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.

Commissioned Systematic Review

The task force commissioned two systematic reviews to support this guideline. The first one aimed to summarize the available evidence on the effect of sex steroid use in transgender individuals on lipids and cardiovascular outcomes. The review identified 29 eligible studies at moderate risk of bias. In transgender males (female to male), sex steroid therapy was associated with a statistically significant increase in serum triglycerides and low-density lipoprotein cholesterol levels. High-density lipoprotein cholesterol levels decreased significantly across all follow-up time periods. In transgender females (male to female), serum triglycerides were significantly higher without any changes in other parameters. Few myocardial infarction, stroke, venous thromboembolism (VTE), and death events were reported. These events were more frequent in transgender females. However, the quality of the evidence was low. The second review summarized the available evidence regarding the effect of sex steroids on bone health in transgender individuals and identified 13 studies. In transgender males, there was no statistically significant difference in the lumbar spine, femoral neck, or total hip BMD at 12 and 24 months compared with baseline values before initiating masculinizing hormone therapy. In transgender females, there was a statistically significant increase in lumbar spine BMD at 12 months and 24 months compared with baseline values before initiation of feminizing hormone therapy. There was minimal information on fracture rates. The quality of evidence was also low.

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Next Section

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.

processing....

Endocrine Treatment of Gender-dysphoric/Gender-Incongruent Persons

An Endocrine Society Clinical Practice Guideline

Commissioned Systematic Review

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Most Popular Articles

Email This

Feedback