave ovaries in situ and undergo oocyte retrieval later.⁷⁰

GYNECOLOGIC CONCERNS IN TRANSGENDER ADOLESCENTS

Genital anatomy on gender- affirming hormones

Those in reproductive health need to understand the changes induced in the ovaries, Mullerian, and urogenital structures on testosterone. In general, high doses of androgens produce a hypoestrogenic environment. Ovarian function is relatively suppressed, with decreased frequency of ovulation and lower estrogen levels. Ovaries are typically within the normal volume for reproductive age. While some exhibit ovarian atrophy, numerous studies find the preservation of function, with individuals successfully discontinuing testosterone and undergoing oocyte retrieval or pregnancy, suggesting the majority of ovaries are not irreversibly impaired.^64,71 Uteri are also small to normal size; endometrial linings are thin.^52,72 Some endometrium are inactive while others have proliferative endometrium. Secretory endometrium is rarely seen, likely reflective of the lack of progestins due to the lack of ovulation.⁶⁵ However, testosterone does not completely suppress ovarian and uterine function. Those on testosterone can still produce age-appropriate pathologies such as ovarian cysts and masses, fibroids and polyps, and breakthrough ovulation may occur. Cervices are similarly atrophic and have decreased cellularity.⁷³ The vulva and vagina may be atrophic due to the hypoestrogenic environment though not all patients on testosterone have vulvovaginal atrophy. The clitoris is enlarged on androgens.⁷⁴

A hyperandrogenic environment decreases the testicular volume and can lead to erectile dysfunction.³³ The prostate also shrinks in size.⁷⁵

Counseling on cancer risk

Discussing lifelong screening and management of cancers in transgender individuals on testosterone is beyond the scope of this chapter due to its adolescent focus. However, it is important for clinicians counseling on gender- affirming hormone therapy in adolescence to understand the current data. Transgender adolescents initiating hormone therapy should be counseled to follow all screening guidelines as per cisgender guidelines for hormone-sensitive cancers.^31,76

Transgender individuals on testosterone continue to have a risk for estrogen-sensitive pathology. However, increased rates of hormone-sensitive cancers are not currently seen in transgender individuals on testosterone.⁵⁷ Testosterone appears to suppress the majority of ovarian and uterine function; however, some endogenous activity may persist, and persons on testosterone have been found to have pathology in the ovaries and uterus that are typical for their age.^52,53 Additionally, testosterone is also not known to decrease hormone-sensitive cancers. Data is likely skewed by the number of persons on testosterone who undergo masculinizing chest reconstructive surgery, which removes the majority of breast tissue, and those who undergo hysterectomy and bilateral oophorectomy prior to the ages at which cancers in these organs typically present.²

Transgender individuals on estrogen have an increased risk of estrogen-sensitive cancers and should start screening in adulthood as per cisgender female guidelines.⁵¹ They are also believed to have a decreased risk of prostate cancer due to the protective effects of estrogen.⁷⁵

Transgender individuals with cervices still need routine cervical cancer screening. However, many face barriers, including dysphoria associated with pelvic exams and increased rates of inconclusive results due to cervical atrophy, which occurs on testosterone.^73,77 Transgender individuals who undergo penile inversion vaginoplasty currently do not have guidance regarding routine cancer screening for the genital tissues.⁷⁸ Some clinicians recommend annual inspections of the vaginal cavity to assess caliber and depth. This can also serve to visualize any skin lesions. However, as patients do not have cervices, pap smears are currently not indicated. All patients are strongly encouraged to follow current guidelines regarding universal HPV vaccination to minimize their chance of HPV-related disease.⁷⁹

Contraception

Some TGD adolescents with ovaries and uteri will engage in penile–-vaginal sex with sperm-producing partners. While testosterone can cause amenorrhea in most patients, it is not an approved form of contraception.^28,80 TGD adolescents on testosterone who are at risk for pregnancy should be counseled on using a concomitant contraceptive. For TGD adolescents who produce sperm and engage in penile-–vaginal sex with partners who have the capacity to achieve pregnancy, they should also be informed that estrogen is not an approved form of contraception.^28,80 All contraceptive options are available for patients on testosterone. No research exists on how testosterone interacts with different forms of hormonal contraceptives. Typical side effect profiles may differ in people on testosterone (e.g., risk of breakthrough bleeding, acne, or contraceptive efficacy).^28,80 Existing data does not identify an increased risk of venous thromboembolism (VTE) on testosterone.⁵⁵ As such, transgender individuals seeking estrogen-containing contraceptives should be counseled on the increased risk of venous thromboembolism (VTE) as per standard guidelines. TGD adolescents may have different or additional goals regarding contraceptive choice beyond what their cisgender peers might typically discuss, such as the need for concealment or desiring to avoid a pelvic exam.^28,80 However, every patient is unique, and goals should not be assumed.

Vaginal bleeding on testosterone

While most (85–100%) of individuals will achieve amenorrhea on testosterone, some will have breakthrough bleeding.^46,81,82 This includes individuals who are on testosterone alone and those who are on testosterone and concomitant menstrual suppression.⁴⁶ The only individuals who have so far not been shown to have breakthrough bleeding are those on pubertal suppression and testosterone.

Present recommendations for evaluating breakthrough bleeding include the full age-appropriate differential that a cisgender female experiencing breakthrough bleeding would have.⁴⁶ In adolescents, this includes medication-related causes such as missed, late or low dosing, thyroid and bleeding disorder concerns, and masses. Endometrial hyperplasia and malignancy are far rarer in this age range in the general population, and as such endometrial sampling is not typically used. Testosterone has not been found to increase rates of endometrial hyperplasia in adolescents, and as such endometrial sampling, unless there are other indications for this concern, is not recommended.^52,72 As testosterone is not an approved contraceptive, in patients who are engaging in penile–-vaginal sex with sperm-producing partners, pregnancy should be evaluated as well.²⁸

A focused history should be taken. This should include evaluating for risk of vaginitis, sexually transmitted infections, or other genitourinary symptoms, which may point to a source of the bleeding being non-breakthrough bleeding such as infectious or vaginal atrophy. The history should ascertain any changes in medications, which can impact uterine bleeding profiles, including changes in testosterone dosing, addition or cessationceszationcessation of a concomitant menstrual or pubertal suppression medication. When breakthrough bleeding is the likely cause of bleeding, an exam may not be needed at the first evaluation, though it can be offered. For those where infections, vulvovaginal atrophy (common on testosterone), or other age-appropriate urogenital sources of bleeding are of concern, exams should be offered to evaluate for these causes. Transabdominal ultrasounds can be non-invasive screening tools to evaluate the uterus in patients where masses or lesions are concerns. When testosterone dosing is a concern, testosterone levels can be helpful to ascertain if they are in the cis male range or have room to increase. Patients whose bleeding or pain is thought to be due to vulvovaginal atrophy can be treated as per standard protocols, including vaginal moisturizers and lubricants and local estrogen.^83,84

When breakthrough bleeding is thought to be due to missed, late, or low dosing, patients should be supported in improving their dosing compliance with testosterone. Longer-acting forms may be more beneficial for these patients. Increasing testosterone dosing in those where possible can also improve amenorrhea. Guidelines recommend allowing up to 1one year for amenorrhea (or 6–12 months of testosterone levels in the male range (320–1000 ng/dl)).³¹ In patients on a concomitant menstrual suppression agent already, they may benefit from discontinuing it if testosterone levels are in cisgender male ranges to see if testosterone alone maintains amenorrhea or if they are trying an alternative medication. Those on testosterone alone with cisgender male ranges can try an additional menstrual suppression agent. All menstrual suppression agents are acceptable for use with testosterone, including pubertal suppression. Data has not shown superiority with any given agent except for GnRHa. Endometrial ablation is currently not recommended for the management of breakthrough bleeding in adolescents, as it has not been studied in persons on testosterone, does not have good long-term amenorrhea profiles, and limits future use of the endometrium, which is of concern in adolescents. Some patients will desire a hysterectomy to manage gender dysphoria and breakthrough bleeding, which can be offered to those who do not desire to carry a future pregnancy, depending on age-related guidelines.⁶⁹

Sexually transmitted infections

Any teen engaging in sexual activity is at risk for sexually transmitted infections. Transgender adolescents are more likely to engage in high-risk sexual behaviors. They may be less likely to undergo infection screening due to genital dysphoria and negative experiences in medical spaces.^77,78,85,86 When discussing infection risk, it is best to take a behavior and anatomy-based approach rather than assuming sexual activities based on gender identity and sexual orientation.⁸⁷ Teenagers should be routinely asked about sexual activity and which body parts they and their partners use to engage in sex. Clinicians should clarify if the anatomy is native or neo (e.g., native vagina vs. neovagina) as the risk factors may differ depending on the types of tissue and anatomy present. For example, someone who has undergone a penile inversion vaginoplasty likely has more resistance to gonorrhea and chlamydia in their neovagina due to the keratinized skin. Current recommendations are to do urethral rather than vaginal screening in these patients. All patients up to age 45 should be offered the HPV vaccination to minimize their risk of acquiring HPV-related disease and transmitting it to their partners.⁷⁹

Surgeries

Gender- affirming surgeries are a diverse and heterogeneous group of procedures that allow TGD individuals to align their bodies with their gender in ways that social and medical affirmation cannot. In that vein, any procedure can be a gender-affirming procedure if it helps a patient achieve their gender goals; however certain surgeries focused on sex traits are those typically considered gender-affirming surgeries, some of which will be reviewed herein. Studies currently show high rates of satisfaction with gender-affirming surgeries.⁸⁸ The WPATH SOC 7 recommends that most surgeries wait until the age of majority, though it recognizes care should be individualized and not follow strict age limits.^89,90,91 Chest surgery is the most common gender-affirming procedure in adolescents. Preliminary data has shown that this surgery has good outcomes in adolescents.⁸⁸ Although most gender-affirming surgeries are deferred until the age of majority, a growing number are being performed in young adulthood, and counseling and preparation may occur in adolescence.⁸⁸ There may be requirements (e.g., from the WPATH SOC, from an individuals' insurance, or local legislation) individuals must meet for specific surgeries (e.g., a diagnosis of gender dysphoria, the acquisition of letters from mental health clinicians supporting the surgery, or a duration of time on hormones prior to surgery).³² TGD adolescents may bring up surgeries as part of their gender goals. Clinicians who care for adolescents should understand some of the nuances regarding surgeries and adolescence that may differ from those who seek these procedures later in life.⁶⁹ This chapter will briefly review select gender-affirming surgeries and the preoperative and counseling considerations related to adolescence.

Gender- affirming surgeries are often broken down into masculinizing and feminizing surgery, similar to hormone therapy. Masculinizing procedures include the following:

• Masculinizing chest surgery: tThis is the removal of chest tissue to create a more masculine chest contour. Incisions, including periareolar or inframammary, are dependent upon starting chest size, contour, and location of the nipple-areola complex.^92,93,94 They may also include free nipple grafts. This surgery does not typically remove all glandular tissue as with a double mastectomy.³¹ Patients should be counseled that tissue that remains should still be surveilled later on in life for risk of breast cancer.
• Hysterectomy: tThis removes the uterus and cervix for gender affirmation in patients who do not desire future pregnancy. It may also be done as a prerequisite to a phalloplasty or metoidioplasty. Typically gender-affirming hysterectomies are performed in a minimally invasive approach, including laparoscopic or vaginal.⁹⁵ It does not require removal of the ovaries (including those done as a prerequisite for metoidioplasty or phalloplasty) unless desired by the patient.⁶⁹ Patients should be counseled on the age-appropriate risks and benefits of removing the ovaries. Younger patients have more years following a hysterectomy where ovaries may be used, and as such, the counseling should include a discussion of this. This includes discussing that removal of the ovaries requires the patient to continue taking exogenous sex steroids (e.g., testosterone) during their reproductive years, as discontinuing exogenous hormones would render them hypogonadal after oophorectomy.⁷⁰ Patients should be counseled that loss of exogenous hormones can arise due to access issues (e.g., cost, insurance, geography) or personal choice. Patients should consider these when they consider oophorectomy at the time of hysterectomy.⁷⁰ Younger patients may also desire to use their oocytes in the future in a gestational carrier.⁵⁸ Reasons younger patients desire to remove their ovaries include specific dysphoria regarding their ovaries or a personal history of ovarian pathology for which they would have undergone an oophorectomy for another reason. Personal and family histories of ovarian or breast cancer may also impact a patients' consideration. Regardless of the decision regarding oophorectomy, risk-reducing bilateral salpingectomies should be performed.⁹⁶
• Metiodioplasty: tThis is the creation of a small phallus using the hormonally enlarged clitoral tissue following gender-affirming testosterone use.⁶⁹ Typically performed alongside vaginectomy (which requires a prior hysterectomy) and urethral lengthening along the ventral aspect of the neophallus to allow the patient to stand to void. Patients may also undergo scrotal implants in the labial folds to create a contour similar to the natal scrotum.
• Phalloplasty: uUtilizing the foundation of the metoidioplasty, the phalloplasty elongates the neophallus using a skin flap, which can arise from locations such as the thigh, buttocks, stomach, or forearm.⁶⁹ It also typically extends the urethra to the tip of the neophallus. Patients may also undergo scrotal implants. The phallus does not self-erect, but internal and external erectile devices may be used.

Feminizing procedures include the following:

• Facial feminization: aA term used for the various procedures used to soften the bony and soft tissue contours of the face, head, and neck.⁹⁷ This includes reshaping the hairline, brow ridge, jaw, chin, rhinoplasty, and others. It also includes chondrolaryngoplasty or tracheal shave to reduce the prominence of Adam's apple.
• Vocal feminizing surgery: bBehavioral voice therapy is the first-line voice feminization intervention.⁹⁷ However, some patients will also pursue laryngoplasty to alter the pitch of their voice, which is also termed vocal feminizing surgery.
• Breast augmentation: sSimilar to these procedures in cisgender women, breast augmentation utilizes silicone or saline implants to enhance shape and size.⁶⁹ Placement of implants is commonly under the muscle or the breast parenchyma. In TGD patients, anatomic differences in chest width and nipple position are considered.
• Bilateral orchiectomy: mMay be done in isolation or combination with a vaginoplasty (see below).⁹⁸ There are several reasons patients may seek this surgery in isolation. Due to the typical need for anti-androgens in addition to estrogens to suppress endogenous testosterone, some TGD patients will undergo orchiectomy to remove the need for anti-androgens. Others may have a bilateral orchiectomy as a "first step" towards vaginoplasty. However, there is no surgical benefit to this. Finally, others may have scrotal contour dysphoria and may only desire an orchiectomy but not additional genital surgeries to alleviate dysphoria.
• Vaginoplasty: tThis procedure includes the deconstruction of the external genitalia, bilateral orchiectomy, creation of a clitoris (using the neurovascular bundle and glans penis), shortened urethra, labia (using scrotal skin), and functional vagina in Denonvilliers' fascia, typically using the penoscrotal skin but can also use other graft sources including peritoneal, buccal, and intestinal.⁶⁹
• Vulvoplasty or "zero-depth" vaginoplasty": tThis has the same approach as vaginoplasty except without creating a vaginal canal.⁶⁹ Patients who seek this do not desire future penetrative intercourse but still desire the external genital contour changes. This surgery is more common in older patients than in younger patients.

Finally, there are body contouring procedures in addition to masculinizing and feminizing surgeries. These are surgical procedures to alter the body's fat distribution or bony structures to align with a person's gender identity.⁶⁹ They may be masculinizing or feminizing depending on the individual and their goals.

Gender- affirming surgeries in adolescence

Surgeries are permanent procedures. They should not occur until a patient can fully participate in the decision-making and understand the risks, benefits, alternatives, and any lifelong care (such as the need for dilation following penile inversion vaginoplasty) which may be required. Adolescents mature at different rates, so different individuals may be ready to engage in these conversations and undergo procedures at different ages.⁶⁹ An individualized approach should be taken in assessing adolescent readiness, just as done for other surgeries. In any presurgical counseling, the most important part is understanding why a patient is interested in a given surgery and their desired timeline.⁶⁹ In adolescence, it is even more important to have these conversations privately with patients to disentangle parental goals and timelines from those of the patient.

Some adolescents may also seek other gender-affirming surgeries prior to the age of majority for other reasons. Some may seek procedures due to safety or socialization. For example, facial feminization can be uniquely helpful in aiding patients to present their gender in a way closer to social alignment, which improves safety. Transgender women, particularly transgender women of color, are at high risk of assault and violence. Some may stem from the inability to safely move through life due to natal sex traits that hormone therapy cannot undo, such as bony facial contour.^99,100,101 Safety is relative to the individual and their situation. As such, certain surgeries may render someone more safe at a specific point in time. Particularly time points specific to adolescents, such as those who may be going off to live in dorms or away from families for the first time, may seek genital surgeries not only for embodiment but for social safety in these new situations.⁶⁹ Aging out of insurance may be another reason for adolescents' timing of surgery, as not all insurances cover these surgeries.¹⁰² Adolescents will also have different support structures than older patients. These supports may be more or less stable, and as such, the timing of surgery may center around when adolescents feel they have more guaranteed support or are away from family structures where they feel unsafe.

Most clinicians try to avoid sterilizing procedures prior to the age of majority due to issues related to assent and sterilization and a history of having forced sterilization of many marginalized populations, including transgender individuals.^103,104 However, these surgeries may be done shortly after their transition to adulthood for reasons such as safety, insurance issues, and support. Family building counseling should be addressed prior to those surgeries that will alter a patient's future fertility, including hysterectomy, metoidioplasty, phalloplasty, orchiectomy, or vaginoplasty.

For TGD adolescents, pubertal suppression may also alter the need or timing of certain gender-affirming surgeries. Pubertal suppression may minimize the need for facial feminization or masculinizing chest surgery as the pubertal changes that often produce these would not occur to as great of an extent. Pubertal suppression will also limit the development of genital tissues, which are influenced by hormones. For patients seeking penile inversion vaginoplasty, patients may need additional grafting if they do not have as much penoscrotal skin. However, this is not true for all patients on pubertal suppression seeking this procedure, and other graft sources such as buccal are available. Patients should not have pubertal suppression withheld out of concern for lack of penoscrotal tissue for a potential future surgery due to the data supporting their use in positive outcomes.^44,105

Certain surgeries may have recommended hormone therapy prerequisites, however only some for physiologic reasons. For example, it is recommended to use 1–2 years of hormone therapy before breast augmentation due to the changes in breast contour, which can occur on estrogen, which can impact implant placement. It also recommends hormone therapy before hysterectomy. However, there are no physiologic benefits of having testosterone prior to hysterectomy.

CONCLUSION

Transgender health is a growing field in medicine. Clinicians who provide care to transgender adolescents are from diverse specialties. Similarly, TGD adolescents have diverse paths regarding gender- affirming goals, including legal, social, medical, and surgical affirmation. Regardless of a patient's desire for transition-specific care, all patients deserve welcoming and inclusive care that respects their identity. Providing gender-inclusive care for all patients will reduce barriers that TGD adolescents face and improve their health outcomes.

PRACTICE RECOMMENDATIONS