Medical Interventions for Transgender Youth

Natalie J. Nokoff

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Medical Interventions for Transgender Youth

Natalie J. Nokoff, MD, MSCS.

Author Information and Affiliations

Last Update: January 19, 2022.

ABSTRACT

Up to 1.8% of youth and 0.6% of adults in the United States identify as transgender, meaning their gender identity differs from or is opposite their sex designated at birth. This chapter provides an overview including epidemiology and gender development. Then, it aims to summarize medical interventions for transgender youth as outlined in the Endocrine Society Clinical Practice Guidelines and World Professional Association for Transgender Health standards of care. The chapter concludes with research on mental health in this population and future directions. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Throughout history and across cultures there have been people who live with, what we would now term, gender incongruence (definitions in Table 1). Prior to identification of sex steroids in the 1930s (1-5), and the development of exogenous sex steroids and surgical techniques, there were no options to change one’s secondary sex characteristics. The first modern orchiectomy for gender reassignment was performed in 1930 (6), and the first feminizing genital surgeries in the 1940s and 50s in Germany and Denmark, respectively (7,8). Harry Benjamin, known for his 1966 book, The Transsexual Phenomenon (9), treated Christine Jorgensen, the first widely published case of a transgender female in the United States (U.S.), treated with feminizing hormones and surgery. In 1979, the Harry Benjamin International Gender Dysphoria Association was formed, now the World Professional Association for Transgender Health (WPATH). The first standards of care were published in 1979, with the 7^th edition released in 2012, and the 8^th edition coming soon. The Endocrine Society first published a clinical practice guideline regarding the care of transgender persons, including support for pubertal suppression and gender affirming hormone therapy (GAHT) in 2009, with an updated guideline released in 2017 (10,11). In the over 40 years since the first edition of the WPATH Standards of Care, transgender rights, access to care, bathroom use, and sports participation, among other topics, are often featured and debated in mainstream media, politics, and healthcare (12). Furthermore, as care becomes increasingly politicized, numerous bills to both expand or limit the rights of transgender people and their access to medical care are being introduced in the U.S.(13). Medical care that respects the gender identity of the patient is recommended by numerous medical organizations, including the American Academy of Pediatrics (14), Endocrine Society (11), and the American Psychological Association (15).

Table 1.

Definitions

Agender	A person with very little or no connection to the traditional systems of gender; existing without gender
Cisgender	Gender identity aligns with biologic sex
Gender affirming hormone therapy	Hormones, including testosterone and /or estradiol, that are prescribed to eligible individuals to induce development of secondary sex characteristics that align with gender identity
Gender affirming surgery (sometimes referred to as gender-confirming or gender-reassignment surgery)	Surgery or surgeries to align one’s body with one’s gender identity
Gender diverse	Individuals with a variety of gender identities across the gender spectrum, including those who identify as transgender
Gender dysphoria	Distress experienced when gender identity and body are not congruent. Defined in the DSM-5, which replaced “gender identity disorder” in the DSM-IV
Gender expression	External manifestations of gender, expressed through name, pronouns, clothing, haircut, behavior, voice, or other characteristics
Gender identity/experienced gender	One’s internal, deeply held sense of gender; not visible to others
Gender incongruence	Umbrella term used when gender identity and/or expression differ from what is typically/societally associated with their sex designated at birth
Gender role	Behaviors, attitudes, and personality trait that a society (in a given culture and historical period) designates as masculine or feminine and/or that society associates with the typical social role of men or women
Non-binary	A person whose gender identity is neither male nor female, both male and female or some combination of genders
Sex designated at birth	Sex at birth, typically based on external appearance of genitalia
Sex	Attributes that characterize biologic maleness or femaleness; factors that influence sex include sex chromosomes, gonads, sex steroids, internal reproductive structures, external genitalia, secondary sex characteristics
Sexual orientation	Physical and emotional attraction to others. Gender identity and sexual orientation are not the same
Transgender	Gender identity differs from sex designated at birth
Transgender male (also transgender man, female-to-male)	Individuals designed female at birth who identify and live as men
Transgender female (also transgender woman, male-to-female)	Individuals designated male at birth who identify and live as women
Transition	Process during which persons change their physical, social, and/or legal characteristics consistent with their affirmed gender identity

: Adapted from Table 1 in the 2017 Endocrine Society Guidelines (11)

Centers around the world are seeing a rise in the number of transgender and gender diverse (TGD, Table 1) people seeking care to align their bodies with their identities (16). Despite the rise in the number of TGD people seeking care, there remains a lack of education and knowledge among providers as to how best serve this group (17). This article will define terminology, briefly review gender development, review current guidelines regarding medical treatment of pediatric TGD individuals, and mental health considerations.

EPIDEMIOLOGY

Recent population-based studies in the U.S. report that 1.8% of youth and 0.6% of adults identify as transgender (18,19). Gender diverse describes individuals with a variety of gender identities across the gender spectrum, including those who identify as transgender (Table 1). Gender dysphoria, which describes the distress associated with a conflict between gender identity and anatomy or sex, is a listed diagnosis in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5, Table 2) (20).

Table 2.

DSM-5 Criteria for Gender Dysphoria (20)

A marked incongruence between one’s experienced/expressed gender and natal gender of at least 6 months in duration, as manifested by at least two of the following:

A.: A marked incongruence between one’s experienced/expressed gender and primary and/or secondary sex characteristics (or in young adolescents, the anticipated secondary sex characteristics)
B.: A strong desire to be rid of one’s primary and/or secondary sex characteristics because of a marked incongruence with one’s experienced/expressed gender (or in young adolescents, a desire to prevent the development of the anticipated secondary sex characteristics)
C.: A strong desire for the primary and/or secondary sex characteristics of the other gender
D.: A strong desire to be of the other gender (or some alternative gender different from one’s designated gender)
E.: A strong desire to be treated as the other gender (or some alternative gender different from one’s designated gender)
F.: A strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one’s designated gender)

The condition is associated with clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify if:

A.: The condition exists with a disorder of sex development.
B.: The condition is post-transitional, in that the individual has transitioned to full-time living in the desired gender (with or without legalization of gender change) and has undergone (or is preparing to have) at least one sex-related medical procedure or treatment regimen—namely, regular sex hormone treatment or gender reassignment surgery confirming the desired gender (e.g., penectomy, vaginoplasty in natal males; mastectomy or phalloplasty in natal females).

One’s sex refers to the physical attributes that characterize biologic maleness or femaleness and is typically assigned or designated at birth based on the appearance of the external genitalia (or prior to birth based on sex chromosome complement and/or the appearance of the genitalia on the prenatal anatomy ultrasound).

Note that terminology in this field is constantly evolving, and for clinicians, it is important to ask individuals what terms they use to describe their gender identity, and what that term means to them. Table 3 includes suggestions on how to ask these questions.

Table 3.

Suggested Ways of Asking About Name and Gender Identity

Name	“Is there a name you go by other than your legal name?” “What name do you go by?” “What would you like me to call you?”
Pronouns	“What pronouns do you use?” “I’d like to use the pronouns that feel best to you. What pronouns would you like me to use?” Model pronoun use: “Hello, my name is Dr. ____ I use ___ pronouns.”
Gender identity	“How do you identify your gender?” “What does [gender identity term] mean to you?” Suggestion for children: “Some kids tell me think of themselves as girls, some as boys, some as part girl and boy, or something entirely different. How do you think about yourself?” Suggestion for adolescents: “There are lots of ways people think about their gender identity, how do you think of yours?”

GENDER IDENTITY DEVELOPMENT AND NATURAL HISTORY OF GENDER INCONGRUENCE

Gender identity is multidimensional with biological, cultural, and environmental contributions (21,22). Studies of gender identity among individuals with differences/disorders of sex development underscore the influence of the hormonal milieu, and prenatal androgen exposure in particular, in gender development (23-26). There are also genetic influences, as some studies show concordance rates of gender dysphoria up to 39% among identical twins (27). Although studies have sought to identify genes associated with transgender identity, results have largely been inconsistent or inconclusive, with a possible role for genes related to sex steroids and their receptors (28-32).

In childhood, learning about gender starts early, and progress through many stages (33). In their review of gender development in childhood, Perry, Pauletti, and Cooper describe eight dimensions of gender identity: (1) gender self-categorization, (2) felt same-gender typicality, (3) felt other-gender typicality, (4) gender contentedness, (5) felt pressure for gender differentiation, (6) intergroup bias, (7) gender centrality, and (8) gender frustration. By age 18-24 months most children can categorize their own and others’ gender (34), and by age 6, have a developed gender identity (35). More individuals with a female sex designated at birth express dissatisfaction with their gender (36,37). This reflects the current sex ratio of individuals being referred to gender clinics, with more individuals with a female sex designated at birth currently referred, but the opposite being true prior to the 2000s (38-40).

Despite adolescence being a period of identity formation (41,42), there is a surprising lack of research on adolescent gender identity development. Development of identity is an individual and social process and shaped by external surroundings (42). However, there are also numerous psychological and biological factors that influence gender identity, as outlined in a review by Steensma and colleagues (43).

Overall, there is still much to learn about gender development among gender variant or nonconforming individuals. Prospective studies of children referred to gender clinics, primarily in Europe, show that less than a quarter of children will remain or meet criteria for gender identity disorder (the DSM-IV diagnosis prior to the DSM-5 gender dysphoria) after adolescence (44-47). In follow-up studies, the period of early adolescence/puberty, age 10-13 is critically important. There are three possible factors that contribute to an increase or decrease in gender discomfort and cross-gender identification: (1) physical puberty, (2) changing environment and being treated as their sex assigned at birth, and (3) the discovery of sexuality (47). More recent studies that reflect the rise in referral rates, and in various places around the world, will be critically important.

MEDICAL MANAGEMENT

The WPATH Standards of Care (48) outline three categories of physical interventions for adolescents, indulging (1) fully reversible interventions, such as the use of gonadotropin releasing hormone (GnRH) agonists, medications to suppress menses (such as progestins), and medications to decrease the effects of androgens (such as spironolactone); (2) partially reversible interventions, including testosterone or estradiol; and (3) irreversible interventions, such as surgical procedures. Many individuals also seek care, including behavioral health consultation, for reversible interventions such as name, pronoun and gender marker change, discussing gender identity with friends, family and school, voice therapy, or wearables (including binders and packers to flatten the chest or give the appearance of male genitalia, respectively) (48).

It is important to note, as outlined in the WPATH Standards of Care (48), individuals who have gender variance or incongruence, but whom do not experience distress may not require clinical attention or intervention. Furthermore, there is an increasing recognition that interventions should align with one’s individuals gender goals and gender embodiment (49).

Pubertal Blockade

The onset of puberty (gonadarche) is characterized by breast budding in people designated female at birth and by testicular enlargement to 4mL or greater in people designated male at birth, characterized as Tanner or Sexual Maturity Rating stage 2 (50,51). The average age of pubertal onset is age 10-11 years in someone designated female at birth (range 8-13 years, can be younger in African Americans), and 11-12 years in individuals designated male at birth (range 9-14 years). For individuals designated male at birth, external virilization typically starts around a testicular volume of 10 mL (11), voice drop at ≥8-10mL (52), and spermarche at 11-12 mL (53). In individuals designated female at birth, breast developmental progresses from stage 2 to 5 (fully developed) within 4-5 years and menarche typically occurs about 2-2.5 years after breast budding (54). Pubic hair and/or axillary hair and/or body odor reflect the onset of adrenarche or adrenal androgen production, which, by themselves are not indicative of central puberty (50,51). Height velocity increases during puberty and peaks about 2.5 years after the start of pubertal growth acceleration (55). An understanding of typical pubertal development and timing of external secondary sex characteristics is useful in counseling families about the timeliness and risk/benefit of GnRH agonist therapy to halt further pubertal progression. For example, towards the end of puberty or in post-pubertal individuals, GnRH agonist therapy may be used in certain circumstances for sex steroid suppression but would not block any pubertal changes, as these are complete.

GnRH agonists were first used in youth for the treatment of central precocious puberty in the 1980s (56). In 1998, Drs. Cohen-Kettenis and van Goozen in the Netherlands published the first report of a transgender patient treated with triptorelin, a GnRH agonist (57). The “Dutch model” of using pubertal suppression followed by gender affirming hormones (testosterone or estradiol) subsequently became incorporated into the WPATH and Endocrine Society standards of care (10,48). Their use became more widespread in the U.S. after publication of the 2009 Endocrine Society guidelines (10). The 2017 Endocrine Society guidelines suggest that “adolescents who meet diagnostic criteria for gender dysphoria/gender incongruence, fulfill criteria for treatment, and are requesting treatment should initially undergo treatment to suppress pubertal development”(11). The guidelines suggest beginning pubertal hormone suppression after the onset of the physical changes of puberty (Tanner Stage or Sexual Maturity Rating 2) for individuals who meet criteria, including being diagnosed with gender dysphoria, experienced worsening dysphoria with the onset of puberty, existing psychological, medical and/or social problems are addressed and the adolescent has sufficient mental capacity to consent to treatment (11). Treatment with a GnRH agonists suppresses gonadotropins (after an initial increase of gonadotropins) (58). There are also gonadotropin releasing hormone antagonists that immediately suppress gonadotropins, but are not available in children. GnRH agonists are typically administered as either an injection (IM or SQ) or as an implant (preparations listed in Table 4). Insurance coverage for this off-label, and costly therapy, varies (59). GnRH agonist treatment will pause or halt pubertal changes and may cause slight regression of breast tissue or testicular volume (11). On their own, these are reversible interventions, and if the individual decided that they wanted to progress through their endogenous puberty, these medications can be discontinued. During GnRH agonist treatment, the Endocrine Society recommends measurement of height, weight, sitting height, blood pressure, and Tanner stages every 3-6 months, measurement of LH, FSH, estradiol or testosterone, and 25OH vitamin D every 6-12 months, and bone density using dual-energy X-ray absorptiometry (DXA) and bone age x-ray of the left hand every 1-2 years (11).

Table 4.

Hormonal Interventions for Transgender Adolescents

Pubertal blockade/inhibition of sex steroid secretion
GnRH agonist: inhibition of the hypothalamic-pituitary-gonadal access	Leuprolide acetate IM (1-, 3-, 4- or 6-mo preparations) or SQ (1-, 3-, 4- or 6-mo preparation) Triptorelin IM (4-, 12- or 24-week preparation) Histrelin acetate SQ implant (one-yearly dosing, although reports of longer effectiveness)
Medroxyprogesterone acetate: inhibition of the hypothalamic-pituitary-gonadal access and direct inhibition of gonadal steroidogenesis	Orally (up to 40 mg/day) or IM (150 mg every 3 mo, may be given more frequently for suppression of sex steroids)
Inhibition of testosterone secretion or action
Spironolactone: inhibition of testosterone synthesis and action	Titrate up to 10-300 mg/day orally (typically in divided doses)
Cyproterone acetate: inhibition of testosterone synthesis and action (not available in US)	25-50 mg/day orally
Finasteride: inhibition of type II 5 α-reductase, blocks conversion of testosterone to 5 α-dihydrotestosterone	2.5-5 mg/day orally
Bicalutamide: androgen receptor blockade	50 mg/day orally
Sex steroids
Estrogen/17β-estradiol	Oral/sublingual: start with lower doses for pubertal induction, titrate up to adult doses 2-6 mg/day Transdermal: start with lower doses for pubertal induction, titrate up to adult doses 0.025-0.2 mg/day (patches are typically once or twice weekly) Parenteral: estradiol valerate (5-30 mg every 2 weeks) or cypionate (2-10 mg IM every week)
Testosterone	Parenteral IM or SQ testosterone cyptionate or enanthate (start at 12.5 mg/week or 25 mg q2 week with gradual increases to 50-100 mg/week or 100-200 mg every 2 weeks) Transdermal (typically after full adult dose has been achieved parenterally): patch (2.5-7.5 mg/day or 1% or 1.6% gel

: Note that all medications are currently off-label for gender non-conforming/transgender youth. Note that certain GnRH preparations are approved in children for central precocious puberty and other formulations are approved for adults only, with off-label use in children. Different formulations are available in different countries. This table was adapted from the following references (11,178). Note that some centers/providers also use GnRH agonists for testosterone blockade in older adolescents and/or adults. GnRH: gonadotropin releasing hormone, IM: intramuscular, SQ: subcutaneous

Recent reviews of puberty blockade have been published (60-62). Small studies have demonstrated effectiveness of GnRH agonist treatment for suppression of the hypothalamic-pituitary-gonadal axis in transgender youth (63). Studies, primarily in Europe, have demonstrated improvements in psychological functioning, behavioral/emotional problems, and depressive symptoms during GnRH agonist treatment in transgender youth (64,65). A recent systemic review found that GnRH agonist therapy is associated with decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life (61).

Potential risks of GnRH agonist therapy include impacts on growth, bone health, body composition, fertility, and neurodevelopment, as well as difficulties accessing treatment due to cost and insurance coverage (61,62,66). GnRH agonist use in TGD youth is associated with increased body fat and decrease in lean mass after initiation (67,68), and compared to age- and BMI-matched control youth (69), and may also have an adverse effect on insulin sensitivity (69). If GnRH agonists are started prior to skeletal maturity, they will decrease skeletal advancement during monotherapy due to suppression of sex steroids, which are necessary for growth plate closure (70,71). There is a dearth of research on growth trajectories during treatment with a GnRH agonist in this population. One multicenter study in the U.S. showed that transgender youth treated with GnRH therapy have growth velocity similar to prepubertal children, but those who start GnRH agonist treatment later in puberty have growth velocity below the prepubertal range (72). The growth spurt and skeletal advancement will progress either when exogenous testosterone or estradiol are started, or if the GnRH agonists are discontinued and the individual progresses through their endogenous puberty. There is a growing body of research of bone health in transgender individuals, as well as the impact of GnRH agonists and later gender affirming hormones on bone health. Studies in the Netherlands have demonstrated decreased bone turnover, and a decrease in bone mineral apparent density Z-scores of the lumbar spine in transwomen after initiation of GnRH agonist therapy (73). However, studies in the U.S. (74), United Kingdom (75) and Netherlands (73,76) have also shown decreased bone mineral density Z-scores determined by DXA are low prior to treatment with GnRH agonist, and some studies showing Z-scores did not completely normalize with sex hormone treatment (73,76). In the U.S., the individuals with lower baseline bone mineral density Z-scores also reported less physical activity, an area warrants further research (74).

Overall, there is a paucity of research on neurodevelopment and a recent consensus parameter was published with recommended research methodologies to evaluate the neurodevelopmental effects of puberty suppression in this population (77). There is also very little research on sexual function and future surgical options among individuals who received early puberty blockade. Recently, there has been a call for more information to better inform the impacts on future sexual function(78,79) (as GnRH agonists limit penile and testicular growth/size (80)) and on implications for future surgical intervention for those individuals pursuing vaginoplasty (as the scrotal tissue is used to construct the vagina) (80). Finally, treatment with GnRH agonists will impair spermatogenesis and oocyte maturation temporarily, and the Endocrine Society recommends fertility counseling (11). Treatment may be delayed to preserve fertility, but many individuals do not choose this, as delay will also cause further progression of unwanted secondary sex characteristics (11). There are limited options available for early tissue cryopreservation, an area that is gaining more attention (81).

If GnRH analogues are not available or are cost prohibitive, medroxyprogesterone may be used as an alternative agent for pubertal suppression (Table 4) (11,48). At high doses, medroxyprogesterone inhibits the pituitary-gonadal axis and suppresses testosterone (82-84). Medroxyprogesterone was used for treatment of precocious puberty in the 1960s and 70s (85-87). It is typically safe, although may have some side effects, including due to the estrogenic effects (bloating, nausea/vomiting, breast fullness, breakthrough bleeding for those menstruating, irritability, headache, hypertension), progestational effects (headache, breast pain/tenderness, hypertension), and androgenic effects (acne, oily skin, weight gain, hirsutism, fatigue, depression) (88). At extremely high doses (100 mg four times a day), it may cause Cushing’s syndrome, adrenal insufficiency, and diabetes (89). There is one small study of medroxyprogesterone in transgender youth demonstrating effective sex steroid suppression with doses of oral medroxyprogesterone 10-30 mg BID or 150 mg IM every 2-3 months (90).

Gender Affirming Hormone Therapy

Gender affirming hormone therapy (GAHT) refer to hormones that induce secondary sex characteristics to align the body with one’s gender identity. The Endocrine Society recommends treatment with sex steroids (testosterone or estradiol) “using a gradually increasing dose schedule after a multidisciplinary team of medical and mental health professionals has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent, which most adolescents have by age 16 years” (full criteria in guidelines) (11). However, they also state that “there may be compelling reasons to initiate sex hormone treatment prior to age 16 years in some adolescents” (11). The WPATH Standards of Care, 8^th version are forthcoming, but in the current 7^th version, the criteria for hormone therapy are: “(1) persistent, well-documented gender dysphoria; (2) capacity to make a fully informed decision and to consent for treatment; (3) age of majority in a given country; (4) if significant medical or mental concerns are present, they must be reasonably well-controlled” (48). It is recommended, that for adolescents who have not reached the age of majority in their country, that consent from all parents or medical decision-makers is obtained prior to starting this partially irreversible therapy.

Feminizing Hormone Therapy

ESTRADIOL THERAPY

For eligible adolescents, the Endocrine Society recommends a gradually increasing dose schedule of oral or transdermal 17β-estradiol (11). This will cause feminization of the body, with expected effects including body fat redistribution, decreased muscle mass/strength, softening of the skin/decreased oiliness, decreased libido/erections, breast growth, decreased testicular volume, decreased sperm production, and thinning and slowed growth of body and facial hair occurring one to several months after treatment with maximum effects generally about 2-3 years or more into treatment (11,48). For younger individuals, the Endocrine Society recommends starting oral estradiol at a dose of 5 µg/kg/day and increasing doses every 6 months up to a dose of 2-6 mg/day for an adult (11). In post-pubertal individuals, the starting dose may be higher and titrated more quickly (start at 1 mg/day for 6 months and increase to 2 mg/day orally) (11). For transdermal estradiol, it is recommended to start at a dose of 6.25-12.5 µg/24 hours and increase the dose every 6 months to an adult dose of 50-200 µg/24 hours. During induction of puberty, it is recommended to measure height, weight, sitting height, blood pressure, and Tanner stages every 3-6 months, and measure prolactin, estradiol and 25OH vitamin D every 6-12 months (11). Additionally, DXA and bone age (if clinically indicated or a growing patient) is recommended every 1-2 years (11).

Potential Adverse Effects of Estradiol Therapy

Risks with estradiol therapy as outlined in the Endocrine Society guidelines include thromboembolic disease, macroprolactinoma, breast cancer, coronary artery disease, cerebrovascular disease, cholelithiasis, and hypertriglyceridemia (11).

In adults, studies using three large cohorts have shown an increased risk of myocardial infarction and venous thromboembolism. In Europe, transgender women on estradiol therapy have a higher risk of stroke and venous thromboembolism than both cisgender reference women and men, and a higher risk of myocardial infarction than cisgender women (but not men) (91). In the U.S., two large cohorts have been used to examine outcomes, the Kaiser STRONG cohort and self-report data from the Behavioral Risk Factor Surveillance System (BRFSS). Data on hormone treatment is not collected in BRFSS. Transgender women in BRFSS were more likely (>2-fold increase risk) to have a history of myocardial infarction than cisgender women (but not men) (92,93). In the Kaiser STRONG cohort (94), both prevalent and incident type 2 diabetes was more common in the transfeminine cohort compared to cisgender females (95). In a meta-analysis commissioned by the Endocrine Society to accompany the 2017 updated guidelines, transgender women on estradiol therapy had increased triglycerides, but no changes in other lipid parameters (96). There were few reports of myocardial infarction, stroke, venous thromboembolism or death (96). It is well-known that transgender women on estradiol therapy have increases in body weight and fat and decreases in lean body mass (97). Estradiol therapy is associated with increases in lumbar spine bone mineral density compared to baseline (98).

In youth, there is a growing body of literature on the effects of GAHT, particularly on cardiometabolic health. TGD youth on estradiol have changes in HDL, aspartate aminotransferase, potassium, prolactin, and hemoglobin after about two years (99). One study found that transgender females on estradiol therapy were more insulin resistant than matched cisgender males (100). The presence of obesity attenuates the beneficial effect of estradiol on HDL (101). There are also studies investigating baseline differences between TGD youth and cisgender controls prior to hormone therapy, with recent studies showing TGD youth have lower HDL and low bone mineral density (72,102).

Testosterone Blockade/Suppression

There are many options for blockade and/or suppression of testosterone (all off-label use, Table 4). When available and affordable, some centers utilize GnRH agonists for suppression of testosterone. For example, in the United Kingdom, GnRH analogues are heavily subsidized (103). There are also many antiandrogens available, and a systemic review of options has recently been published (104). Spironolactone is widely available, inexpensive, and commonly used in the U.S. and Australia. Spironolactone is a weak androgen receptor antagonist (105,106), weak progesterone receptor agonist, and weak estrogen receptor agonist (104). It also partially inhibits 17α-hydroxylase/17,20 lyase, which are involved in testosterone synthesis (107). Even at high doses, spironolactone does not cause a significant reduction in serum total testosterone concentration (108). Although the combination of spironolactone with estradiol does appear to suppress testosterone in transgender women (109). Side effects include irregular menses (only for people who are menstruating, not a consideration for transgender women), hypotension, polyuria, and hyperkalemia (110,111).

Cyproterone acetate is available in Europe and Australia, but not in the U.S. and is a moderate androgen receptor antagonist, strong progesterone receptor agonist, and does not have any estrogen receptor activity but does suppress the hypothalamic pituitary gonadal axis (104). Cyproterone acetate has been associated with increased risk of meningiomas (112) and prolactinomas (113). Other side effects include weight gain, headache, gastrointestinal disorders, mood effects, and edema (114).

Nonsteroidal antiandrogens, such as bicalutamide have also been used at some centers. Bicalutamide has strong androgen receptor antagonist activity and does not have any estrogen or progesterone agonist activity (104). It does not cause a reduction in testosterone concentrations. There is some feminization, thought to be due to increased aromatization of testosterone to estradiol (115). There is currently one published study of the use of bicalutamide in transgender adolescents as an alternative to GnRH agonists (115). In that study, hepatic enzymes remained normal and there were no adverse effects, however, effectiveness and the potential risk of liver toxicity needs to be examined in larger studies.

Finally, 5-alpha reductase inhibitors, such as finasteride, block conversion of testosterone to dihydrotestosterone. These are not recommended by the Endocrine Society due to adverse effects (11), but the WPATH guidelines state, “these medications have beneficial effects on scalp hair loss, body hair growth, sebaceous glands, and skin consistency” (48). Side effects include sexual dysfunction and decreased muscle (which may be perceived as a risk or benefit in this population), anhedonia, and trouble concentrating (116).

Overall, the selection of which agent alone or in combination with estradiol depends on many factors including patient age, country, insurance coverage, cost, goals of care, and tolerability of side effects (e.g. severe and fatal hepatotoxicity has been reported with cyproterone acetate and bicalutamide (117)). Further studies are needed to determine superiority for relevant patient outcomes including body composition, breast development, facial and body hair (104).

Masculinizing Hormone Therapy

TESTOSTERONE

For eligible adolescents, the Endocrine Society recommends a gradually increasing dose schedule of testosterone (typically injectable IM or SQ) (11). This will cause masculinization of the body, with expected effects including skin oiliness/acne, facial/body hair growth, scalp hair loss, increased muscle mass/strength, body fat redistribution, cessation of menses, clitoral enlargement, vaginal atrophy, and deepened voice with onset occurring one to several months after treatment with maximum effects generally about 2-5 years or more into treatment (11,48). For younger individuals, the Endocrine Society recommends starting injectable testosterone esters at a dose of 25 mg/m² IM or SQ every 2 weeks and increasing every 6 months up to an adult dose of 100-200 mg every 2 weeks (11). In post-pubertal individuals, the starting dose may be higher and titrated more quickly (start at 75 mg every 2 weeks for 6 months and increase to 125 mg every 2 weeks) (11). Subcutaneous testosterone is gaining in popularity, and has shown to be effective and preferred by patients (118-120). Pharmacokinetic studies of weekly subcutaneous testosterone injections show that steady state is approached after the third dose, and that serum concentrations stay relatively constant throughout the week between doses (121). Finally, SQ testosterone doses may be lower than those delivered IM, with two studies reporting doses of 50-80 mg/week to achieve target testosterone concentrations in adults or older adolescents (118,119). During induction of puberty, it is recommended to measure height, weight, sitting height, blood pressure, and Tanner stages every 3-6 months, and measure hemoglobin/hematocrit, lipids, testosterone, and 25OH vitamin D every 6-12 months (11). Additionally, DXA and bone age (if clinically indicated or a growing patient) is recommended every 1-2 years (11).

The most common adverse effect of testosterone is erythrocytosis/polycythemia (hematocrit >50%) (11). Other risks as outlined in the Endocrine Society guidelines include liver dysfunction, coronary artery disease, cerebrovascular disease, hypertension, and breast or uterine cancer (11).

In adults, studies using three large cohorts have shown conflicting results. In Europe, transgender men on testosterone therapy have a higher risk of myocardial infarction than cisgender women (but not men) and no increased risk of stroke or venous thromboembolism compared to reference populations (91). Transgender men in the 2015 U.S. BRFSS survey had no increased risk of hypertension, myocardial infarction, stroke, angina/coronary heart disease compared to cisgender men or women (92). However, another analysis of BRFSS data (years 2014-2017) reported a >2-fold increase risk of myocardial infarction compared to cisgender women and 4-fold increase compared to cisgender women (93). In the Kaiser STRONG cohort, there was no increased risk of type 2 diabetes among transgender men compared to cisgender men (95). In a meta-analysis, testosterone therapy in transgender men was associated with increases in serum triglycerides and low-density lipoprotein cholesterol (LDL-C) concentrations and decreases in high-density lipoprotein cholesterol (HDL) (96). Testosterone therapy in transgender men is known to result in increased body weight and lean mass and decreased body fat (97). In meta-analyses, testosterone therapy is not associated with significant changes in bone mineral density (98,122). There is a recent position statement from the International Society for Clinical Densitometry on bone densitometry in TGD individuals (123).

Among TGD youth starting testosterone therapy, there is an increase in BMI and decrease in HDL (124). The decrease in HDL is exacerbated by obesity (101). Other studies have found that testosterone treatment in TGD youth is associated with statistical, but not clinically significant increases in triglycerides, alanine aminotransferase, potassium, and hemoglobin (99).

Non-Binary Care

Non-binary or gender non-conforming individuals represent a growing proportion of patients presenting to gender clinics and may have additional challenges accessing healthcare (125). Limited studies have reported worse mental and physical health among individuals who identify as gender non-conforming compared to matched controls (92). An individualized approach to understand the individual’s gender identity, sources of dysphoria (if any), and gender goals are important. Some individuals may desire reversible interventions such as menstrual suppression, others may request certain hormones and/or surgical interventions as a part of their gender goals. The 8^th version of the WPATH standards of care will include a chapter on non-binary care.

Menstrual Management

Many transmasculine and non-binary individuals who are designated female at birth seek medical attention or desire interventions for menstrual management (126). Some also utilize these methods for contraception. It is important to ask individuals about their individual goals, as well as their sexual orientation, partners (including sex assigned at birth and what body parts they currently have), and types of sex they are engaging in. These factors can guide choice of intervention for menstrual management and/or contraception. An overview of options is in Table 5. Progestin-only methods, including norethindrone or depo medroxyprogesterone are particularly popular choices among this population (126). Review of options for menstrual management and contraceptive options for transgender individuals was recently published (127). For those patients wishing to and eligible for testosterone therapy, menses suppression typically is achieved within 6-12 months of the start of testosterone therapy (128).

Table 5.

Options for Menstrual Suppression/Management

Combined hormonal contraceptives (pills, patch, ring)
Progestins
Norethindrone acetate (5-15 mg/day orally)
Medroxyprogesterone acetate (150 mg IM every 3 months)
Etonogestrel implant
Levonorgestrel IUD

: IUD: intrauterine device

SURGICAL MANAGEMENT

Surgeries that impact fertility are generally not available until the individual has reached the age of majority in their country. There are a wide variety of surgical options for transgender adults (and some options, primarily chest surgery, for adolescents), and this has recently been reviewed (129). Physicians (including surgeons and non-surgeons) and behavioral health providers should be aware of the criteria needed for each surgical procedure, including whether social transition is recommended, whether hormonal therapy is needed (and length), and how many referral letters are needed and by whom (48,130). In general, a documentation of persistent gender dysphoria by a qualified mental health provider is a requirement for surgery (48). Additionally, guidelines may change over time (the 8^th version of the WPATH standards of care are coming soon) and may vary by location (country/state) and insurance coverage. Table 6 summarizes the various gender affirming surgical options. Genital surgery or removal of the gonads is generally not performed until the individual is the age of majority in a given country (age 18 years or older in the U.S.). Individuals younger than 18 may be eligible for chest/breast surgery, with consent from medical decision-makers. The WPATH Standards of Care state for mastectomy/chest masculinizing surgery or for breast augmentation surgery, the individual must have “(1) persistent, well-documented gender dysphoria, (2) capacity to make s fully informed decision and to consent for treatment, (3) age of majority in a given country, (4) if significant medical or mental health concerns are present, they must be reasonably well controlled.” Although masculinizing hormone therapy (testosterone) is not a prerequisite for chest masculinizing surgery in the WPATH guidelines, it is recommended (although not an explicit criterion) that individuals on feminizing hormone therapy be on for a minimum of 12 months prior to breast augmentation surgery for better aesthetic results (48). However, the Endocrine Society Guidelines recommend 2 years of testosterone therapy prior to mastectomy/chest masculinizing surgery. Neither the WPATH or Endocrine Society guidelines recommend a specific age cutoff, but “suggest that clinicians determine the timing of breast surgery for transgender males based upon the physical and mental health status of the individual” (11).

Table 6.

Gender Affirming Surgical Options

Feminizing surgeries
Breast augmentation	Increasing the size of the breasts
Facial feminization surgery	May include: forehead feminization, rhinoplasty, periorbital rejuvenation, rhytidectomy (face lift), cheek augmentation, rhinoplasty, lip feminization, gonial angle shave, genioplasty
Genital surgery/vaginoplasty	May include penectomy, orchiectomy, surgical creation of a vagina (penile inversion, intestinal conduit), clitoroplasty, labiaplasty
Orchiectomy	Removal of testes
Tracheal shave	Thyroid cartilage shave
Masculinizing surgeries
Chest masculinizing surgery (mastectomy)	Removal of breast tissue
Facial masculinization surgery	Rhinoplasty, gonial implants, genioplasty
Hysterectomy, salpingectomy, oophorectomy	Removal of uterus and/or fallopian tubes, and/or ovaries
Metoidioplasty	Creation of a phallus using existing genital tissue
Phalloplasty	Construction of phallus, glansplasty, urethroplasty, erectile prosthesis, scrotoplasty, testicular implants

MENTAL HEALTH

Recently studies have demonstrated a strikingly high prevalence of behavioral health diagnoses among youth diagnosed with gender dysphoria (up to 60%) (131,132). Studies evaluating behavioral health outcomes among TGD youth have most frequently demonstrated disproportionate anxiety (132-134), depression (133-136), suicidality (19,132-134,137), self-harm (132-135), and substance use problems (19). Large surveys of TGD individuals in the U.S. have shown that 40% of adults (138) and 35% of youth (19) have attempted suicide. Poor behavioral health outcomes may be conceptualized as the result of complex and layered socio-cultural and political factors that impact TGD youth (15,139). Risk factors that are likely to impact overall mental health for TGD individuals include minority stress (e.g., victimization, discrimination) (19,140), gender dysphoria and appearance congruence (141), feelings of isolation, inadequate family support (142), emotional/social isolation (143), lack of autonomy over decision making (143), barriers to accessing gender affirming care (143-145), employment discrimination (143), and limited financial resources (143). In the Youth Risk Behavior Survey, TGD youth were two to six times more likely to be victimized, including experiencing sexual dating violence, experiencing physical dating violence, being bullied at school, being electronically bullied, feeling unsafe during travel to or from school, and being forced to have sexual intercourse (19).

The co-occurrence of autism spectrum disorders (ASD) and gender dysphoria is a growing area of interest (132,146-150). A recent meta-analysis found that the prevalence of ASD among those with GD has ranged from 6% to 68% depending on the methodology of the study (151). In a large 2020 study, TGD individuals were 3.0 to 6.4 times more likely to be diagnosed with ASD than their cisgender counterparts (136). Other samples have shown that youth with gender dysphoria are about 2-3x as likely to have a diagnosis of ASD than their matched cisgender counterparts (131,132). The exact link between GD and ASD is not known, but factors contributing may include: symptom overlap between the two diagnoses, misclassification due to symptom overlap, children with ASD may be more likely to express their gender identity and dysphoria, or they may be more likely to be referred to care to be diagnosed with either GD or ASD (152).

Protective factors including social support (153,154), parental support/affirmation of gender identity (155,156), higher self-esteem (153), resiliency (153,157), and access to affirming care (144,158,159) have improved well-being and decreased mental health distress. Access to gender-affirming interventions, including hormone therapy and surgery, has been shown to improve gender dysphoria, psychological symptoms and quality of life in small samples and meta-analyses (28). Recent studies have shown that those who were older at presentation have worse mental health than those who presented to care at a younger age (160) and those who had access to GnRH agonists had lower lifetime odds of suicidal ideation than those who did not have access (144).

Finally, there are many other important topics that impact the care of transgender individuals that are beyond the scope of this chapter including dermatologic considerations and hair loss (161-163), chest binding (164), sexual health (79), HIV prevention and treatment (165-167), fertility (81), sleep (168), athletic performance and sports participation (169), eating disorders (170,171), homelessness, the impact of family support, and the underpinnings of links between gender diversity and neurodiversity (172).

CONCLUSION

An improved understanding of the variety of individual gender trajectories is needed, as well as how best to individualize care, how to improve mental health, and minimize risks of medical intervention. Large, multi-center, prospective cohorts, as are currently established in the U.S. (94,173) and Europe (174), will help answer some of these important questions. And community-based participatory research and hearing the voices of individuals from the community about their own research priorities and dissemination of results is of utmost importance. There is also much to be learned about the impact of early GnRH agonist therapy on growth, bone health, physical development, long-term health, mental health, cognitive development, and overall wellbeing. Finally, an improved understanding on the impact of other stressors including minority stress and depression on overall health (175,176) for TGD persons is needed. The American Heart Association published a scientific statement with recommendations to assess and address cardiovascular health among TGD people (177).

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Nokoff NJ. Medical Interventions for Transgender Youth. [Updated 2022 Jan 19]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

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ABSTRACT
INTRODUCTION
EPIDEMIOLOGY
GENDER IDENTITY DEVELOPMENT AND NATURAL HISTORY OF GENDER INCONGRUENCE
MEDICAL MANAGEMENT
SURGICAL MANAGEMENT
MENTAL HEALTH
CONCLUSION
REFERENCES

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Endotext [Internet].

Medical Interventions for Transgender Youth

ABSTRACT

INTRODUCTION

Table 1.

EPIDEMIOLOGY

Table 2.

Table 3.

GENDER IDENTITY DEVELOPMENT AND NATURAL HISTORY OF GENDER INCONGRUENCE

MEDICAL MANAGEMENT

Pubertal Blockade

Table 4.

Gender Affirming Hormone Therapy

Feminizing Hormone Therapy

ESTRADIOL THERAPY

Potential Adverse Effects of Estradiol Therapy

Testosterone Blockade/Suppression

Masculinizing Hormone Therapy

TESTOSTERONE

Non-Binary Care

Menstrual Management

Table 5.

SURGICAL MANAGEMENT

Table 6.

MENTAL HEALTH

CONCLUSION

REFERENCES

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