Endocrine Treatment of Gender-dysphoric/Gender-Incongruent Persons

An Endocrine Society Clinical Practice Guideline

Wylie C. Hembree; Peggy T. Cohen-Kettenis; Louis Gooren; Sabine E. Hannema; Walter J. Meyer; M. Hassan Murad; Stephen M. Rosenthal; Joshua D. Safer; Vin Tangpricha; Guy G. T'Sjoen

Disclosures

J Clin Endocrinol Metab. 2017;102(11):3869-3903.

Treatment of Adolescents

During the past decade, clinicians have progressively acknowledged the suffering of young adolescents with GD/gender incongruence. In some forms of GD/gender incongruence, psychological interventions may be useful and sufficient. However, for many adolescents with GD/gender incongruence, the pubertal physical changes are unbearable. As early medical intervention may prevent psychological harm, various clinics have decided to start treating young adolescents with GD/gender incongruence with puberty-suppressing medication (a GnRH analog). As compared with starting gender-affirming treatment long after the first phases of puberty, a benefit of pubertal suppression at early puberty may be a better psychological and physical outcome.

In girls, the first physical sign of puberty is the budding of the breasts followed by an increase in breast and fat tissue. Breast development is also associated with the pubertal growth spurt, and menarche occurs ~2 years later. In boys, the first physical change is testicular growth. A testicular volume ≥4 mL is seen as consistent with the initiation of physical puberty. At the beginning of puberty, estradiol and testosterone levels are still low and are best measured in the early morning with an ultrasensitive assay. From a testicular volume of 10 mL, daytime testosterone levels increase, leading to virilization.^[83] Note that pubic hair and/or axillary hair/odor may not reflect the onset of gonadarche; instead, it may reflect adrenarche alone.

1. We suggest that adolescents who meet diagnostic criteria for GD/gender incongruence, fulfill criteria for treatment (Table 5), and are requesting treatment should initially undergo treatment to suppress pubertal development. (2 |⊕⊕⊖⊖)

2. We suggest that clinicians begin pubertal hormone suppression after girls and boys first exhibit physical changes of puberty (Tanner stages G2/B2). (2 |⊕⊕⊖⊖)

Evidence

Pubertal suppression can expand the diagnostic phase by a long period, giving the subject more time to explore options and to live in the experienced gender before making a decision to proceed with gender-affirming sex hormone treatments and/or surgery, some of which is irreversible.^[84,85] Pubertal suppression is fully reversible, enabling full pubertal development in the natal gender, after cessation of treatment, if appropriate. The experience of full endogenous puberty is an undesirable condition for the GD/gender-incongruent individual and may seriously interfere with healthy psychological functioning and well-being. Treating GD/gender-incongruent adolescents entering puberty with GnRH analogs has been shown to improve psychological functioning in several domains.^[86]

Another reason to start blocking pubertal hormones early in puberty is that the physical outcome is improved compared with initiating physical transition after puberty has been completed.^[60,62] Looking like a man or woman when living as the opposite sex creates difficult barriers with enormous life-long disadvantages. We therefore advise starting suppression in early puberty to prevent the irreversible development of undesirable secondary sex characteristics. However, adolescents with GD/gender incongruence should experience the first changes of their endogenous spontaneous puberty, because their emotional reaction to these first physical changes has diagnostic value in establishing the persistence of GD/gender incongruence.^[85] Thus, Tanner stage 2 is the optimal time to start pubertal suppression. However, pubertal suppression treatment in early puberty will limit the growth of the penis and scrotum, which will have a potential effect on future surgical treatments.^[87]

Clinicians can also use pubertal suppression in adolescents in later pubertal stages to stop menses in transgender males and prevent facial hair growth in transgender females. However, in contrast to the effects in early pubertal adolescents, physical sex characteristics (such as more advanced breast development in transgender boys and lowering of the voice and outgrowth of the jaw and brow in transgender girls) are not reversible.

Values and Preferences

These recommendations place a high value on avoiding an unsatisfactory physical outcome when secondary sex characteristics have become manifest and irreversible, a higher value on psychological well-being, and a lower value on avoiding potential harm from early pubertal suppression.

Remarks

Table 6 lists the Tanner stages of breast and male genital development. Careful documentation of hallmarks of pubertal development will ensure precise timing when initiating pubertal suppression once puberty has started. Clinicians can use pubertal LH and sex steroid levels to confirm that puberty has progressed sufficiently before starting pubertal suppression.^[88] Reference ranges for sex steroids by Tanner stage may vary depending on the assay used. Ultrasensitive sex steroid and gonadotropin assays will help clinicians document early pubertal changes.

Irreversible and, for GD/gender-incongruent adolescents, undesirable sex characteristics in female puberty are breasts, female body habitus, and, in some cases, relative short stature. In male puberty, they are a prominent Adam's apple; low voice; male bone configuration, such as a large jaw, big feet and hands, and tall stature; and male hair pattern on the face and extremities.

3. We recommend that, where indicated, GnRH analogues are used to suppress pubertal hormones. (1 |⊕⊕⊖⊖)

Evidence

Clinicians can suppress pubertal development and gonadal function most effectively via gonadotropin suppression using GnRH analogs. GnRH analogs are long-acting agonists that suppress gonadotropins by GnRH receptor desensitization after an initial increase of gonadotropins during ~10 days after the first and (to a lesser degree) the second injection.^[89] Antagonists immediately suppress pituitary gonadotropin secretion.^[90,91] Long-acting GnRH analogs are the currently preferred treatment option. Clinicians may consider longacting GnRH antagonists when evidence on their safety and efficacy in adolescents becomes available.

During GnRH analog treatment, slight development of secondary sex characteristics may regress, and in a later phase of pubertal development, it will stop. In girls, breast tissue will become atrophic, and menses will stop. In boys, virilization will stop, and testicular volume may decrease.^[92]

An advantage of using GnRH analogs is the reversibility of the intervention. If, after extensive exploration of his/her transition wish, the individual no longer desires transition, they can discontinue pubertal suppression. In subjects with precocious puberty, spontaneous pubertal development has been shown to resume after patients discontinue taking GnRH analogs.^[93]

Recommendations 2.1 to 2.3 are supported by a prospective follow-up study from The Netherlands. This report assessed mental health outcomes in 55 transgender adolescents/young adults (22 transgender females and 33 transgender males) at three time points: (1) before the start of GnRH agonist (average age of 14.8 years at start of treatment), (2) at initiation of gender-affirming hormones (average age of 16.7 years at start of treatment), and (3) 1 year after "gender-reassignment surgery" (average age of 20.7 years).^[63] Despite a decrease in depression and an improvement in general mental health functioning, GD/gender incongruence persisted through pubertal suppression, as previously reported.^[86] However, following sex hormone treatment and genderreassignment surgery, GD/gender incongruence was resolved and psychological functioning steadily improved.^[63] Furthermore, well-being was similar to or better than that reported by age-matched young adults from the general population, and none of the study participants regretted treatment. This study represents the first longterm follow-up of individuals managed according to currently existing clinical practice guidelines for transgender youth, and it underscores the benefit of the multidisciplinary approach pioneered in The Netherlands; however, further studies are needed.

Side Effects

The primary risks of pubertal suppression in GD/gender-incongruent adolescents may include adverse effects on bone mineralization (which can theoretically be reversed with sex hormone treatment), compromised fertility if the person subsequently is treated with sex hormones, and unknown effects on brain development. Few data are available on the effect of GnRH analogs on BMD in adolescents with GD/gender incongruence. Initial data in GD/gender-incongruent subjects demonstrated no change of absolute areal BMD during 2 years of GnRH analog therapy but a decrease in BMD z scores.^[85] A recent study also suggested suboptimal bone mineral accrual during GnRH analog treatment. The study reported a decrease in areal BMD z scores and of bone mineral apparent density z scores (which takes the size of the bone into account) in 19 transgender males treated with GnRH analogs from a mean age of 15.0 years (standard deviation = 2.0 years) for a median duration of 1.5 years (0.3 to 5.2 years) and in 15 transgender females treated from 14.9 (±1.9) years for 1.3 years (0.5 to 3.8 years), although not all changes were statistically significant.^[94] There was incomplete catch-up at age 22 years after sex hormone treatment from age 16.6 (±1.4) years for a median duration of 5.8 years (3.0 to 8.0 years) in transgender females and from age 16.4 (±2.3) years for 5.4 years (2.8 to 7.8 years) in transgender males. Little is known about more prolonged use of GnRH analogs. Researchers reported normal BMD z scores at age 35 years in one individual who used GnRH analogs from age 13.7 years until age 18.6 years before initiating sex hormone treatment.^[65]

Additional data are available from individuals with late puberty or GnRH analog treatment of other indications. Some studies reported that men with constitutionally delayed puberty have decreased BMD in adulthood.^[95] However, other studies reported that these men have normal BMD.^[96,97] Treating adults with GnRH analogs results in a decrease of BMD.^[98] In children with central precocious puberty, treatment with GnRH analogs has been found to result in a decrease of BMDduring treatment by some^[99] but not others.^[100] Studies have reported normal BMD after discontinuing therapy.^{[69,72,73,101,102]} In adolescents treated with growth hormone who are small for gestational age and have normal pubertal timing, 2-year GnRH analog treatments did not adversely affect BMD.^[103] Calcium supplementation may be beneficial in optimizing bone health in GnRH analog–treated individuals.^[104] There are no studies of vitamin D supplementation in this context, but clinicians should offer supplements to vitamin D–deficient adolescents. Physical activity, especially during growth, is important for bone mass in healthy individuals^[103] and is therefore likely to be beneficial for bone health in GnRH analog–treated subjects.

GnRH analogs did not induce a change in body mass index standard deviation score in GD/genderincongruent adolescents^[94] but caused an increase in fat mass and decrease in lean body mass percentage.^[92] Studies in girls treated for precocious puberty also reported a stable body mass index standard deviation score during treatment^[72] and body mass index and body composition comparable to controls after treatment.^[73]

Arterial hypertension has been reported as an adverse effect in a few girls treated with GnRH analogs for precocious/early puberty.^[105,106] Blood pressure monitoring before and during treatment is recommended.

Individuals may also experience hot flashes, fatigue, and mood alterations as a consequence of pubertal suppression. There is no consensus on treatment of these side effects in this context.

It is recommended that any use of pubertal blockers (and subsequent use of sex hormones, as detailed below) include a discussion about implications for fertility (see recommendation 1.3). Transgender adolescents may want to preserve fertility, which may be otherwise compromised if puberty is suppressed at an early stage and the individual completes phenotypic transition with the use of sex hormones.

Limited data are available regarding the effects of GnRH analogs on brain development. A single crosssectional study demonstrated no compromise of executive function,^[107] but animal data suggest there may be an effect of GnRH analogs on cognitive function.^[108]

Values and Preferences

Our recommendation of GnRH analogs places a higher value on the superior efficacy, safety, and reversibility of the pubertal hormone suppression achieved (as compared with the alternatives) and a relatively lower value on limiting the cost of therapy. Of the available alternatives, depot and oral progestin preparations are effective. Experience with this treatment dates back prior to the emergence of GnRH analogs for treating precocious puberty in papers fromthe 1960s and early 1970s.^[109–112] These compounds are usually safe, but some side effects have been reported.^[113–115] Only two recent studies involved transgender youth.^[116,117] One of these studies described the use of oral lynestrenol monotherapy followed by the addition of testosterone treatment in transgender boys who were at Tanner stage B4 or further at the start of treatment.^[117] They found lynestrenol safe, but gonadotropins were not fully suppressed. The study reported metrorrhagia in approximately half of the individuals, mainly in the first 6 months. Acne, headache, hot flashes, and fatigue were other frequent side effects. Another progestin that has been studied in the United States is medroxyprogesterone. This agent is not as effective as GnRH analogs in lowering endogenous sex hormones either and may be associated with other side effects.^[116] Progestin preparations may be an acceptable treatment for persons without access to GnRH analogs or with a needle phobia. If GnRH analog treatment is not available (insurance denial, prohibitive cost, or other reasons), postpubertal, transgender female adolescents may be treated with an antiandrogen that directly suppresses androgen synthesis or action (see adult section).

Remarks

Measurements of gonadotropin and sex steroid levels give precise information about gonadal axis suppression, although there is insufficient evidence for any specific short-term monitoring scheme in children treated with GnRH analogs.^[88] If the gonadal axis is not completely suppressed—as evidenced by (for example) menses, erections, or progressive hair growth—the interval of GnRH analog treatment can be shortened or the dose increased. During treatment, adolescents should be monitored for negative effects of delaying puberty, including a halted growth spurt and impaired bonemineral accretion. Table 7 illustrates a suggested clinical protocol.

Anthropometric measurements and X-rays of the left hand to monitor bone age are informative for evaluating growth. To assess BMD, clinicians can perform dualenergy X-ray absorptiometry scans.

4. In adolescents who request sex hormone treatment (given this is a partly irreversible treatment), we recommend initiating treatment using a gradually increasing dose schedule (see Table 8) after a multidisciplinary team of medical and MHPs has confirmed the persistence of GD/gender incongruence and sufficient mental capacity to give informed consent, which most adolescents have by age 16 years (Table 5). (1 |⊕⊕⊖⊖)

5. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/gender incongruence, even though there are minimal published studies of gender-affirming hormone treatments administered before age 13.5 to 14 years. As with the care of adolescents ≥16 years of age, we recommend that an expert multidisciplinary team of medical and MHPs manage this treatment. (1 |⊕⊖⊖⊖)

6. We suggest monitoring clinical pubertal development every 3 to 6 months and laboratory parameters every 6 to 12 months during sex hormone treatment (Table 9). (2 |⊕⊕⊖⊖)

Evidence

Adolescents develop competence in decision making at their own pace. Ideally, the supervising medical professionals should individually assess this competence, although no objective tools to make such an assessment are currently available.

Many adolescents have achieved a reasonable level of competence by age 15 to 16 years,^[119] and in many countries 16-year-olds are legally competent with regard to medical decision making.^[120] However, others believe that although some capacities are generally achieved before age 16 years, other abilities (such as good risk assessment) do not develop until well after 18 years.^[121] They suggest that health care procedures should be divided along a matrix of relative risk, so that younger adolescents can be allowed to decide about low-risk procedures, such as most diagnostic tests and common therapies, but not about high-risk procedures, such as most surgical procedures.^[121]

Currently available data from transgender adolescents support treatment with sex hormones starting at age 16 years.^[63,122] However, some patients may incur potential risks by waiting until age 16 years. These include the potential risk to bone health if puberty is suppressed for 6 to 7 years before initiating sex hormones (e.g., if someone reached Tanner stage 2 at age 9–10 years old). Additionally, there may be concerns about inappropriate height and potential harm to mental health (emotional and social isolation) if initiation of secondary sex characteristics must wait until the person has reached 16 years of age. However, only minimal data supporting earlier use of gender-affirming hormones in transgender adolescents currently exist.^[63] Clearly, long-term studies are needed to determine the optimal age of sex hormone treatment in GD/gender-incongruent adolescents.

The MHP who has followed the adolescent during GnRH analog treatment plays an essential role in assessing whether the adolescent is eligible to start sex hormone therapy and capable of consenting to this treatment (Table 5). Support of the family/environment is essential. Prior to the start of sex hormones, clinicians should discuss the implications for fertility (see recommendation 1.5). Throughout pubertal induction, an MHP and a pediatric endocrinologist (or other clinician competent in the evaluation and induction of pubertal development) should monitor the adolescent. In addition to monitoring therapy, it is also important to pay attention to general adolescent health issues, including healthy life style choices, such as not smoking, contraception, and appropriate vaccinations (e.g., human papillomavirus).

For the induction of puberty, clinicians can use a similar dose scheme for hypogonadal adolescents with GD/gender incongruence as they use in other individuals with hypogonadism, carefully monitoring for desired and undesired effects (Table 8). In transgender female adolescents, transdermal 17β-estradiol may be an alternative for oral 17β-estradiol. It is increasingly used for pubertal induction in hypogonadal females. However, the absence of low-dose estrogen patches may be a problem. As a result, individuals may need to cut patches to size themselves to achieve appropriate dosing.^[123] In transgender male adolescents, clinicians can give testosterone injections intramuscularly or subcutaneously.^[124,125]

When puberty is initiated with a gradually increasing schedule of sex steroid doses, the initial levels will not be high enough to suppress endogenous sex steroid secretion. Gonadotropin secretion and endogenous production of testosterone may resume and interfere with the effectiveness of estrogen treatment, in transgender female adolescents.^[126,127] Therefore, continuation of GnRH analog treatment is advised until gonadectomy. Given that GD/gender-incongruent adolescents may opt not to have gonadectomy, long-term studies are necessary to examine the potential risks of prolonged GnRH analog treatment. Alternatively, in transgender male adolescents, GnRH analog treatment can be discontinued once an adult dose of testosterone has been reached and the individual is well virilized. If uterine bleeding occurs, a progestin can be added. However, the combined use of a GnRH analog (for ovarian suppression) and testosterone may enable phenotypic transition with a lower dose of testosterone in comparison with testosterone alone. If there is a wish or need to discontinue GnRH analog treatment in transgender female adolescents, they may be treated with an antiandrogen that directly suppresses androgen synthesis or action (see section 3.0 "Hormonal Therapy for Transgender Adults").

Values and Preferences

The recommendation to initiate pubertal induction only when the individual has sufficient mental capacity (roughly age 16 years) to give informed consent for this partly irreversible treatment places a higher value on the ability of the adolescent to fully understand and oversee the partially irreversible consequences of sex hormone treatment and to give informed consent. It places a lower value on the possible negative effects of delayed puberty. We may not currently have the means to weigh adequately the potential benefits of waiting until around age 16 years to initiate sex hormones vs the potential risks/harm to BMD and the sense of social isolation from having the timing of puberty be so out of sync with peers.^[128]

Remarks

Before starting sex hormone treatment, effects on fertility and options for fertility preservation should be discussed. Adult height may be a concern in transgender adolescents. In a transgender female adolescent, clinicians may consider higher doses of estrogen or a more rapid tempo of dose escalation during pubertal induction. There are no established treatments yet to augment adult height in a transgender male adolescent with open epiphyses during pubertal induction. It is not uncommon for transgender adolescents to present for clinical services after having completed or nearly completed puberty. In such cases, induction of puberty with sex hormones can be done more rapidly (see Table 8). Additionally, an adult dose of testosterone in transgendermale adolescentsmay suffice to suppress the gonadal axis without the need to use a separate agent. At the appropriate time, the multidisciplinary team should adequately prepare the adolescent for transition to adult care.

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Table 1. Definitions of Terms Used in This Guideline
Biological sex, biological male or female: These terms refer to physical aspects of maleness and femaleness. As these may not be in line with each other (e.g., a person with XY chromosomes may have female-appearing genitalia), the terms biological sex and biological male or female are imprecise and should be avoided.
Cisgender: This means not transgender. An alternative way to describe individuals who are not transgender is "non-transgender people."
Gender-affirming (hormone) treatment: See "gender reassignment"
Gender dysphoria: This is the distress and unease experienced if gender identity and designated gender are not completely congruent (see Table 2). In 2013, the American Psychiatric Association released the fifth edition of the DSM-5, which replaced "gender identity disorder" with "gender dysphoria" and changed the criteria for diagnosis.
Gender expression: This refers to external manifestations of gender, expressed through one's name, pronouns, clothing, haircut, behavior, voice, or body characteristics. Typically, transgender people seek to make their gender expression align with their gender identity, rather than their designated gender.
Gender identity/experienced gender: This refers to one's internal, deeply held sense of gender. For transgender people, their gender identity does not match their sex designated at birth. Most people have a gender identity of man or woman (or boy or girl). For some people, their gender identity does not fit neatly into one of those two choices. Unlike gender expression (see below), gender identity is not visible to others.
Gender identity disorder: This is the term used for GD/gender incongruence in previous versions of DSM (see "gender dysphoria"). The ICD-10 still uses the term for diagnosing child diagnoses, but the upcoming ICD-11 has proposed using "gender incongruence of childhood."
Gender incongruence: This is an umbrella term used when the gender identity and/or gender expression differs from what is typically associated with the designated gender. Gender incongruence is also the proposed name of the gender identity–related diagnoses in ICD-11. Not all individuals with gender incongruence have gender dysphoria or seek treatment.
Gender variance: See "gender incongruence"
Gender reassignment: This refers to the treatment procedure for those who want to adapt their bodies to the experienced gender by means of hormones and/or surgery. This is also called gender-confirming or gender-affirming treatment.
Gender-reassignment surgery (gender-confirming/gender-affirming surgery): These terms refer only to the surgical part of genderconfirming/gender-affirming treatment.
Gender role: This refers to behaviors, attitudes, and personality traits that a society (in a given culture and historical period) designates as masculine or feminine and/or that society associates with or considers typical of the social role of men or women.
Sex designated at birth: This refers to sex assigned at birth, usually based on genital anatomy.
Sex: This refers to attributes that characterize biological maleness or femaleness. The best known attributes include the sex-determining genes, the sex chromosomes, the H-Y antigen, the gonads, sex hormones, internal and external genitalia, and secondary sex characteristics.
Sexual orientation: This term describes an individual's enduring physical and emotional attraction to another person. Gender identity and sexual orientation are not the same. Irrespective of their gender identity, transgender people may be attracted to women (gynephilic), attracted to men (androphilic), bisexual, asexual, or queer.
Transgender: This is an umbrella term for people whose gender identity and/or gender expression differs from what is typically associated with their sex designated at birth. Not all transgender individuals seek treatment.
Transgender male (also: trans man, female-to-male, transgender male): This refers to individuals assigned female at birth but who identify and live as men.
Transgender woman (also: trans woman, male-to female, transgender female): This refers to individuals assigned male at birth but who identify and live as women.
Transition: This refers to the process during which transgender persons change their physical, social, and/or legal characteristics consistent with the affirmed gender identity. Prepubertal children may choose to transition socially.
Transsexual: This is an older term that originated in the medical and psychological communities to refer to individuals who have permanently transitioned through medical interventions or desired to do so.

Table 2. DSM-5 Criteria for Gender Dysphoria in Adolescents and Adults
A. A marked incongruence between one's experienced/expressed gender and natal gender of at least 6 mo in duration, as manifested by at least two of the following:
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) 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) A strong desire for the primary and/or secondary sex characteristics of the other gender A strong desire to be of the other gender (or some alternative gender different from one's designated gender) A strong desire to be treated as the other gender (or some alternative gender different from one's designated gender) 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)
B. The condition is associated with clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Specify if:
The condition exists with a disorder of sex development. The condition is posttransitional, 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).

Reference: American Psychiatric Association.^[14]

Table 3. ICD-10 Criteria for Transsexualism
Transsexualism (F64.0) has three criteria:
The desire to live and be accepted as a member of the opposite sex, usually accompanied by the wish to make his or her body as congruent as possible with the preferred sex through surgery and hormone treatments. The transsexual identity has been present persistently for at least 2 y. The disorder is not a symptom of another mental disorder or a genetic, DSD, or chromosomal abnormality.

Table 4. Criteria for Gender-Affirming Hormone Therapy for Adults
Persistent, well-documented gender dysphoria/gender incongruence The capacity to make a fully informed decision and to consent for treatment The age of majority in a given country (if younger, follow the criteria for adolescents) Mental health concerns, if present, must be reasonably well controlled

Reproduced from World Professional Association for Transgender Health.^[16]

Table 5. Criteria for Gender-Affirming Hormone Therapy for Adolescents
Adolescents are eligible for GnRH agonist treatment if:
1. A qualified MHP has confirmed that:
the adolescent has demonstrated a long-lasting and intense pattern of gender nonconformity or gender dysphoria (whether suppressed or expressed), gender dysphoria worsened with the onset of puberty, any coexisting psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adolescent's situation and functioning are stable enough to start treatment, the adolescent has sufficient mental capacity to give informed consent to this (reversible) treatment,
2. And the adolescent:
has been informed of the effects and side effects of treatment (including potential loss of fertility if the individual subsequently continues with sex hormone treatment) and options to preserve fertility, has given informed consent and (particularly when the adolescent has not reached the age of legal medical consent, depending on applicable legislation) the parents or other caretakers or guardians have consented to the treatment and are involved in supporting the adolescent throughout the treatment process,
3. And a pediatric endocrinologist or other clinician experienced in pubertal assessment
agrees with the indication for GnRH agonist treatment, has confirmed that puberty has started in the adolescent (Tanner stage ≥G2/B2), has confirmed that there are no medical contraindications to GnRH agonist treatment.
Adolescents are eligible for subsequent sex hormone treatment if:
1. A qualified MHP has confirmed:
the persistence of gender dysphoria, any coexisting psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adolescent's situation and functioning are stable enough to start sex hormone treatment, the adolescent has sufficient mental capacity (which most adolescents have by age 16 years) to estimate the consequences of this (partly) irreversible treatment, weigh the benefits and risks, and give informed consent to this (partly) irreversible treatment,
2. And the adolescent:
has been informed of the (irreversible) effects and side effects of treatment (including potential loss of fertility and options to preserve fertility), has given informed consent and (particularly when the adolescent has not reached the age of legal medical consent, depending on applicable legislation) the parents or other caretakers or guardians have consented to the treatment and are involved in supporting the adolescent throughout the treatment process,
3. And a pediatric endocrinologist or other clinician experienced in pubertal induction:
agrees with the indication for sex hormone treatment, has confirmed that there are no medical contraindications to sex hormone treatment.

Reproduced from World Professional Association for Transgender Health (16).

Table 6. Tanner Stages of Breast Development and Male External Genitalia
The description of Tanner stages for breast development:
Prepubertal Breast and papilla elevated as small mound; areolar diameter increased Breast and areola enlarged, no contour separation Areola and papilla form secondary mound Mature; nipple projects, areola part of general breast contour
For penis and testes:
Prepubertal, testicular volume <4mL Slight enlargement of penis; enlarged scrotum, pink, texture altered, testes 4–6mL Penis longer, testes larger (8–12 mL) Penis and glans larger, including increase in breadth; testes larger (12–15 mL), scrotum dark Penis adult size; testicular volume > 15 ml

Adapted from Lawrence.^[56]

Table 7. Baseline and Follow-Up Protocol During Suppression of Puberty
Every 3–6mo
Anthropometry: height, weight, sitting height, blood pressure, Tanner stages
Every 6–12 mo
Laboratory: LH, FSH, E2/T, 25OH vitamin D
Every 1–2y
Bone density using DXA
Bone age on X-ray of the left hand (if clinically indicated)

Adapted from Hembree et al. (118). Abbreviations: DXA, dual-energy X-ray absorptiometry; E2, estradiol; FSH, follicle stimulating hormone; LH, luteinizing hormone; T, testosterone;

Table 8. Protocol Induction of Puberty
Induction of female puberty with oral 17β-estradiol, increasing the dose every 6 mo:
5 μg/kg/d
10 μg/kg/d
15 μg/kg/d
20 μg/kg/d
Adult dose = 2–6 mg/d
In postpubertal transgender female adolescents, the dose of 17β-estradiol can be increased more rapidly:
1 mg/d for 6 mo
2 mg/d
Induction of female puberty with transdermal 17β-estradiol, increasing the dose every 6 mo (new patch is placed every 3.5 d):
6.25–12.5 μg/24 h (cut 25-μg patch into quarters, then halves)
25 μg/24 h
37.5 μg/24 h
Adult dose 5 50–200 μg/24 h
For alternatives once at adult dose, see Table 11.
Adjust maintenance dose to mimic physiological estradiol levels (see Table 15).
Induction of male puberty with testosterone esters increasing the dose every 6 mo (IM or SC):
25 mg/m₂/2 wk (or alternatively, half this dose weekly, or double the dose every 4 wk)
50 mg/m₂/2 wk
75 mg/m₂/2 wk
100 mg/m₂/2 wk
Adult dose = 100–200 mg every 2 wk
In postpubertal transgender male adolescents the dose of testosterone esters can be increased more rapidly:
75 mg/2 wk for 6 mo
125 mg/2 wk
For alternatives once at adult dose, see Table 11.
Adjust maintenance dose to mimic physiological testosterone levels (see Table 14).

Adapted from Hembree et al. (118). Abbreviations: IM, intramuscularly; SC, subcutaneously.

Table 9. Baseline and Follow-up Protocol During Induction of Puberty
Every 3–6mo
Anthropometry: height, weight, sitting height, blood pressure, Tanner stages
Every 6–12 mo
In transgender males: hemoglobin/hematocrit, lipids, testosterone, 25OH vitamin D In transgender females: prolactin, estradiol, 25OH vitamin D
Every 1–2y
BMD using DXA Bone age on X-ray of the left hand (if clinically indicated)
BMD should be monitored into adulthood (until the age of 25–30 y or until peak bone mass has been reached).
For recommendations on monitoring once pubertal induction has been completed, see Tables 14 and 15.

Adapted from Hembree et al. (118). Abbreviation: DXA, dual-energy X-ray absorptiometry.

Table 10. Medical Risks Associated With Sex Hormone Therapy
Transgender female: estrogen
Very high risk of adverse outcomes:
Thromboembolic disease
Moderate risk of adverse outcomes:
Macroprolactinoma Breast cancer Coronary artery disease Cerebrovascular disease Cholelithiasis Hypertriglyceridemia
Transgender male: testosterone
Very high risk of adverse outcomes:
Erythrocytosis (hematocrit > 50%)
Moderate risk of adverse outcomes:
Severe liver dysfunction (transaminases ≥ threefold upper limit of normal) Coronary artery disease Cerebrovascular disease Hypertension Breast or uterine cancer

Table 11. Hormone Regimens in Transgender Persons
Transgender females^a
Estrogen
Oral
Estradiol	2.0–6.0 mg/d
Transdermal
Estradiol transdermal patch (New patch placed every 3–5d)	0.025–0.2 mg/d
Parenteral
Estradiol valerate or cypionate	5–30 mg IM every 2 wk
	2–10 mg IM every week
Anti-androgens
Spironolactone	100–300 mg/d
Cyproterone acetate^b	25–50 mg/d
GnRH agonist	3.75 mg SQ (SC) monthly
	11.25 mg SQ (SC) 3-monthly
Transgender males
Testosterone
Parenteral testosterone
Testosterone enanthate or cypionate	100–200mgSQ(IM)every 2wkorSQ (SC) 50% perweek
Testosterone undecanoate^c	1000 mg every 12 wk
Transdermal testosterone
Testosterone gel 1.6%^d	50–100 mg/d
Testosterone transdermal patch	2.5–7.5 mg/d

Abbreviations: IM, intramuscularly; SQ, sequentially; SC, subcutaneously.
^aEstrogens used with or without antiandrogens or GnRH agonist.
^bNot available in the United States.
^cOne thousand milligrams initially followed by an injection at 6 wk then at 12-wk intervals.
^dAvoid cutaneous transfer to other individuals.

Table 12. Masculinizing Effects in Transgender Males
Effect	Onset	Maximum
Skin oiliness/acne	1–6mo	1–2y
Facial/body hair growth	6–12 mo	4–5y
Scalp hair loss	6–12 mo	—^a
Increased muscle mass/strength	6–12 mo	2–5y
Fat redistribution	1–6mo	2–5y
Cessation of menses	1–6mo	—^b
Clitoral enlargement	1–6mo	1–2y
Vaginal atrophy	1–6mo	1–2y
Deepening of voice	6–12 mo	1–2y

Estimates represent clinical observations: Toorians et al. (149), Asscheman et al. (156), Gooren et al. (157), Wierckx et al. (158).
^aPrevention and treatment as recommended for biological men.
^bMenorrhagia requires diagnosis and treatment by a gynecologist.

Table 13. Feminizing Effects in Transgender Females
Effect		Maximum
Redistribution of body fat	3–6mo	2–3y
Decrease in muscle mass and strength	3–6mo	1–2y
Softening of skin/decreased oiliness	3–6 mo	Unknown
Decreased sexual desire	1–3mo	3–6mo
Decreased spontaneous erections	1–3mo	3–6mo
Male sexual dysfunction	Variable	Variable
Breast growth	3–6mo	2–3y
Decreased testicular volume	3–6mo	2–3y
Decreased sperm production	Unknown	>3y
Decreased terminal hair growth	6–12 mo	>3y^a
Scalp hair	Variable	—^b
Voice changes	None	—^c

Estimates represent clinical observations: Toorians et al. (149), Asscheman et al. (156), Gooren et al. (157).
^aComplete removal of male sexual hair requires electrolysis or laser treatment or both.
^bFamilial scalp hair loss may occur if estrogens are stopped.
^cTreatment by speech pathologists for voice training is most effective.

Table 14. Monitoring of Transgender Persons on Gender-Affirming Hormone Therapy: Transgender Male
1. Evaluate patient every 3 mo in the first year and then one to two times per year to monitor for appropriate signs of virilization and for development of adverse reactions.
2. Measure serum testosterone every 3 mo until levels are in the normal physiologic male range:^a
a. For testosterone enanthate/cypionate injections, the testosterone level should be measured midway between injections. The target level is 400–700 ng/dL to 400 ng/dL. Alternatively, measure peak and trough levels to ensure levels remain in the normal male range.
b. For parenteral testosterone undecanoate, testosterone should be measured just before the following injection. If the level is <400 ng/dL, adjust dosing interval.
c. For transdermal testosterone, the testosterone level can be measured no sooner than after 1 wk of daily application (at least 2 h after application).
3. Measure hematocrit or hemoglobin at baseline and every 3 mo for the first year and then one to two times a year. Monitor weight, blood pressure, and lipids at regular intervals.
4. Screening for osteoporosis should be conducted in those who stop testosterone treatment, are not compliant with hormone therapy, or who develop risks for bone loss.
5. If cervical tissue is present, monitoring as recommended by the American College of Obstetricians and Gynecologists.
6. Ovariectomy can be considered after completion of hormone transition.
7. Conduct sub-and periareolar annual breast examinations if mastectomy performed. If mastectomy is not performed, then consider mammograms as recommended by the American Cancer Society.

^aAdapted from Lapauw et al. (154) and Ott et al. (159).

Table 15. Monitoring of Transgender Persons on Gender-Affirming Hormone Therapy: Transgender Female
1. Evaluate patient every 3 mo in the first year and then one to two times per year to monitor for appropriate signs of feminization and for development of adverse reactions.
2. Measure serum testosterone and estradiol every 3 mo.
a. Serum testosterone levels should be <50 ng/dL.
b. Serum estradiol should not exceed the peak physiologic range: 100–200 pg/mL.
3. For individuals on spironolactone, serum electrolytes, particularly potassium, should be monitored every 3 mo in the first year and annually thereafter.
4. Routine cancer screening is recommended, as in nontransgender individuals (all tissues present).
5. Consider BMD testing at baseline (160). In individuals at low risk, screening for osteoporosis should be conducted at age 60 years or in those who are not compliant with hormone therapy.

This table presents strong recommendations and does not include lower level recommendations.

Table 16. Criteria for Gender-Affirming Surgery, Which Affects Fertility
Persistent, well-documented gender dysphoria Legal age of majority in the given country Having continuously and responsibly used gender-affirming hormones for 12 mo (if there is no medical contraindication to receiving such therapy) Successful continuous full-time living in the new gender role for 12 mo If significant medical or mental health concerns are present, they must be well controlled Demonstrable knowledge of all practical aspects of surgery (e.g., cost, required lengths of hospitalizations, likely complications, postsurgical rehabilitation)

Authors and Disclosures

Wylie C. Hembree¹, Peggy T. Cohen-Kettenis², Louis Gooren³, Sabine E. Hannema⁴, Walter J. Meyer⁵, M. Hassan Murad⁶, Stephen M. Rosenthal⁷, Joshua D. Safer⁸, Vin Tangpricha⁹ and Guy G. T'Sjoen¹⁰
¹New York Presbyterian Hospital, Columbia University Medical Center, New York, New York 10032 (Retired); ²VU University Medical Center, 1007 MB Amsterdam, Netherlands (Retired); ³VU University Medical Center, 1007 MB Amsterdam, Netherlands (Retired); ⁴Leiden University Medical Center, 2300 RC Leiden, Netherlands; ⁵University of Texas Medical Branch, Galveston, Texas 77555; ⁶Mayo Clinic Evidence-Based Practice Center, Rochester, Minnesota 55905; ⁷University of California San Francisco, Benioff Children's Hospital, San Francisco, California 94143; ⁸Boston University School of Medicine, Boston, Massachusetts 02118; ⁹Emory University School of Medicine and the Atlanta VA Medical Center, Atlanta, Georgia 30322; and ¹⁰Ghent University Hospital, 9000 Ghent, Belgium

Correspondence and Reprint Requests
The Endocrine Society, 2055 L Street NW, Suite 600, Washington, DC 20036. E-mail: publications@endocrine.org; Phone: 202971-3636.

Disclosure Summary
See Financial Disclosures.

Financial Disclosures of the Task Force* Wylie C. Hembree (chair)—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared. Peggy T. Cohen-Kettenis—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared. Louis Gooren—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared. Sabine E. Hannema—financial or business/organizational interests: none declared, significant financial interest or leadership position: Ferring Pharmaceuticals Inc. (lecture/conference), Pfizer (lecture). Walter J. Meyer—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared. M. Hassan Murad**—financial or business/organizational interests: Mayo Clinic, Evidence-based Practice Center, significant financial interest or leadership position: none declared. Stephen M. Rosenthal—financial or business/organizational interests: AbbVie (consultant), National Institutes of Health (grantee), significant financial interest or leadership position: Pediatric Endocrine Society (immediate past president). Joshua D. Safer, FACP—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared. Vin Tangpricha—financial or business/organizational interests: Cystic Fibrosis Foundation (grantee), National Institutes of Health (grantee), significant financial interest or leadership position, Elsevier Journal of Clinical and Translational Endocrinology (editor). Guy G. T'Sjoen—financial or business/organizational interests: none declared, significant financial interest or leadership position: none declared.* Financial, business, and organizational disclosures of the task force cover the year prior to publication. Disclosures prior to this time period are archived.**Evidence-based reviews for this guideline were prepared under contract with the Endocrine Society.

*Cosponsoring Associations
American Association of Clinical Endocrinologists, American Society of Andrology, European Society for Pediatric Endocrinology, European Society of Endocrinology, Pediatric Endocrine Society, and World Professional Association for Transgender Health.

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Endocrine Treatment of Gender-dysphoric/Gender-Incongruent Persons

An Endocrine Society Clinical Practice Guideline

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