Chapter 23 - Transgender Endocrinology

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Greenspan's Basic & Clinical Endocrinology, 10e
Chapter 23: Transgender Endocrinology
Stephen M. Rosenthal; Wylie C. Hembree
INTRODUCTION
5αRD2 5αreductase2
1 7βHSD3 17βhydroxysteroid dehydrogenase3
AR Androgen receptor
BMD Bone mineral density
CAH Congenital Adrenal Hyperplasia
CAIS Complete androgen insensitivity syndrome
DSD Disorder of Sex Development
DSM Diagnostic and Statistical Manual of Mental Disorders
DXA Dual energy xray absorptiometry
ER Estrogen receptor
ES Endocrine Society
FSH Follicle stimulating hormone
FTM Femaleto male
GID Gender Identity Disorder
GnRH Gonadotropin releasing hormone
HPG Hypothalamicpituitarygonadal
LH Luteinizing hormone
MTF Maleto female
PGR Progesterone receptor
SOC Standards of Care
W P A T H202423 10:25 A Your

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Chapter 23: Transgender Endocrinology, Stephen M. Rosenthal; Wylie C. Hembree Page 1 / 22
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PART I: ENDOCRINE MANAGEMENT OF TRANSGENDER YOUTH

Stephen M. Rosenthal; Wylie C. Hembree
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INTRODUCTION
5αRD2 5αreductase2
1 7βHSD3 17βhydroxysteroid dehydrogenase3
AR Androgen receptor
BMD Bone mineral density
CAH Congenital Adrenal Hyperplasia
CAIS Complete androgen insensitivity syndrome
DSD Disorder of Sex Development
DSM Diagnostic and Statistical Manual of Mental Disorders
DXA Dual energy xray absorptiometry
ER Estrogen receptor
ES Endocrine Society
FSH Follicle stimulating hormone
FTM Femaleto male
GID Gender Identity Disorder
GnRH Gonadotropin releasing hormone
HPG Hypothalamicpituitarygonadal
LH Luteinizing hormone
MTF Maleto female
PGR Progesterone receptor
SOC Standards of Care
WPATH World Professional Association for Transgender Health
PART I: ENDOCRINE MANAGEMENT OF TRANSGENDER YOUTH

Introduction
Gender nonconforming/transgender youth, in increasing numbers, are seeking medical services to enable the development of physical characteristics
consistent with their experienced gender. These services including use of agents to block endogenous puberty at Tanner stage 2 with subsequent use
of crosssex hormones are based on longitudinal studies demonstrating that those individuals who were first identified as gender dysphoric in early or
middle childhood and continue to meet the mental health criteria for being transgender at early puberty are likely to be transgender as adults. The
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goals of Part
Chapter I of this chapter
23: Transgender are to reviewStephen
Endocrinology, terms and
M.definitions
Rosenthal;applicable to gender nonconforming youth (and adults), endocrine, genetic
Wylie C. Hembree and2 / 22
Page
neuroanatomical
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clinical practice guidelines for transgender youth, and limitations and challenges to optimal care.
Introduction
Gender nonconforming/transgender youth, in increasing numbers, are seeking medical services to enable the development of physical
Access Provided by: characteristics
consistent with their experienced gender. These services including use of agents to block endogenous puberty at Tanner stage 2 with subsequent use
of crosssex hormones are based on longitudinal studies demonstrating that those individuals who were first identified as gender dysphoric in early or
middle childhood and continue to meet the mental health criteria for being transgender at early puberty are likely to be transgender as adults. The
goals of Part I of this chapter are to review terms and definitions applicable to gender nonconforming youth (and adults), endocrine, genetic and
neuroanatomical studies that shed light on the biologic underpinnings of gender identity and to review the natural history of transgenderism, current
clinical practice guidelines for transgender youth, and limitations and challenges to optimal care.
Terms and Definitions
“Gender identity” refers to a person’s inner sense of self as male or female (and is not always binary). In contrast, a person’s “sex” refers to the physical
attributes that characterize biologic maleness or femaleness (eg, the genitalia). Most children, at birth, are assigned a “sex of rearing” (some mental
health providers prefer the term “gender of rearing”) based on genital anatomy. With that assignment comes societal expectations of gender roles,
behaviors, and expressions, which are sometimes referred to as a child’s “assigned (or natal) gender.” In contrast to “sex (or gender) of rearing,”
“gender identity” can only be assumed, and not, in fact, known until an individual achieves a particular level of psychological development and self
awareness. “Cisgender” refers to an individual for whom gender identity and physical sex characteristics are in alignment.
“Gender nonconforming” is a term sometimes used when gender identity is not consistent with the gender assumed based on birth sex assignment. As
defined by the American Psychiatric Association, “transgender” refers to a person who transiently or persistently identifies with a gender different
from their “natal gender.” The World Professional Association for Transgender Health (WPATH) Standards of Care (SOC) describes “transgender”
(adjective) as “a diverse group of individuals who cross or transcend culturally defined categories of gender” and “transsexual” (adjective) as
“individuals who seek to change or have changed their primary and/or secondary sex characteristics through feminizing or masculinizing medical
interventions (hormones and/or surgery), typically accompanied by a permanent change in gender role.” “Transsexual” has also been used to
describe a person who identifies as a member of the gender opposite to that assigned at birth, but who has not necessarily sought medical and/or
surgical interventions.
“Transgender,” defined more narrowly, refers to an individual whose gender identity is the “opposite” of their “assigned” or “natal gender.” A person
with a female gender identity and male assigned sex would be referred to as a “transgender girl/woman,” “transfemale,” or MTF (male to female); a
person with a male gender identity and female assigned sex would be referred to as a “transgender boy/man,” “transmale,” or FTM.
The terms “gender queer,” “gender variant,” “gender expansive,” “gender creative,” or “gender independent” are increasingly used to describe
individuals who state that their gender identities are neither male nor female. Some of these individuals accept their assigned genders but not the
cultural expectations for those genders. “Gender fluid” refers to an individual whose gender identity changes over time or is not a fixed binary. In this
context, it is not clear whether core gender identity is, in fact, changing, or whether gender fluidity reflects an ongoing process of selfawareness.
“Gender behavior” is not equivalent to gender identity, and the majority of youth with gender nonconforming behavior will not turn out to have a
transgender identity. In the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5, “Gender dysphoria” refers to clinically significant distress
related to the incongruence between one’s “affirmed” or “experienced gender” and one’s “assigned (or natal) gender.” This term was replaced
“Gender Identity Disorder” (GID) found in the earlier DSM IV. The DSM 5 has distinct diagnostic criteria for “gender dysphoria in children” and “gender
dysphoria in adolescents and adults” [specifying with or without a disorder of sex development (DSD)]. Replacing “disorder” with “dysphoria”
depathologizes the transgender identity, and instead, focuses on dysphoria as the clinical problem. It should be noted that the majority of patients
with “gender dysphoria” do not have a DSD. Whether in children or adolescents, a core feature of “gender dysphoria” is “a marked incongruence
between one’s experienced/expressed gender and assigned gender” of at least 6 months’ duration.
“Sexual identity” (or “sexual orientation”) is often confused with “gender identity.” While the former refers to whom one is sexually attracted, the latter
refers to whom one “is” as male, female, or somewhere on the gender continuum. As with cisgender individuals, gender nonconforming/transgender
individuals may have a heterosexual, homosexual, or bisexual orientation.
Prevalence of Transgenderism in Youth
While prevalence data for younger transgender adolescents are lacking, multidisciplinary clinics for transgender youth and adolescents in Europe and
North America have seen a steadily increasing demand for services in recent years, with a ratio of phenotypic males to females close to 1:1.
Mental Health Concerns and Impact of Family Support
Lifethreatening behaviors represent a significant risk for transgender youth and adolescents. A retrospective cohort study of 180 transgender
individuals aged 12 to 29 years seen in a Boston clinic between 2002 and 2011 were compared to an equal number of cisgender, agematched controls.
In comparison
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attempts, and selfharm without lethal intent. The impact of the degree of parental support on mental health outcomes was reported in a cohort of
transgender youth and young adults age 16 to 24 years (n = 84) from Ontario, Canada: Satisfaction with life and selfesteem were significantly greater in
While prevalence data for younger transgender adolescents are lacking, multidisciplinary clinics for transgender youth and adolescents in Europe and
North America have seen a steadily increasing demand for services in recent years, with a ratio of phenotypic males to females close to 1:1.
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Mental Health Concerns and Impact of Family Support
Lifethreatening behaviors represent a significant risk for transgender youth and adolescents. A retrospective cohort study of 180 transgender
individuals aged 12 to 29 years seen in a Boston clinic between 2002 and 2011 were compared to an equal number of cisgender, agematched controls.
In comparison to controls, transgender youth/young adults had a two to threefold increased risk of anxiety, depression, suicidal ideation, suicide
attempts, and selfharm without lethal intent. The impact of the degree of parental support on mental health outcomes was reported in a cohort of
transgender youth and young adults age 16 to 24 years (n = 84) from Ontario, Canada: Satisfaction with life and selfesteem were significantly greater in
transgender youth whose parents were “very supportive” versus those whose parents were “somewhat to not at all supportive.” In addition,
depression and suicide attempts were significantly decreased in transgender youth whose parents were supportive in comparison to those whose
parents were not supportive. Even with supportive parents, transgender youth still have a significant risk for depression, perhaps in part from their
experience of transphobia from members of their communities and feelings of rejection and social isolation.
Biologic Underpinnings of Gender Identity
Numerous studies from a variety of biomedical disciplines—endocrine, genetic, and neuroanatomical—have begun to shed light on the biologic
underpinnings of gender identity. Results of these studies support the concept that gender identity is not simply a psychosocial construct, but likely
reflects a complex interplay of biologic, environmental, and cultural factors.
While the majority of transgender patients do not have a DSD, studies of gender identity outcome within the endocrine discipline have been principally
carried out in patients with a variety of DSDs, primarily exploring the role of prenatal and postnatal androgens in gender identity development. For
example, studies in 46, XX patients with “classical” congenital adrenal hyperplasia (CAH) caused by mutations in the CYP21A2 gene resulting in 21
hydroxylase deficiency and varying degrees of genital masculinization, demonstrate a greater than expected number of patients with gender
dysphoria, “atypical gender identity,” or who were transgender. In a metaanalysis of 250 patients with 46, XX 21hydroxylase deficiency leading to
virilizing CAH and raised female, nearly 95% of patients reported a female gender identity without gender dysphoria, while 5.2% reported either a male
gender identity or gender dysphoria. Of note, there was no apparent correlation with the degree of genital masculinization and gender identity
outcome. A study of adult women with classical 21hydroxylase deficiency demonstrated a relationship between severity of disease and gender identity
outcome: Of 42 patients with the saltwasting form, 3 (7.1%) had either gender dysphoria or had changed gender to male; no gender dysphoria was
seen in less severely affected individuals. These and other studies demonstrate that the majority of 46, XX patients with virilizing CAH from 21
hydroylase deficiency appear to have a female gender identity. However, the finding that 5.2% to 11.6% of such patients have gender dysphoria, an
“atypical gender identity” or are transgender would appear to be much more common than expected based on the reported prevalence of FTM
transsexualism, implying that there is some role for prenatal/postnatal androgens in gender identity outcome. It is noteworthy that in 46, XX
individuals with virilizing CAH from 21hydroylase deficiency, prenatal androgens are more likely to affect gender behavior and sexual orientation than
gender identity.
The potential effects of prenatal and postnatal androgen exposure on gender identity outcome and “gender role change” have also been explored in
other hormonal and nonhormonal DSDs. For example, in 5αreductase2 deficiency (5αRD2), among 46 XY individuals raised female, a “gender role
change from female to male” (typically after puberty) was reported in 56% to 63% of the patients. Gender role changes from female to male were also
reported in 39% to 64% of 46 XY individuals raised female with 17βhydroxysteroid dehydrogenase3 deficiency (17βHSD3). In the largest series of
patients with 5αRD2 and 17βHSD3 reviewed by CohenKettenis and colleagues, individuals undergoing gender role change from female to male had
intact testes, implying a potential role of prenatal as well as postnatal androgen exposure in gender identity outcome.
Gender identity outcome has also been studied in patients with a variety of “nonhormonal” DSDs, including cloacal exstrophy, penile ablation, and
penile agenesis. A study of patients with 46 XY cloacal exstrophy reported that the majority (8 of 14) who had undergone neonatal sex reassignment to
female (castration) subsequently declared a male gender identity, and that 2 patients raised as males remained male. A literature review of individuals
with 46 XY cloacal exstrophy found that of 51 patients assigned female, the majority (65%) were living as female while 14% were living as female but
with possible gender dysphoria, and approximately 22% were living as male. In addition, of 16 males with penile agenesis assigned female at birth and
of 7 males with penile ablation reassigned to female in infancy or early childhood, the majority were living as female.
These studies of gender identity outcome in hormonal and nonhormonal DSDs, taken together, indicate that gender identity is not solely dependent
on prenatal and postnatal androgen exposure; however, the occurrence of gender identity change (in comparison to the “natal gender”) at a rate
significantly higher than would be expected in the general population supports some role of prenatal and possibly postnatal androgens in gender
identity development. Potential limitations of all these survey/questionnairebased studies to assess gender identity include a person’s degree of self
awareness and one’s willingness to disclose this information in the study context.
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some role of androgens in male gender identity, a case report in a 46, XY individual with complete androgen
insensitivity syndrome (CAIS) challenges the concept that androgen receptor (AR) signaling is required for male gender identity development.
Individuals with CAIS typically have unambiguous female genitalia and a female gender identity; however, an individual with CAIS, associated with an
unambiguous female phenotype and an AR gene mutation resulting in a premature stop codon, was found to have a male gender identity (26). As
These studies of gender identity outcome in hormonal and nonhormonal DSDs, taken together, indicate that gender identity is not solely dependent
on prenatal and postnatal androgen exposure; however, the occurrence of gender identity change (in comparison to the “natal gender”)
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significantly higher than would be expected in the general population supports some role of prenatal and possibly postnatal androgens
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identity development. Potential limitations of all these survey/questionnairebased studies to assess gender identity include a person’s degree of self
awareness and one’s willingness to disclose this information in the study context.
While the abovenoted studies support some role of androgens in male gender identity, a case report in a 46, XY individual with complete androgen
insensitivity syndrome (CAIS) challenges the concept that androgen receptor (AR) signaling is required for male gender identity development.
Individuals with CAIS typically have unambiguous female genitalia and a female gender identity; however, an individual with CAIS, associated with an
unambiguous female phenotype and an AR gene mutation resulting in a premature stop codon, was found to have a male gender identity (26). As
acknowledged by the authors of that study, this patient may have had a postzygotic de novo AR gene mutation (the mother’s DNA was not available)
and could theoretically have brain mosaicism (with a normal AR in the brain).
With respect to genetics and gender identity, heritability of transsexualism has been suggested primarily from studies describing concordance of
transsexualism in monozygotic twin pairs. A study of survey responses from parents of twins (96 monozygotic pairs and 61 dizygotic pairs, ages 714
years) demonstrated a 2.3% prevalence of clinically significant GID (based on DSMIV criteria). These authors reported that heritability accounted for
62% of the variance for GID in their twin sample. A more recent study supporting a role for genetic factors in gender identity outcome demonstrated a
39.1% concordance for GID (based on DSMIV criteria) in 23 monozygotic female and male twin pairs, with no concordance in 21 samesex dizygotic
female and male twin pairs or in 7 oppositesex twin pairs. However, with respect to specific candidate genes [estrogen receptor α (ERα) and β (ERβ),
androgen receptor (AR), aromatase, (CYP19), progesterone receptor (PGR), and the CYP17 gene], association studies of polymorphisms with
transsexualism have been inconsistent and lacking strong statistical significance.
With respect to neuroanatomical considerations and gender identity, it has been known for some time that some brain structures are sexually
dimorphic, while one component of the hypothalamus has been reported to be sexual orientationdimorphic. Numerous studies in transgender
adults, carried out prior to any crosssex hormone treatment, have provided evidence indicating that some sexually dimorphic structures appear to
align more closely with a person’s gender identity than with their physical sex characteristics. A trend towards similar findings has also been reported
in MRI studies of gray matter of gender dysphoric youth.
Transgender Youth: Natural History
Once puberty has begun, the majority of gender dysphoric prepubertal youth will no longer meet the mental health criteria for gender dysphoria.
While gender fluidity may be a contributing factor, the lack of persistence of gender dysphoria in the majority of gender dysphoric prepubertal youth
likely reflects the heterogeneous nature of this group. Many such individuals will turn out to be homosexual (natal males, in particular) rather than
transgender. Investigators have attempted to identify factors that predict gender dysphoria “persisters” versus “desisters.” Persisters reported
relatively greater degrees of gender dysphoria and were more likely to have experienced social transition (to their affirmed gender) during childhood.
In addition, persisters believed they “were” the other sex, while desisters “wished they were” the other sex. The limitations in prediction of persistence,
coupled with the observation that most gender dysphoric children will not become transgender adolescents or adults, have led some investigators
and/or practitioners to promote efforts to encourage gender dysphoric children to accept their natal gender. In contrast, a model of care that affirms a
child’s gender expression is thought to have a more optimal mental health outcome. Longterm outcomes studies are needed to resolve these
differences in approach to the care of gender dysphoric prepubertal youth.
Clinical Practice Guidelines for Transgender Youth
Persistence of gender dysphoria following initiation of puberty implies a very high likelihood that such individuals will be transgender as adults; in fact,
the emergence or worsening of gender dysphoria with onset of puberty is thought to have significant diagnostic value in the determination of being
transgender. With the availability of genderaffirming medical interventions (as detailed later), however, awareness of such treatment options may
positively impact and, thus, limit the degree of dysphoria that might otherwise accompany the onset of puberty in a transgender individual. It is
therefore essential that gender dysphoric youth undergo a thorough psychological diagnostic evaluation by a qualified mental health provider. An
important role of the mental health/gender specialist is not only to determine the presence or absence of gender dysphoria, but also to evaluate for
the presence of other mental health concerns. For example, while there is an increased association of gender dysphoria and autism spectrum
disorder, the majority of gender dysphoric children and adolescents do not have an underlying severe psychiatric illness.
Management of Early Pubertal Transgender Youth
Pubertal suppression with a gonadotropin releasing hormone (GnRH) agonist (classically used for the treatment of precocious puberty) in early/mid
pubertal gender dysphoric adolescents was first described in studies from the Netherlands. This treatment is fully reversible and allows additional
time for gender exploration without the pressure of ongoing pubertal development. The physical changes of puberty, once completed, cannot be
reversed (by means
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Chapter 23:males
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developmentStephen M. Rosenthal;
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females. Preventing pubertal development that does not match a person’s genderPage 5 / 22
identity
can theoretically lead to decreased distress and can ultimately enable the individual to more easily “blend” in society as an adult. Subsequently, if the
individual continues to identify as transgender, crosssex hormones can be added while continuing GnRH agonist suppression of endogenous
puberty, enabling the individual to experience only the physical changes of puberty that match the person’s experienced/affirmed gender identity. The
Management of Early Pubertal Transgender Youth
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Pubertal suppression with a gonadotropin releasing hormone (GnRH) agonist (classically used for the treatment of precocious puberty) in early/mid
pubertal gender dysphoric adolescents was first described in studies from the Netherlands. This treatment is fully reversible and allows additional
time for gender exploration without the pressure of ongoing pubertal development. The physical changes of puberty, once completed, cannot be
reversed (by means other than surgical or, for voice, other than by voice training)—for example, low voice, Adam’s apple, and facial features in
phenotypic males and breast development in phenotypic females. Preventing pubertal development that does not match a person’s gender identity
can theoretically lead to decreased distress and can ultimately enable the individual to more easily “blend” in society as an adult. Subsequently, if the
individual continues to identify as transgender, crosssex hormones can be added while continuing GnRH agonist suppression of endogenous
puberty, enabling the individual to experience only the physical changes of puberty that match the person’s experienced/affirmed gender identity. The
Endocrine Society (ES) guidelines and WPATH SOC endorse the use of pubertal blockers (using GnRH agonists) at Tanner 2/3 in individuals
experiencing a significant increase in gender dysphoria with onset of puberty. While agespecific guidelines for subsequent interventions are not
delineated in the WPATH SOC, the ES guidelines suggest that crosssex hormones can be initiated at about the age of 16 years (the legal age for medical
decisionmaking in some countries), while surgical procedures (with the exception of mastectomy) should be deferred until the individual is at least 18
years of age. Delaying crosssex hormone treatment until age 16 could not only be detrimental to bone health, but, by keeping someone in a
prepubertal state until this age, would isolate the individual further from agematched peers, with potentially negative consequences for emotional
wellbeing. Gender centers at our institution and elsewhere are therefore studying the impact of crosssex hormone treatment initiation at 14 years of
age (which approximates the upper end of the age range for normal pubertal onset in natal males and 1 year beyond the upper end of the age range in
natal females). In this group, sex steroids are increased gradually over the course of 2 to 3 years.
The abovenoted ES and WPATH recommendations are supported by limited available outcomes data. A prospective followup study from the
Netherlands assessed 70 gender dysphoric adolescents (33 MTF, 37 FTM), average age 13.65 years (range 11.117 years) at initial assessment, who were
Tanner Stage 2 to 3, had “lifelong gender dysphoria” that increased with puberty, had stable psychological function, and were supported by their
families. These adolescents were studied at the initiation of GnRH agonist treatment and approximately 2 years later, just before starting crosssex
hormones. While gender dysphoria persisted, depressive symptoms decreased, general mental health functioning improved, no subjects withdrew
from pubertal suppression, and all went on to crosssex hormone treatment. A subsequent report from this initial cohort in the Netherlands assessed
mental health outcomes in 55 transgender adolescents/young adults (22 MTF, 33 FTM) at 3 time points: before the start of GnRH agonist treatment, at
initiation of crosssex hormones (average 16.7 years at start of treatment), and at least 1 year after “gender reassignment surgery” (average age 20.7
years). Despite a decrease in depression and an improvement in general mental health functioning, gender dysphoria persisted during the period of
pubertal suppression (as noted in earlier reports); however, following crosssex hormone treatment and “gender reassignment surgery,” gender
dysphoria was resolved, and psychological functioning steadily improved. Wellbeing was found to be similar to or better than that in agematched
young adults from the general population, and none of the study participants regretted treatment. This study represents the first longterm followup
of patients managed according to currently existing clinical practice guidelines for transgender youth and underscores the benefit of the
multidisciplinary approach to care.
The primary risks of pubertal suppression in gender dysphoric youth treated with GnRH agonists include adverse effects on bone mineralization,
compromised fertility, and unknown effects on brain development.
Bone mineral density (BMD) studies of the lumbar spine, femoral neck, and total body were initially carried out in a small number of gender dysphoric
adolescents during 2 years of GnRH agonist alone and for an additional 2 years of combination treatment with GnRH agonist and crosssex hormones.
BMD (g/cm2) did not change significantly during treatment with GnRH agonist alone, though zscores decreased; during combination therapy with
GnRH agonist and crosssex hormones, absolute BMD increased, as did zscores.
A 6year longitudinal, observational study assessed BMD in 34 transgender adolescents (15 MTF, 19 FTM) who had received GnRH agonist beginning at
an average age of 14.9 to 15 years (individuals were midlate pubertal at study onset by testicular volume or breast stage), had initiation of crosssex
hormones at 16.4 to 16.6 years, followed by gonadectomy with discontinuation of GnRH agonist at a minimum age of 18 years. Over the 6year
observation period, areal BMD zscores decreased significantly in MTF individuals with a trend for a decrease in FTM individuals, suggesting either a
delay in attainment of peak bone mass, or an attenuation of peak bone mass, itself. As acknowledged by the authors, potential study limitations
included a relatively small number of subjects, the fact that individuals were already late pubertal at the time of GnRH agonist initiation, the possibility
that relatively low doses of crosssex hormones were used during the initial period of that phase of treatment, and that information was not available
regarding dietary calcium intake, vitamin D levels, and weight bearing exercise, all of which can influence BMD. It would seem important, particularly
during GnRH agonist treatment, to ensure adequate intake of calcium and vitamin D, to encourage weightbearing exercise, and to monitor levels of 25
OH vitamin D routinely.
Any use of pubertal blockers and crosssex hormones in transgender youth should include an informed consent process and a discussion about
implications for fertility. Transgender adolescents may wish to preserve fertility, which may be otherwise compromised if puberty is suppressed at an
early stage and
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Chapter 23: Transgender Endocrinology, Stephen M. Rosenthal;
been achieved in humans, promising studies have been carried outWylie C. Hembree
in mice. Page 6 / 22
Regarding potential adverse effects of GnRH agonists (and crosssex hormones) on the brain, a recent study investigated whether GnRH agonist
treatment of gender dysphoric adolescents would impair executive functioning (reasoning, problem solving, etc.), thought to reflect prefrontal brain
regarding dietary calcium intake, vitamin D levels, and weight bearing exercise, all of which can influence BMD. It would seem important, particularly
during GnRH agonist treatment, to ensure adequate intake of calcium and vitamin D, to encourage weightbearing exercise, and to monitor levels of 25
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OH vitamin D routinely.
Any use of pubertal blockers and crosssex hormones in transgender youth should include an informed consent process and a discussion about
implications for fertility. Transgender adolescents may wish to preserve fertility, which may be otherwise compromised if puberty is suppressed at an
early stage and the patient completes phenotypic transition with the use of crosssex hormones. While full in vitro maturation of germ cells has not yet
been achieved in humans, promising studies have been carried out in mice.
Regarding potential adverse effects of GnRH agonists (and crosssex hormones) on the brain, a recent study investigated whether GnRH agonist
treatment of gender dysphoric adolescents would impair executive functioning (reasoning, problem solving, etc.), thought to reflect prefrontal brain
activation, and to have significant development during puberty. No significant detrimental effects of GnRH agonist treatment on executive functioning
were observed.
A report from Vancouver, Canada, assessed potential adverse effects of GnRH agonist treatment in transgender youth. Relatively few adverse effects
were observed: Of 27 patients receiving GnRH agonist, one developed a sterile abscess at the injection site, one developed transient leg pains and
headaches, and one developed significant weight gain.
Management of Late Pubertal Transgender Youth
It is not unusual for some transgender adolescents to first come to medical attention when they are late pubertal (Tanner 4/5). FTM individuals can be
treated with testosterone alone while MTF individuals are optimally treated with estrogen with concurrent use of an agent that blocks testosterone
secretion and/or action. GnRH agonists can be used to suppress the hypothalamicpituitarygonadal axis, potentially enabling use of lower doses of
crosssex hormones to induce phenotypic transition to the affirmed gender, thereby decreasing potential toxicities associated with crosssex hormone
treatment. In this older cohort, crosssex hormone regimens may be increased to full replacement doses over a shorter interval than used for the
younger cohort that had been initially treated with pubertal blockers at Tanner 2/3. While GnRH agonists are the preferred option for pubertal
suppression in both the early and late pubertal individuals, this treatment is costly and often inaccessible. Options for pubertal suppression and cross
sex hormone treatment are listed in Table 23–1. With respect to estrogen treatment, 17 βestradiol (transdermal, oral, or parenteral) is preferred to
conjugated (eg, premarin) or synthetic estrogens (eg, ethinyl estradiol) given that conjugated and synthetic estrogen levels cannot be monitored in the
serum and that ethinyl estradiol (in comparison to 17 βestradiol) is associated with an increased risk for venous thromboembolic disease and death
from cardiovascular causes. MTF individuals treated with estrogen may have impaired insulin sensitivity and hyperprolactinemia. Principal risks
associated with testosterone treatment in FTM individuals include cystic acne, polycythemia, hypertension, an atherogenic lipid profile, and possible
decreased insulin sensitivity. Table 23–2 summarizes surveillance recommendations for desired as well as adverse effects during treatment with
pubertal blockers alone and in combination with crosssex hormones, adapted from the current ES guidelines.
TABLE 23–1
Hormonal interventions for transgender adolescents (all currently offlabel for gender nonconforming/transgender youth).
A. Inhibitors of gonadal sex steroid secretion or action

1. GnRH analogues: Inhibition of the hypothalamicpituitarygonadal (HPG) axis (FTM and MTF)
a. Leuprolide acetate IM (1 or 3month preparations) or SC (1, 3, 4, or 6month preparations) at dose sufficient to suppress pituitary
gonadotropins and gonadal sex steroids
b. Histrelin acetate 50 mg SC implant (onceyearly dosing, though may have longer effectiveness)
c. Other options: goserelin acetate SC implant (4 or 12week preparations); nafarelin acetate intranasal (multiple daily doses) also available, but
no reported use in this population
2. Alternative approaches
a. Medroxyprogesterone acetate orally (up to 40 mg/d) or IM (150 mg q 3 months): Inhibition of HPG axis and direct inhibition of gonadal
steroidogenesis (FTM and MTF)
b. Spironolactone (2550 mg/d with gradual increase to 100300 mg/d orally, divided into BID dosing): Inhibition of testosterone synthesis and
action (MTF)
c. Cyproterone acetate (gradual increase up to 100 mg/d orally; not available in United States): Inhibition of testosterone synthesis and action
(MTF)
d. Finasteride (2.55 mg/d orally): Inhibition of Type II 5αreductase, blocking conversion of testosterone to 5αdihydrotestosterone (MTF)
B. Crosssex hormones
1. MTF: Estrogen: 17 βestradiol
a. Transdermal: twice weekly patches [6.25 μg (achieved by cutting a 25 mcg patch) with gradual increase to full adult dose (typically, 100200 μg
patch)] Oral/sublingual: daily (0.25 mg with gradual increase to full adult dose of 26 mg/d)
b. Parenteral
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of 17 βestradiol): estradiolPolicy
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• Notice up to 3040 mg q 2 weeks) or estradiol cypionate (210
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mg q 1 week)
2. FTM: Testosterone
from cardiovascular causes. MTF individuals treated with estrogen may have impaired insulin sensitivity and hyperprolactinemia. Principal risks
associated with testosterone treatment in FTM individuals include cystic acne, polycythemia, hypertension, an atherogenic lipid profile, and possible
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decreased insulin sensitivity. Table 23–2 summarizes surveillance recommendations for desired as well as adverse effects during treatment with
pubertal blockers alone and in combination with crosssex hormones, adapted from the current ES guidelines.
TABLE 23–1
Hormonal interventions for transgender adolescents (all currently offlabel for gender nonconforming/transgender youth).
A. Inhibitors of gonadal sex steroid secretion or action

1. GnRH analogues: Inhibition of the hypothalamicpituitarygonadal (HPG) axis (FTM and MTF)
a. Leuprolide acetate IM (1 or 3month preparations) or SC (1, 3, 4, or 6month preparations) at dose sufficient to suppress pituitary
gonadotropins and gonadal sex steroids
b. Histrelin acetate 50 mg SC implant (onceyearly dosing, though may have longer effectiveness)
c. Other options: goserelin acetate SC implant (4 or 12week preparations); nafarelin acetate intranasal (multiple daily doses) also available, but
no reported use in this population
2. Alternative approaches
a. Medroxyprogesterone acetate orally (up to 40 mg/d) or IM (150 mg q 3 months): Inhibition of HPG axis and direct inhibition of gonadal
steroidogenesis (FTM and MTF)
b. Spironolactone (2550 mg/d with gradual increase to 100300 mg/d orally, divided into BID dosing): Inhibition of testosterone synthesis and
action (MTF)
c. Cyproterone acetate (gradual increase up to 100 mg/d orally; not available in United States): Inhibition of testosterone synthesis and action
(MTF)
d. Finasteride (2.55 mg/d orally): Inhibition of Type II 5αreductase, blocking conversion of testosterone to 5αdihydrotestosterone (MTF)
B. Crosssex hormones
1. MTF: Estrogen: 17 βestradiol
a. Transdermal: twice weekly patches [6.25 μg (achieved by cutting a 25 mcg patch) with gradual increase to full adult dose (typically, 100200 μg
patch)] Oral/sublingual: daily (0.25 mg with gradual increase to full adult dose of 26 mg/d)
b. Parenteral IM (synthetic esters of 17 βestradiol): estradiol valerate (520 mg increasing up to 3040 mg q 2 weeks) or estradiol cypionate (210
mg q 1 week)
2. FTM: Testosterone
a. Parenteral IM or SC (synthetic esters of testosterone): testosterone cypionate or enanthate (12.5 mg q week or 25 mg q 2 weeks, with gradual
increase to 50100 mg q week or 100200 mg q 2 weeks)
b. Transdermal (consider once full adult testosterone dose has been achieved parenterally): patch (26 mg/d) or 1.62% gel (20.2581 mg/d)
Abbreviations: MTF, MaletoFemale; FTM, FemaletoMale.
Reproduced with permission from Rosenthal SM. Approach to the patient: transgender youth: endocrine considerations. J Clin Endocrinol Metab. 2014 Dec;99(12):
43794389.
TABLE 23–2
Monitoring during pubertal suppression and during crosssex hormone treatment.*
A. Pubertal suppression
Measure Frequency
1. Physical examination: height, weight, Tanner Staging T 0 & q 3 mo
2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T 0 & q 3 mo
3. Metabolic: Ca, phos, alk phos, 25OH Vitamin D (see also ref. 3) T 0 & q 1 yr
4. Bone mineral density: DXA T 0 & q 1 yr

Chapter 5.
23:Bone age
Transgender Endocrinology, Stephen M. Rosenthal; Wylie C. Hembree T 0 & qPage
1 yr 8 / 22
B. Crosssex hormone treatment in previously suppressed patients or in late pubertal patients not previously suppressed
Abbreviations: MTF, MaletoFemale; FTM, FemaletoMale. Universitas Diponegoro Library
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Reproduced with permission from Rosenthal SM. Approach to the patient: transgender youth: endocrine considerations. J Clin Endocrinol Metab. 2014 Dec;99(12):
43794389.
TABLE 23–2
Monitoring during pubertal suppression and during crosssex hormone treatment.*
A. Pubertal suppression
Measure Frequency
1. Physical examination: height, weight, Tanner Staging T 0 & q 3 mo
2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T 0 & q 3 mo
3. Metabolic: Ca, phos, alk phos, 25OH Vitamin D (see also ref. 3) T 0 & q 1 yr
4. Bone mineral density: DXA T 0 & q 1 yr
5. Bone age T 0 & q 1 yr
B. Crosssex hormone treatment in previously suppressed patients or in late pubertal patients not previously suppressed
Measure Frequency
1. Physical examination: height, weight, Tanner Staging, BP (for FTM, in particular); monitor for adverse reactions T0&q3
mo**
2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T0&q3

If MTF: also monitor prolactin mo**
T 0 & q 1 yr
3. Metabolic: Ca, phos, alk phos, 25OH vitamin D, complete blood count, renal & liver function, fasting lipids, glucose, insulin, T0&q3
glycosylated hemoglobin mo**
If MTF on spironolactone: serum electrolytes (potassium) T0&q3
mo**
4. Bone mineral density: DXA (if puberty previously suppressed) T0&q1

yr***
5. Bone age (if puberty previously suppressed) T0&q1

yr***
*Modified from Hembree WC et al., 2009; **q 312 mo after 1st yr; ***Until puberty is completed.
Abbreviations: MTF, MaletoFemale; FTM, FemaletoMale.
Data from Hembree WC, CohenKettenis P, Delemarrevan de Waal HA, et al. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab. 2009 Sep;94(9):31323154.
Some Tanner 4/5transgender adolescents present for medical services before 16 years of age. As with the group treated with GnRH agonists at early
puberty, we and others are studying the consequences of crosssex hormone treatment at 14 years of age. Some gender dysphoric youth first come to
medical attention when they are Tanner 4/5, but less than 14 years of age. These individuals would be candidates for pubertal blockers (eg, to stop
menses in an FTM adolescent), but without supportive outcomes data, they would not currently be candidates for crosssex hormone use under most
circumstances.
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Areas of Uncertainty/Barriers to Care/and Priorities for Research Policy • Notice • Accessibility
Areas of uncertainty and barriers to stateofthe art practice limit the ability to provide optimal health care to gender dysphoric/transgender youth.
guideline. J Clin Endocrinol Metab. 2009 Sep;94(9):31323154.
Some Tanner 4/5transgender adolescents present for medical services before 16 years of age. As with the group treated withProvided
Access GnRHby:agonists at early
puberty, we and others are studying the consequences of crosssex hormone treatment at 14 years of age. Some gender dysphoric youth first come to
medical attention when they are Tanner 4/5, but less than 14 years of age. These individuals would be candidates for pubertal blockers (eg, to stop
menses in an FTM adolescent), but without supportive outcomes data, they would not currently be candidates for crosssex hormone use under most
circumstances.
Areas of Uncertainty/Barriers to Care/and Priorities for Research
Areas of uncertainty and barriers to stateofthe art practice limit the ability to provide optimal health care to gender dysphoric/transgender youth.
Currently, there are only limited safety and efficacy studies, with virtually no published data on the use of pubertal blockers in gender dysphoric
individuals less than 12 years of age or crosssex hormones in transgender youth less than 16 years of age. In addition, randomized controlled trials for
hormonal interventions in gender dysphoric youth have not been considered feasible or ethical. Current clinical practice guidelines are based on best
available evidence, with significant reliance on expert opinion. The Institute of Medicine of the National Academies in the United States has endorsed
the need for prospective, longitudinal safety, and efficacy studies of medical interventions in gender nonconforming/transgender youth. Challenges
to implementation of current clinical practice guidelines in the United States include the fact that pubertal blockers and crosssex hormone treatments
are offlabel for gender dysphoric youth, are expensive, and coverage is often denied by insurance companies. In addition, while an increasing number
of clinical programs have emerged in recent years, there are many geographic regions in which such services do not exist, limiting access to care and
often requiring patients and families to travel long distances. Furthermore, lack of training of providers and prejudice and misunderstanding on the
part of family, community, and medical and mental health professionals may limit access to optimal care. A report surveying the memberships of the
Pediatric Endocrine Society and the Society for Adolescent Health and Medicine explored providers’ clinical experiences, comfort, and confidence with
and barriers to providing care to transgender youth. Principal barriers to provision of transgenderrelated care included lack of the following: training,
exposure to transgender patients, available qualified mental health providers, and insurance reimbursement.
Endocrine Management of Transgender Youth: Conclusions
Significant advances in our understanding of gender nonconforming/transgender youth have been achieved, though many gaps in knowledge remain.
Compelling studies have demonstrated that gender identity is not simply a psychosocial construct, but likely reflects a complex interplay of biologic,
environmental, and cultural factors. The replacement of “disorder” with “dysphoria” in DSM5 removes the connotation that a transgender identity,
itself, is pathologic, and instead, focuses on dysphoria as the clinical concern. A landmark study from the Netherlands indicates that mental health
comorbidities in genderdysphoric youth significantly diminish or resolve when such individuals are subject to a genderaffirming model of care,
optimally delivered in a multidisciplinary clinical setting. Further prospective studies focused on longterm safety and efficacy are necessary to
optimize medical and mental health care for transgender youth.
PART II: ENDOCRINE MANAGEMENT OF TRANSGENDER ADULTS

Introduction
The age adulthood begins is variably defined at age 18 to 21 years, at which time persons can independently give informed consent for invasive
procedures. Most persons this age who have persistent gender dysphoria are treated with adult protocols. The natural history of gender dysphoria in
adults has not been well documented although when most adults present for hormone treatment they describe the occurrence of symptoms
beginning during childhood. The goals of Part II of this chapter are to review adult presentation of gender dysphoria, endocrine status in adults with
gender dysphoria, strategies for sex steroid treatment, potential adverse effects of estradiol and testosterone treatment, genital and breast surgery
options, reproductive decisions, the role of voice therapy, and considerations for care of elder transgender individuals.
Adult Presentation of Gender Dysphoria
Adults with gender dysphoria variably present to mental health professionals, to physicians experienced in endocrine treatment, to surgeons, or to
clinics with all of these types of providers. Appropriate clinical management may require all of the above. The first step is confirmation of the diagnosis,
gender dysphoria, assessment of readiness of the person to begin treatment and evaluation of risk factors for medical treatment (Table 23–3). Rarely,
adults with psychological and/or developmental problems may present with gender problems but are not confirmed to exhibit gender dysphoria. The
second step is exploration of appropriate hormonal protocols, including the associated risks, benefits, and contraindications. Third, hormone
treatment is initiated using varying protocols suitable for transgender women (MTF) or transgender men (FTM) (Table 23–4). Consultation with
surgeons who specialize in genital surgery occurs after at least 1 year of crosssex hormone treatment. Breast and facial surgery are commonly
explored.
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adults with psychological and/or developmental problems may present with gender problems but are not confirmed to exhibit gender dysphoria. The
Universitas
second step is exploration of appropriate hormonal protocols, including the associated risks, benefits, and contraindications. Diponegoro
Third, hormone Library
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treatment is initiated using varying protocols suitable for transgender women (MTF) or transgender men (FTM) (Table 23–4). Consultation with
explored.
TABLE 23–3
Hormone protocols for transgender adults.
A. Maletofemale (MTF) protocols
a. Phase 1: Blocking testosterone production

(May be given initially to reduce testosterone levels or simultaneously with estrogen)
i. Spironolactone 100200 mg/d
ii. Cyproterone acetate 50100 mg/d
iii. GnRH analog 3.76 mg/mo
(Gonadotropin Releasing Hormone Agonist)
b. Phase 2: Estradiol administration
i. Oral estradiol 2.05.0 mg daily
ii. Transdermal E2 patch 0.10.4 23× weekly*
iii. Parenteral E2 valerate or cypionate 210 mg/wk
B. Femaletomale (FTM) protocols
a. Phase 1: Blocking ovulation/estradiol production

(Note: Testosterone injections alone at early follicular phase may block ovulation)
i. Medroxyprogesterone acetate 3040 mg/d
iii. GnRH analog 3.7515 mg q 13 mo
b. Phase 2: Testosterone administration

(Note: Phase 1 medications may be given before, simultaneously or not at all with testosterone)
i. Transdermal
1. Testosterone Gel 1% 2.510 mg/d
2. Testosterone transdermal patch 2.510 mg/q 23 d
ii. Parenteral
1. Testosterone enanthate/cypionate 50100 mg q 2 wks
3060 mg q wk
2. Testosterone undecanoate 1000 mg q 812 wks

©2024
* McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Recommended for MTF over 40 years old
**Synthetic estradiol esters not recommended

explored. Universitas Diponegoro Library
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TABLE 23–3
Hormone protocols for transgender adults.
A. Maletofemale (MTF) protocols
a. Phase 1: Blocking testosterone production

(May be given initially to reduce testosterone levels or simultaneously with estrogen)
i. Spironolactone 100200 mg/d
iii. GnRH analog 3.76 mg/mo
(Gonadotropin Releasing Hormone Agonist)
b. Phase 2: Estradiol administration
i. Oral estradiol 2.05.0 mg daily
ii. Transdermal E2 patch 0.10.4 23× weekly*
iii. Parenteral E2 valerate or cypionate 210 mg/wk
B. Femaletomale (FTM) protocols
a. Phase 1: Blocking ovulation/estradiol production

(Note: Testosterone injections alone at early follicular phase may block ovulation)
i. Medroxyprogesterone acetate 3040 mg/d
iii. GnRH analog 3.7515 mg q 13 mo
b. Phase 2: Testosterone administration

(Note: Phase 1 medications may be given before, simultaneously or not at all with testosterone)
i. Transdermal
1. Testosterone Gel 1% 2.510 mg/d
2. Testosterone transdermal patch 2.510 mg/q 23 d
ii. Parenteral
1. Testosterone enanthate/cypionate 50100 mg q 2 wks
3060 mg q wk
*Recommended for MTF over 40 years old

TABLE 23–4
Transgender medical evaluation.
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*Recommended for MTF over 40 years old
TABLE 23–4
Transgender medical evaluation.
1. Review gender dysphoria history

a. If present, review mental health professional recommendation
2. Medical and mental health history
a. Assess risk factors to sex steroids
i. Transgender women (MTF)
1. Thromboembolic disease/history
2. Hyperprolactinemia
3. Cerebrovascular disease
4. Severe migraine headaches
5. Breast cancer
ii. Transgender men (FTM)
1. Erythrocytosis
2. Severe liver dysfunction
3. Hypertension
4. Breast or uterine cancer
b. Family history
i. Reproductive tract cancer
ii. Diagnosis of mental health illness
iii. Osteoporosis/history of bone fracture
3. Medications and allergies
4. Alcohol use, smoking, addiction history, hospitalizations
5. Physical examination
a. Breast examination
b. Reproductive tract examination
In clinical practice, persons with gender dysphoria who seek treatment with sex steroids, genital surgery and social transition to a new gender may
present at any time during adulthood. Clinical histories usually describe genderrelated conflicts with their natal sex, especially during puberty. Many
have married, become parents, and lived as a person of their natal sex, a man or a woman. Conflicts between natal sex and gender often occasion
presentation to a mental health professional, although the diagnosis of gender dysphoria may not be apparent. Most give a history of incomplete
resolution of childhood symptoms despite living in their natal sex as adults. Exploration of the components of gender change includes discussions of
hormone treatment as well as surgical options. New onset of gender dysphoria as an adult is unusual.
Endocrine Considerations and Management
Endocrine evaluation of adults with gender dysphoria usually discovers normal development of the body that reflects natal sex changes as well as,
after puberty, body changes produced by appearance of their natal sex hormones. However, amongst some persons with a DSD, CAH, AIS, and 5αRD,
there is more frequent occurrence of gender dysphoria and gender change than in the general population. Studies of the relationship of early
exposure to androgens may explain sexual and social behavior, but they do not clarify patientinitiated gender choice. However, circulating levels of
testosterone, metabolism to estrogens, and impact upon bone development in natal males are determined, in large part, genetically. This may account
for the variability observed in bone responses during sex steroid treatment.
The design of the sex steroid protocols used is based upon, first, the treatment that will most appropriately and completely suppress natal sex
steroids, either before or at the same time exogenous sex steroids are given (see Table 23–4). Second, the protocol should utilize the most effective
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by which sexAsteroids
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182.255.0.242
person’s new gender can be administered. For example, some FTM protocols may use testosterone
Chapter 23: Transgender Endocrinology, Stephen M. Rosenthal;
alone, thereby suppressing ovulation, preventing uterine bleeding,Wylie C. Hembree
achieving
Page 13 / 22
effective virilization, while avoiding adverse effects. On the other hand,
MTF protocols using physiologic replacement doses of estradiol alone may not sufficiently suppress endogenous testosterone levels and, thereby,
result in insufficient feminization. In such cases, it may be necessary to use additional agents, initially alone or as a combination with estrogens, that
exposure to androgens may explain sexual and social behavior, but they do not clarify patientinitiated gender choice. However, circulating levels of
testosterone, metabolism to estrogens, and impact upon bone development in natal males are determined, in large part, genetically. This may account
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for the variability observed in bone responses during sex steroid treatment.
The design of the sex steroid protocols used is based upon, first, the treatment that will most appropriately and completely suppress natal sex
steroids, either before or at the same time exogenous sex steroids are given (see Table 23–4). Second, the protocol should utilize the most effective
available method by which sex steroids of the person’s new gender can be administered. For example, some FTM protocols may use testosterone
alone, thereby suppressing ovulation, preventing uterine bleeding, achieving effective virilization, while avoiding adverse effects. On the other hand,
MTF protocols using physiologic replacement doses of estradiol alone may not sufficiently suppress endogenous testosterone levels and, thereby,
result in insufficient feminization. In such cases, it may be necessary to use additional agents, initially alone or as a combination with estrogens, that
will effectively suppress endogenous testosterone levels to those of natal women. Progestins have been used frequently to suppress endogenous sex
steroids, as have GnRH analogs. The doses of exogenous sex steroids required to suppress endogenous sex steroids may vary with the individual, the
dose used, the method of administration and their natal sex.
The goal of testosterone treatment in transgender men (FTM) with regular menses is to suppress ovulation and, thereby, maintain low estradiol levels.
Thus, the time to initiate testosterone treatment in protocols for transgender men (FTM) is important. Treatment should begin during or immediately
following menses when estradiol and progesterone levels are lowest, when there is little stimulation of the endometrium and there is no follicular
development (estrogen levels are in the male normal range). Levels of free testosterone should be maintained above the midrange of the adult natal
male in order to suppress follicular development and uterine bleeding. Testosterone may be given by intramuscular injection or by transdermal
application of testosterone gel. Transdermal patches do not permit easy dose adjustment. Total and free testosterone, total estradiol, and LH/FSH
levels should be measured at 3month intervals initially to ensure ovarian suppression and to avoid adverse effects (Table 23–5).
TABLE 23–5
Monitoring sex steroid treatment in adults maletofemale (MTF).
1. Signs of feminization
a. Evaluate 34 times year 1 and 12 times years 24
b. Breast growth
c. Loss of terminal hair growth
d. Body fat redistribution
e. Decrease testicular size
2. Assess hormone levels
a. Evaluate 34 times year 1 and 12 times year 24
b. Estradiol: 100200 pg/dL
c. Testosterone: <50 ng/dL
d. Prolactin: Pretreatment, annual
e. LH/FSH: if testosterone levels >100 ng/dL
3. Spironolactone use
a. Electrolytes (potassium): Baseline, every 23 months × 2 and after increased dose × 2
4. Bone mineral density assessment
a. Baseline if risk factors present
b. Age 60 years old
c. Noncompliant sex steroid use
d. Cessation of sex steroids
5. Routine breast, colon, and prostate cancer screening
Femaletomale (FTM)
1. Signs of virilization:
b. Cessation of menses
c. Facial/body hair growth
d. Increase muscle mass
e. Deepening of voice
f. Clitoral enlargement
Chapter 23:a.Transgender
Measure testosterone every 3 months
Endocrinology, StephenuntilM.
levels remain inWylie
Rosenthal; physiologic range of natal adult male;
C. Hembree Page 14 / 22
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levels within• physiologic
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range of natal adult male × 2;
c. Transdermal testosterone: assess after 2 weeks of use, measure more than 2 hours after application;
d. Testosterone undecanoate: measure testosterone prior to next injection; if <400 ng/dL, increase dose/interval;
development (estrogen levels are in the male normal range). Levels of free testosterone should be maintained above the midrange of the adult natal
male in order to suppress follicular development and uterine bleeding. Testosterone may be given by intramuscular injection or by transdermal
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application of testosterone gel. Transdermal patches do not permit easy dose adjustment. Total and free testosterone, total estradiol, and LH/FSH
levels should be measured at 3month intervals initially to ensure ovarian suppression and to avoid adverse effects (Table 23–5).
TABLE 23–5
Monitoring sex steroid treatment in adults maletofemale (MTF).
1. Signs of feminization
b. Breast growth
c. Loss of terminal hair growth
d. Body fat redistribution
e. Decrease testicular size
a. Evaluate 34 times year 1 and 12 times year 24
b. Estradiol: 100200 pg/dL
c. Testosterone: <50 ng/dL
d. Prolactin: Pretreatment, annual
e. LH/FSH: if testosterone levels >100 ng/dL
3. Spironolactone use
a. Electrolytes (potassium): Baseline, every 23 months × 2 and after increased dose × 2
4. Bone mineral density assessment
a. Baseline if risk factors present
b. Age 60 years old
c. Noncompliant sex steroid use
d. Cessation of sex steroids
5. Routine breast, colon, and prostate cancer screening
Femaletomale (FTM)
1. Signs of virilization:
b. Cessation of menses
c. Facial/body hair growth
d. Increase muscle mass
e. Deepening of voice
f. Clitoral enlargement
a. Measure testosterone every 3 months until levels remain in physiologic range of natal adult male;
b. Testosterone enanthate/cypionate: demonstrate peak and trough levels within physiologic range of natal adult male × 2;
c. Transdermal testosterone: assess after 2 weeks of use, measure more than 2 hours after application;
d. Testosterone undecanoate: measure testosterone prior to next injection; if <400 ng/dL, increase dose/interval;
3. Obtain weight, CBC, blood pressure, lipids every 34 months year 1 and 12 times yearly thereafter;
4. Annual PAP if cervix present;
5. If mastectomy, regular examination of periareolar tissue; if no mastectomy, mammograms as recommended by the American Cancer Society.
When transgender men are given high doses of testosterone, the biologically active free testosterone is determined by the clearance rate of
testosterone, the binding to SHBG and the aromatization to estradiol. Variation in each of the above will determine the appropriate testosterone dose
needed for each person. At the onset of puberty in natal males and during testosterone replacement in hypogonadal men, high aromatase levels may
result in high estradiol levels and transient gynecomastia. In adult natal women who are transgender men (FTM), aromatase activity is higher than
adult men. Thus, when a full adult male dose of testosterone is given to an FTM, high estradiol levels may result. Little is known about aromatization of
testosterone in the endometrium and its potential for causing uterine bleeding, although aromatase inhibitors have been used successfully to treat
endometrial spotting.
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Your IP isusing testosterone alone for transgender men (FTM) report cessation of ovulation and little uterine
182.255.0.242
Chapter
bleeding.23: Transgender
However, Endocrinology,
initial suppression Stephen with
of ovulation M. Rosenthal;
progestinsWylie
or GnRH agonist may be necessary. In addition to the effect of changesPage
C. Hembree in 15 / 22
aromatase levels, alterations in testosterone clearance and binding by sex hormone binding globulin (SHBG) may alter the testosterone dose required.
Monitoring of blood pressure and hemoglobin levels will prevent adverse effects; while estradiol and gonadotropin levels will monitor ovarian
suppression (see Table 23–5).
testosterone, the binding to SHBG and the aromatization to estradiol. Variation in each of the above will determine the appropriate testosterone dose
needed for each person. At the onset of puberty in natal males and during testosterone replacement in hypogonadal men, high aromatase levels may
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result in high estradiol levels and transient gynecomastia. In adult natal women who are transgender men (FTM), aromatase activity is higher than
adult men. Thus, when a full adult male dose of testosterone is given to an FTM, high estradiol levels may result. Little is known about aromatization of
testosterone in the endometrium and its potential for causing uterine bleeding, although aromatase inhibitors have been used successfully to treat
endometrial spotting. Published protocols using testosterone alone for transgender men (FTM) report cessation of ovulation and little uterine
bleeding. However, initial suppression of ovulation with progestins or GnRH agonist may be necessary. In addition to the effect of changes in
aromatase levels, alterations in testosterone clearance and binding by sex hormone binding globulin (SHBG) may alter the testosterone dose required.
Monitoring of blood pressure and hemoglobin levels will prevent adverse effects; while estradiol and gonadotropin levels will monitor ovarian
suppression (see Table 23–5).
Estradiol treatment of transgender women (MTF) requires suppression of endogenous testosterone levels from 3001000 ng/dL to less than 50 ng/dL.
Oral, transdermal and intramuscular preparations are available. Estradiol levels in natal, ovulatory women average 100200 pg/mL and should be the
goal for transgender women. However, estrogen doses that achieve this range of estradiol in MTF may fail to suppress endogenous testosterone levels
to less than 50 ng/dL. Natal women whose testosterone levels exceed 50 ng/dL may exhibit hirsutism or signs of mild virilization, despite good estradiol
levels. Thus, optimal suppression of endogenous testosterone by exogenous estradiol usually requires use of a second medication. Compounds with
progestin activity (spironolactone, medroxyprogesterone, and cyproterone acetate) are most commonly used. GnRH analogs also effectively reduce
testosterone levels to less than 50 ng/dL. Medications with 5αreductase inhibitory activity may reduce balding in transgender men and women.
However, their use in MTF protocols is not advised due to their failure to suppress endogenous testosterone levels in transgender women and their
adverse effects.
Protocols that effectively suppress endogenous sex steroids and maintain adult levels of the new exogenous sex steroid should have periodic
assessment during the first 1 to 2 years of treatment (see Table 23–5). Variations in transdermal absorption occur over time, as does metabolic
clearance, and SHBG levels. Most of these changes occur within the first 6 to 12 months of treatment. Stable sex steroid levels achieve genderspecific
body changes that begin within 6 months and stabilize within 2 to 5 years. Effects of estrogen include changes in body fat, muscles and skin, decreases
in sexual function, libido, breast growth, minor decreases in testicular size, decreased body hair growth, and slowing of male baldness. Effects of
testosterone include acne, body hair growth, scalp hair loss, changes in muscle mass and body fat, voice deepening, genital changes, and clitoral
enlargement. Increasing sex steroid doses does not change the time course of these changes in adults.
Surveillance for Potential Adverse Effects of Hormonal Treatment
Transgender men and women should be screened for heart disease, hypertension, metabolic syndrome, lipid disorders, diabetes, and breast and
prostate cancer. The frequency of this monitoring varies from 1 to 4 times during the first year to annually after 3 years. Elevated prolactin levels and
prolactinomas, as well as excess cases of thrombophlebitis, have been reported in transgender women. Data suggest that ethinyl estradiol increases
the risk of vascular disease in transgender women. Breast development is variable in MTF persons, is considered inadequate by most transgender
women and is not improved by use of progestins. There is a high request rate for mammoplasty. Low bone mass has been observed in transgender
women despite physiologic levels of estradiol. Cardiovascular disease is higher in MTF persons treated with estrogen than in testosterone treated FTM
persons, reversing the trend observed in natal men and women. Surveillance of laboratory tests that monitor general health should occur at baseline
and be monitored periodically. Normal ranges should be interpreted with caution since studies have shown that the “normal range” for transgender
men and women may not be coincident with those of natal men and women.
Surgical Considerations
Transgender men and women may elect to have both major and minor surgical procedures during gender transition. Transgender women select facial
treatment over chest and genital procedures whilst transgender men opt for chest/breast procedures. MTF persons, especially those 20 to 30 years
old, may plan genital surgery that creates a neovagina. A variety of techniques have been developed, each with advantages and disadvantages.
Clitoroplasty is widely used and results in good sexual sensitivity; creation of labia minora and labia majora utilizes a variety of techniques with variable
success. Breast development during estradiol treatment occurs during a 1 to 2year period, and outcomes are variable. Breast augmentation is
requested in approximately 50% of transgender women. Standard breast cancer screening is required after 2 years of estrogen treatment. For FTM
persons, phalloplasty is available in a greater number of centers, although metoidioplasty is selected more frequently, preserving sensitivity and
facilitating urination while standing. Mastectomy in FTM persons may leave residual subareolar breast tissue for cosmetic reasons. Close surveillance
for cancer screening is required. It is unlikely that screening for endometrial and ovarian cancer occurs regularly in FTM persons and, thus,
hysterectomy/ovariectomy should be considered.
Reproductive Options
Both transgender women and transgender men may elect to have children. A variety of options are available, although the number of transgender
persons
Chapter electing pregnancy
23: Transgender is low. The impact
Endocrinology, of gender
Stephen transitionWylie
M. Rosenthal; upon C.
future reproductive options should be discussed with all transgender
Hembree Page 16 / 22
persons who are Hill.
©2024 McGraw seeking hormonal
All Rights or surgical
Reserved. transition.
Terms of UseIn• Privacy
transgender women,
Policy sperm
• Notice cryopreservation prior to estrogen treatment is available at
• Accessibility
modest cost. Although 51% of MTF persons indicated they would elect sperm cryopreservation, published reports of pregnancy using cryopreserved
sperm from transgender women are few. Testis morphology in adult men treated with estradiol suggests that residual Leydig cells, Sertoli cells and
for cancer screening is required. It is unlikely that screening for endometrial and ovarian cancer occurs regularly in FTM persons and, thus,
hysterectomy/ovariectomy should be considered.
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Reproductive Options
Both transgender women and transgender men may elect to have children. A variety of options are available, although the number of transgender
persons electing pregnancy is low. The impact of gender transition upon future reproductive options should be discussed with all transgender
persons who are seeking hormonal or surgical transition. In transgender women, sperm cryopreservation prior to estrogen treatment is available at
modest cost. Although 51% of MTF persons indicated they would elect sperm cryopreservation, published reports of pregnancy using cryopreserved
sperm from transgender women are few. Testis morphology in adult men treated with estradiol suggests that residual Leydig cells, Sertoli cells and
spermatogonia remain, although no studies have demonstrated recovery of spermatogenesis following cessation of estradiol. Transgender men who
have transitioned with testosterone and maintained reproductive organs have successfully elected pregnancy. Oocyte, ovarian, and embryo
cryopreservation are available prior to initiation of testosterone treatment in transgender men, although the chances of achieving live births from
these tissues are small. In most states and countries, transgender families may also elect adoption.
Voice Therapy
Increasingly, transgender persons seek advice and treatment from speech language pathologists, although one survey indicates that many felt
improperly prepared and that specific training courses are limited. Half of transgender persons surveyed were unaware of available services.
Correlation of speech patterns with body movement also aids identity as female. One chart review of 25 persons undergoing feminizing hormone
treatment found that 80% successfully present as female 100% of the time. Happiness of MTF with their voice after voice training correlates more so
with perceived femininity and quality of life than with achieved pitch. MTF adolescents may also benefit from voice and communication therapy.
Surgical techniques are available for MTF transgender persons. However, comparison of the outcomes of speech therapy alone, surgical techniques
alone, and surgery followed by speech therapy has not been studied. Of the three approaches for FTM, there are no outcome comparison studies. In
contrast to MTF persons, intonation shows little correlation with male identity. Longterm followup of androgen effects upon voice in transgender
men do not differ from those observed in biological males. Hematocrit and CAG repeat lengths in the androgen receptor (an indication of androgen
sensitivity) correlate directly with vocal androgen sensitivity and reflect the extent of voice deepening when treated with testosterone. Difficulties in
pitchlowering occur only in 10% of FTM persons treated long term with testosterone and may be related to decreased androgen sensitivity. Medical
providers of transgender persons, especially MTF, should be aware that speech language pathologists indicate that working with transgender persons
is within their scope of practice.
Aging and Transgender Care
Increasingly, transgender persons have reached the age of 50 years. Many were referred at a younger age to mental health professionals, providers
skilled in sex steroid treatment, and specialized surgeons who provided guidance throughout their gender transition. However, specialized needs for
longterm followup medical care needed during aging are less well known amongst generalists who serve as primary care physicians for transgender
persons. Maintenance of secondary sex characteristics in both MTF and FTM persons is a central concern of most transgender persons. In addition,
concerns about cancer risk are prominent. Regular breast and genital examinations, as well as sexually transmitted disease screening, occur
infrequently in transgender men whereas these examinations are frequent in transgender women. No data are available for prostate and PSA
surveillance in MTF persons.
Considerations for continuing sex steroid treatment (estrogen and testosterone) are similar for transgender men and transgender women to those for
natal men and natal women, respectively. In MTF and FTM who had gonadectomy, LH and FSH levels can be used to monitor maintenance of
prescribed doses of sex steroids. There are no data that estradiol treatment causes prolactinsecreting pituitary adenomas, although estrogen
treatment may increase prolactin levels when adenomas are present. Small increases in prolactin may occur during estradiol treatment in the absence
of adenomas, although these increases usually remain within the normal range and are stable during estrogen treatment. Thus, screening of prolactin
levels is recommended before starting estrogen treatment and should continue periodically in MTF persons who continue estradiol treatment. Use of
transdermal estradiol is preferable in older age, especially for those with heart disease, hypertension, bone disease, and risk of thrombophlebitis. As
in older natal women, dose reduction may be considered for risk reduction. Regular prostate examinations are recommended although cases of
prostate cancer or hypertrophy are rare. The reverse trend in cardiovascular risk factor surveillance should continue in both MTF and FTM persons.
FTM persons who elect hysterectomy may continue testosterone treatment without concerns about aromatization to estradiol. As suggested above,
ovariectomy should be performed when hysterectomy is elected. As in natal men, normal testosterone levels in transgender older men exert no
adverse effects upon cardiovascular disease, diabetes, hypertension or metabolic syndrome. Subareolar breast tissue in FTM should be monitored for
rare cases of cancer in residual tissue following mastectomy. Bone density in older men is usually maintained by testosterone and the estradiol
produced by aromatization of testosterone. Periodic BMD assessments should be done in both transgender men and transgender women, especially
when sex steroid
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202423 is stopped.
10:25 A Your IP is 182.255.0.242
Endocrine
©2024 McGraw Management of Transgender
Hill. All Rights Reserved. Terms ofAdults: Conclusions
Use • Privacy Policy • Notice • Accessibility
Treatment of adult transgender men and transgender women with physiologic replacement doses of testosterone and estradiol, respectively,
FTM persons who elect hysterectomy may continue testosterone treatment without concerns about aromatization to estradiol. As suggested above,
Universitas
ovariectomy should be performed when hysterectomy is elected. As in natal men, normal testosterone levels in transgender Diponegoro
older men exert no Library
adverse effects upon cardiovascular disease, diabetes, hypertension or metabolic syndrome. Subareolar breast tissue Access
in FTM Provided by:
should be monitored for
rare cases of cancer in residual tissue following mastectomy. Bone density in older men is usually maintained by testosterone and the estradiol
produced by aromatization of testosterone. Periodic BMD assessments should be done in both transgender men and transgender women, especially
when sex steroid treatment is stopped.
Endocrine Management of Transgender Adults: Conclusions
Treatment of adult transgender men and transgender women with physiologic replacement doses of testosterone and estradiol, respectively,
facilitates the psychological, metabolic and physical changes that resolve gender dysphoria and enables a successful lifestyle transition to that of their
appropriate gender. The principles of effective treatment are to suppress the natal sex steroids and to replace them with sex steroid levels appropriate
for the transgender person. Guidelines for safe and effective treatment, noting both risks and benefits, are available to physicians providing care
during the transition and during longterm care. Healthcare coverage and protection against discrimination increasingly enable life fulfillment for
transgender persons.
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Greenspan's Basic & Clinical Endocrinology, 10e

Chapter 23: Transgender Endocrinology

Stephen M. Rosenthal; Wylie C. Hembree

1 7β­HSD­3 17β­hydroxysteroid dehydrogenase­3

BMD Bone mineral density

CAH Congenital Adrenal Hyperplasia

CAIS Complete androgen insensitivity syndrome

DSD Disorder of Sex Development

DSM Diagnostic and Statistical Manual of Mental Disorders

DXA Dual energy x­ray absorptiometry

FSH Follicle stimulating hormone

FTM Female­to male

GID Gender Identity Disorder

GnRH Gonadotropin releasing hormone

MTF Male­to female

PGR Progesterone receptor

SOC Standards of Care

W P A T H2024­2­3 10:25 A Your

PART I: ENDOCRINE MANAGEMENT OF TRANSGENDER YOUTH

1 7β­HSD­3 17β­hydroxysteroid dehydrogenase­3

BMD Bone mineral density

CAH Congenital Adrenal Hyperplasia

CAIS Complete androgen insensitivity syndrome

DSD Disorder of Sex Development

DSM Diagnostic and Statistical Manual of Mental Disorders

DXA Dual energy x­ray absorptiometry

FSH Follicle stimulating hormone

FTM Female­to male

GID Gender Identity Disorder

GnRH Gonadotropin releasing hormone

MTF Male­to female

PGR Progesterone receptor

SOC Standards of Care

WPATH World Professional Association for Transgender Health

PART I: ENDOCRINE MANAGEMENT OF TRANSGENDER YOUTH

Terms and Definitions

Prevalence of Transgenderism in Youth

Mental Health Concerns and Impact of Family Support

Mental Health Concerns and Impact of Family Support

Biologic Underpinnings of Gender Identity

Downloaded 2024­2­3 studies

Transgender Youth: Natural History

Clinical Practice Guidelines for Transgender Youth

Management of Early Pubertal Transgender Youth

Management of Late Pubertal Transgender Youth

A. Inhibitors of gonadal sex steroid secretion or action

A. Inhibitors of gonadal sex steroid secretion or action

Abbreviations: MTF, Male­to­Female; FTM, Female­to­Male.

Monitoring during pubertal suppression and during cross­sex hormone treatment.*

1. Physical examination: height, weight, Tanner Staging T 0 & q 3 mo

2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T 0 & q 3 mo

4. Bone mineral density: DXA T 0 & q 1 yr

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Monitoring during pubertal suppression and during cross­sex hormone treatment.*

1. Physical examination: height, weight, Tanner Staging T 0 & q 3 mo

2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T 0 & q 3 mo

4. Bone mineral density: DXA T 0 & q 1 yr

5. Bone age T 0 & q 1 yr

2. Hormonal studies: ultrasensitive LH, FSH, estradiol/testosterone T0&q3

4. Bone mineral density: DXA (if puberty previously suppressed) T0&q1

5. Bone age (if puberty previously suppressed) T0&q1

1 7βHSD3 17βhydroxysteroid dehydrogenase3

DXA Dual energy xray absorptiometry

FTM Femaleto male

MTF Maleto female

W P A T H202423 10:25 A Your

1 7βHSD3 17βhydroxysteroid dehydrogenase3

DXA Dual energy xray absorptiometry

FTM Femaleto male

MTF Maleto female

Downloaded 202423 studies

Abbreviations: MTF, MaletoFemale; FTM, FemaletoMale.

Monitoring during pubertal suppression and during crosssex hormone treatment.*

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Monitoring during pubertal suppression and during crosssex hormone treatment.*

Abbreviations: MTF, MaletoFemale; FTM, FemaletoMale.

A. Maletofemale (MTF) protocols

i. Spironolactone 100200 mg/d

ii. Cyproterone acetate 50100 mg/d

i. Oral estradiol 2.05.0 mg daily

ii. Transdermal E2 patch 0.10.4 23× weekly*

iii. Parenteral E2 valerate or cypionate 210 mg/wk

B. Femaletomale (FTM) protocols

i. Medroxyprogesterone acetate 3040 mg/d

ii. Cyproterone acetate 50100 mg/d

iii. GnRH analog 3.7515 mg q 13 mo

1. Testosterone Gel 1% 2.510 mg/d

2. Testosterone transdermal patch 2.510 mg/q 23 d

1. Testosterone enanthate/cypionate 50100 mg q 2 wks

2. Testosterone undecanoate 1000 mg q 812 wks

A. Maletofemale (MTF) protocols

i. Spironolactone 100200 mg/d

ii. Cyproterone acetate 50100 mg/d

i. Oral estradiol 2.05.0 mg daily

ii. Transdermal E2 patch 0.10.4 23× weekly*

iii. Parenteral E2 valerate or cypionate 210 mg/wk

B. Femaletomale (FTM) protocols

i. Medroxyprogesterone acetate 3040 mg/d

ii. Cyproterone acetate 50100 mg/d

iii. GnRH analog 3.7515 mg q 13 mo

1. Testosterone Gel 1% 2.510 mg/d

2. Testosterone transdermal patch 2.510 mg/q 23 d

1. Testosterone enanthate/cypionate 50100 mg q 2 wks

2. Testosterone undecanoate 1000 mg q 812 wks

Downloaded 202423 10:25 A Your IP is 182.255.0.242

Downloaded 202423 10:25 A Your IP is 182.255.0.242

Downloaded 202423 10:25 A Your IP is 182.255.0.242