Gender Dysphoria in Adults: Kenneth J. Zucker, Anne A. Lawrence, and Baudewijntje P.C. Kreukels

CP12CH20-Zucker ARI 8 January 2016 11:55
Review in Advance first posted online

V I E W
E on January 18, 2016. (Changes may
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still occur before final publication
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online and in print.)
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Gender Dysphoria in Adults

Access provided by Orta Dogu Teknik Universitesi - Middle East Technical University on 01/25/16. For personal use only.
Kenneth J. Zucker,1,∗ Anne A. Lawrence,2

and Baudewijntje P.C. Kreukels3
1
Gender Identity Clinic, Child, Youth, and Family Services, Centre for Addiction and Mental
Health and Department of Psychiatry, University of Toronto, Toronto, Ontario M6J 1H4,
Annu. Rev. Clin. Psychol. 2016.12. Downloaded from www.annualreviews.org
Canada; email: [email protected]

2
Department of Psychology, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada
3
Department of Medical Psychology, VU University Medical Center and EMGO Institute for
Health and Care Research, Amsterdam 1081 HV, The Netherlands
Annu. Rev. Clin. Psychol. 2016. 12:20.1–20.31 Keywords

The Annual Review of Clinical Psychology is online at gender dysphoria, gender identity disorder, transsexualism, causal
clinpsy.annualreviews.org
mechanisms, treatment
This article’s doi:
10.1146/annurev-clinpsy-021815-093034 Abstract
Copyright c 2016 by Annual Reviews. Gender dysphoria (GD), a term that denotes persistent discomfort with one’s
All rights reserved
biologic sex or assigned gender, replaced the diagnosis of gender identity
∗
Corresponding author disorder in the Diagnostic and Statistical Manual of Mental Disorders in 2013.
Subtypes of GD in adults, defined by sexual orientation and age of onset,
have been described; these display different developmental trajectories and
prognoses. Prevalence studies conclude that fewer than 1 in 10,000 adult
natal males and 1 in 30,000 adult natal females experience GD, but such
estimates vary widely. GD in adults is associated with an elevated prevalence
of comorbid psychopathology, especially mood disorders, anxiety disorders,
and suicidality. Causal mechanisms in GD are incompletely understood,
but genetic, neurodevelopmental, and psychosocial factors probably all con-
tribute. Treatment of GD in adults, although largely standardized, is likely
to evolve in response to the increasing diversity of persons seeking treat-
ment, demands for greater patient autonomy, and improved understanding
of the benefits and limitations of current treatment modalities.
20.1
Changes may still occur before final publication online and in print
Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.2
TERMINOLOGY AND PHENOMENOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.3
Developmental Trajectories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.3
EPIDEMIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.5
Prevalence and Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.5
Sex Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.6

DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.7
Placement in the Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.7
Substantive Changes in the DSM-5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.7
Gender Dysphoria and the ICD-11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.8
ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.9
Psychological Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.9

Biological Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.10
ASSOCIATED PSYCHOPATHOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.10
Increased Prevalence of Associated Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.10
Studies that Find Little or No Increased Prevalence
of Associated Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.12
Self-Report Measures of Associated Psychological Symptoms . . . . . . . . . . . . . . . . . . . . .20.13
Increased Prevalence of Suicidality and Self-Harm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.13
Explanations of Associated Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.13
CAUSAL MECHANISMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.14
Biological Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.15
Psychosocial Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.18
THERAPEUTICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.19
Diagnosing GD and Comorbid Conditions and the Role
of Mental Health Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.20
Counseling and Psychotherapy for Adults with Gender Dysphoria . . . . . . . . . . . . . . . .20.21
Real-Life Experience in the Preferred Gender Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.22
Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.23
Sex Reassignment Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.23
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20.24
INTRODUCTION
Gender dysphoria (GD) is a technical term that is familiar to specialist clinicians and researchers,
but it is perhaps less familiar to clinicians who have little or no experience in this area. It is also
a diagnostic term: In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5; Am. Psychiatr. Assoc. 2013), GD replaced prior diagnostic labels, including transsexu-
alism and gender identity disorder.
In the past few years, GD has received an unprecedented amount of attention in all forms of
media, perhaps under the broader rubric of the terms “transgender” or “transgenderism.” In 2014,
an essay in Time suggested that a “tipping point” had been reached with regard to “transgender
visibility” (Gray 2014). In his State of the Union address on January 20, 2015, Barack Obama was
the first US President to use the term “transgender” in public:
20.2 Zucker · Lawrence · Kreukels
As Americans, we respect human dignity. . . . That’s why we defend free speech, and advocate for
political prisoners, and condemn the persecution of women, or religious minorities, or people who are
lesbian, gay, bisexual, or transgender. We do these things not only because they’re right, but because
they make us safer. (Steinmetz 2015)
On May 4, 2015, the New York Times launched a series of editorials, entitled “Transgender
Today,” and around the same time, the American public appeared captivated by the very public
gender change from male to female, at the age of 65, of Olympic athlete Bruce (aka Caitlyn)
Jenner, whose name yielded 79,500,000 “hits” on Google as of July 1, 2015 (Bissinger 2015).
TERMINOLOGY AND PHENOMENOLOGY

The term “gender dysphoria” was first introduced by Fisk (1974) to describe individuals who
experience sufficient discomfort with their biological sex to form the wish for sex reassignment.
In the DSM-5, GD is defined as “an individual’s affective/cognitive discontent with the assigned
gender [usually at birth and referred to as natal gender]” (Am. Psychiatr. Assoc. 2013, p. 451).
The specialist clinician will be well aware of the multitude of terms currently in use to de-
scribe individuals whose gender identity or gender role behavior does not match up with societal
expectations or stereotypes associated with the (biological) male-female binary: apart from GD,
there are many other terms, such as gender variant, gender nonconforming, gender queer, gen-
der fluid, bigender, gender neutral, agender, and nonbinary, along with “trans,” transsexual, and
transgender. And, cross-culturally, there are many terms used to label individuals whose behavior
and subjective identity fall under the rubric of a “third gender” (Herdt 1994).
Developmental Trajectories
Table 1 shows the DSM-5 diagnostic criteria for GD in both children and adolescents/adults.
It is important to include the criteria for children because the phenomenology of GD in adults,
particularly in natal males, has at least two distinct pathways. Some adults with GD will recall a
childhood pattern of sex-typed behavior that corresponds to the behavioral indicators of GD in
childhood. In the contemporary literature, this is known as early-onset GD (Nieder et al. 2011)
or an early-onset of cross-gender identification, which might be present in the absence of an
explicit desire to be of the other gender. For other adults with GD, there is no clear evidence of
childhood cross-gender identification; rather, the indicators of GD emerge at puberty, if not much
later, which is called late-onset GD. An important methodological and interpretive issue pertains
to what “counts” as early onset. On this point, the literature is quite variable: Some researchers
consider early onset to be any time prior to puberty, whereas other researchers consider early
onset to be during the toddler and preschool years, the developmental period in which both
gender identity and gender role behaviors are first expressed (Lawrence 2010, pp. 531–532).
If age of onset is used as the independent variable, one can ask if it correlates with any other
variables that might be of importance from a clinical perspective. One such variable is sexual
orientation. Nieder et al. (2011) found that early-onset female-to-male (FtM) clients were more
likely to be sexually attracted to females than were late-onset clients, and early-onset male-to-
female (MtF ) clients were more likely to be sexually attracted to males than were late-onset
clients, particularly when it was the clinician who classified the client’s sexual orientation.
If sexual orientation is used as the independent variable, one can also ask which, if any, variables
it is correlated with. In the best-studied sexual orientation typological scheme, adults with GD are
divided into two subtypes: in the case of males, the two subtypes are those who are sexually attracted
to males versus those who are sexually attracted to females, both males and females, or neither males
www.annualreviews.org • Gender Dysphoria in Adults 20.3
Table 1 Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for gender dysphoria in
children, adolescents, and adults
Criteria for gender dysphoria in children

A. A marked incongruence between one’s experienced/expressed gender and assigned gender, of at least six months’
duration, as manifested by at least six of the following (one of which must be Criterion A1):
1. A strong desire to be of the other gender or an insistence that one is the other gender (or some alternative gender different from
one’s assigned gender)
2. In boys (assigned gender), a strong preference for cross-dressing or simulating female attire; in girls (assigned gender), a strong
preference for wearing only typical masculine clothing and a strong resistance to the wearing of typical feminine clothing
3. A strong preference for cross-gender roles in make-believe play or fantasy play
4. A strong preference for the toys, games, or activities stereotypically used or engaged in by the other gender
5. A strong preference for playmates of the other gender
6. In boys (assigned gender), a strong rejection of typically masculine toys, games, and activities and a strong avoidance of
rough-and-tumble play; or in girls (assigned gender), a strong rejection of typically feminine toys, games, and activities
7. A strong dislike of one’s sexual anatomy
8. A strong desire for the primary and/or secondary sex characteristics that match one’s experienced gender
B. The condition is associated with clinically significant distress or impairment in social, school, or other important areas
of functioning.
Specify if: with a disorder of sex development
Criteria for gender dysphoria in adolescents and adults
A. A marked incongruence between one’s experienced/expressed gender and assigned gender, of at least six months’
duration, as manifested by at least two of the following:
1. 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)
2. 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)
3. A strong desire for the primary and/or secondary sex characteristics of the other gender
4. A strong desire to be of the other gender (or some alternative gender different from one’s assigned gender)
5. A strong desire to be treated as the other gender (or some alternative gender different from one’s assigned gender)
6. A strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from
one’s assigned gender)
B. The condition is associated with clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
Specify if: with a disorder of sex development
Specify if: posttransition, 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 cross-sex medical procedure or treatment
regimen—namely, regular cross-sex hormone treatment or gender reassignment surgery confirming the desired gender (e.g.,
penectomy, vaginoplasty in a natal male; mastectomy or phalloplasty in a natal female)
or females (Blanchard 1989). In the case of females, the two subtypes are those who are sexually
attracted to females versus those who are sexually attracted to males, both males and females, or
neither males or females. Gender-dysphoric males who are not exclusively sexually attracted to
males often have transvestic disorder (Blanchard 2010), in which there is sexual arousal associated
with cross-dressing or autogynephilia, defined in the DSM-5 as sexual arousal associated with a
man’s thought or image of himself as a woman (for details, see Blanchard 2005, Lawrence 2013).
Although this taxonomic scheme did not begin to receive empirical validation until the 1980s,
the importance of sexual orientation as a subtype goes back to some of the earliest writings by
clinicians who worked with transsexual patients. For example, Harry Benjamin, an endocrinologist
considered to be the father of transsexualism (Green 2009), described quite clearly male patients
who could be classified as either homosexual or nonhomosexual (in relation to birth sex) (Schaefer
& Wheeler 1995).
For natal females, the older literature suggested an almost complete predominance of the
early-onset form of GD, with a corresponding sexual orientation toward females. More recently,
however, a greater proportion of natal females with the late-onset form of GD have been described
in the literature, with a sexual attraction to natal males, and from a subjective point of view, they
identify as gay men (Bockting et al. 2009, Chivers & Bailey 2000).
In contemporary times, consideration of sexual orientation in relation to GD has been an
extremely contentious issue. Some clinicians and transgender activists object to the idea that GD
in males might be associated with autogynephilia because they worry that this might result in the
GD being taken less seriously and viewed simply as a paraphilic sexual condition (Dreger 2008,
Lawrence 2013).
There is a historical reason for this concern. When sex reassignment surgery (SRS), or what
is now called gender-confirming surgery, for adults with GD began to receive more credence as
a legitimate therapeutic option in the 1960s and 1970s (Meyerowitz 2002), clinicians were wary
about recommending this treatment for late-onset males. For example, a male client who had a
history of transvestic fetishism, was (or had been) married to a woman, had children, and had
lived for a long time in the male gender role was viewed as a more dubious candidate for SRS
in comparison with other male clients. And such male patients often present with the request
for SRS at a later age than do early-onset males (Blanchard 1994, Lawrence 2010, Nieder et al.
2011). Indeed, Stoller (1968) considered such patients to be “secondary” rather than “primary”
transsexuals. Other clinicians in this era noted that such patients had a more episodic history with
regard to GD and the wish for sex reassignment, which was deemed to be a reason for caution in
recommending an irreversible medical treatment (Wise & Meyer 1980). And perhaps there was
good reason to be cautious, as there is evidence that instances of “regrets” after SRS are more
common in this subgroup (Blanchard et al. 1989).
The primary-secondary classificatory scheme has now been largely abandoned, and eligibility
for SRS takes into account different parameters, which are described more fully in the section
on therapeutics, but it is noted here that the debate has remained a very political, contentious
issue. In the seventh revision to the Standards of Care for the Health of Transsexual, Transgender,
and Gender-Nonconforming People (SOC-7) published by the World Professional Association for
Transgender Health (Coleman et al. 2011), terms such as sexual orientation, transvestic fetishism,
and autogynephilia are never mentioned. We would argue that this reflects a kind of intellectual
erasure in the discourse on phenomenology, which may inadvertently (or, perhaps, intentionally)
obscure the importance of these parameters with regard to theoretical issues, empirical research
on causal mechanisms, and therapeutic care.
EPIDEMIOLOGY
Prevalence and Incidence

In the late 1970s, the epidemiology of psychiatric disorders was examined with the use of the
Diagnostic Interview Schedule (DIS) (Robins et al. 1981), which was designed to assess DSM-III
diagnoses. Interestingly, Robins and colleagues (1981) noted that the module pertaining to trans-
sexualism was “omitted” because it “had not been cleared by NIMH for submission to [the] OMB
[the US Office of Management and Budget]” (p. 388). Thus, in the 1980s, the US studies on DIS
prevalence did not contain any specific information on transsexualism. However, Hwu et al. (1989)
reported on the prevalence of transsexualism in Taiwan for 11,004 adults ranging in age from 18
to 64+ years. Depending on geographic area, lifetime prevalence ranged from 0.3 to 2.0:1,000,
with a higher prevalence for females than for males (range, 0.7–4.2:1,000 versus 0–0.4:1,000).
One-year prevalence ranged from 0 to 1.0:1,000. Stefánsson et al. (1994) reported prevalence data
on 862 Icelanders at the age of 55 to 57 years, who were all born in 1931: Lifetime prevalence was
0.1%, and point prevalence (one month to one year) was 0.0%.
Estimates of prevalence have also relied on less rigorous methods, such as the number of
adults seeking out clinical care at specialized gender identity clinics in a particular country or
the number of such patients approved for or already receiving cross-sex or gender-affirming
hormonal treatment. Zucker & Lawrence (2009) reviewed this quasi-epidemiological literature
on prevalence and identified 25 relevant studies. Population-based data from European countries
provided the best estimates of the prevalence of GD in Western societies. In Belgium, for example,
the prevalence of transsexualism, defined as having undergone sex reassignment, was 1:12,900 for
adult males and 1:33,800 for adult females; data from the Netherlands were similar: 1:11,900 adult
males and 1:30,400 adult females.
Since the 2009 review, two new studies have been published. Dhejne et al. (2014) reported a
point prevalence in December 2010 of 1:7,750 adult males and 1:13,120 females in Sweden who
had applied for a legal name change, and Judge et al. (2014) reported a prevalence of 1:10,154
adult males and 1:27,668 adult females referred for hormonal treatment in Ireland. Arcelus et al.
(2015) provided a meta-analytic review of 21 studies (many of which were included in Zucker
& Lawrence 2009) and concluded that the prevalence of transsexualism in (predominantly) adult
males was 1:14,705 and 1:38,461 in (predominantly) adult females.
Because these studies have relied on patients seen by gender identity specialists or clinics, it
has been argued that the true prevalence of GD (transsexualism) could be underestimated because
not all affected individuals might seek out such care at specialized centers. Veale (2008) gauged
the prevalence of transsexualism in New Zealand on the basis of the number of individuals,
15 years of age and older, who requested, for example, an “X” on their passport instead of M (for
male) or F (for female) after they had been living as a member of the opposite sex and had made
a legal name change. On this basis, Veale reported a higher prevalence rate of 1:3,630 in males
and 1:22,714 in females.
In the past few years, some novel data have emerged that also suggest higher prevalence rates;
however, these studies have tended to use definitions of “caseness” that are looser than the def-
initions used for patients seen in specialty clinics. Conron et al. (2012) examined a probability
sample of 28,176 adults (age range 18–64 years) who participated in a telephone health survey.
They found that 0.5% of the adults considered themselves to be transgender (e.g., “a person born
into a male body, but who feels female or lives as a woman”) (see also Kuyper & Wijsen 2014,
Van Caenegem et al. 2015). Although these new data should be interpreted with caution because
of the less restricted definition of caseness, they may well reflect a bona fide increase in adults
who self-identify somewhere along the transgender spectrum, and some of these individuals may
eventually seek out gender change with biomedical treatments.
Sex Ratio
From the clinic-based studies, it is apparent that the prevalence of male-to-female transsexualism
is consistently higher than is female-to-male transsexualism in adults. If these estimates reflect,
even in a crude way, sex differences in true prevalence, one can ask why GD is more common
in biological males than in biological females. One explanation pertains to sex differences in
the prevalence of subtypes of GD. As noted previously, the best-established evidence for a sex
difference in subtypes pertains to sexual orientation. This sex × sexual orientation difference may
well explain the higher prevalence in biological males (of course, the interaction itself also requires
an explanation).
DIAGNOSIS
Placement in the Nomenclature

Transsexualism as a psychiatric diagnosis (for adolescents and adults) appeared for the first time
in the DSM in 1980 (the corresponding diagnosis for children was gender identity disorder of
childhood. In 1994, transsexualism and gender identity disorder of childhood were merged into
one diagnosis, gender identity disorder (GID), with distinct criteria sets for children and adoles-
cents/adults (Am. Psychiatr. Assoc. 1994). In the DSM-5 (Am. Psychiatr. Assoc. 2013), GID was
renamed GD, with a chapter of its own.
Substantive Changes in the DSM-5

Zucker et al. (2013) outlined the key changes to the diagnosis of GID between DSM-IV and
DSM-5. Before describing the changes relevant to adults, it should be noted that the subworkgroup
on Sexual and Gender Identity Disorders reflected on a more fundamental matter, namely, whether
to retain the diagnosis in the DSM-5 at all. Some transgendered activists and some clinicians
wanted the diagnosis to be removed in its entirety, arguing that GID was not a mental disorder,
and the arguments for removal drew on many of the same reasons that led homosexuality to be
removed in 1973 from the DSM-II (Am. Psychiatr. Assoc. 1968) (Bayer 1981). Transsexualism
or GID was nothing more than a normal variant of a cisgender identity, that its presence in the
DSM contributed to stigma, and that there was nothing inherently “wrong” with a gender identity
incongruent with one’s natal sex (Ault & Brzuzy 2009, Vance et al. 2010). Two members of the
DSM-5 subworkgroup wrote reviews that, in part, considered the question of whether to leave
the diagnosis in the DSM or take it out (Drescher 2010, Meyer-Bahlburg 2010; see also Zucker
& Duschinsky 2015).
The recommendation of the subworkgroup to retain the diagnosis was based on at least two
key considerations: access to care and a reconceptualization of the diagnosis. If there were no psy-
chiatric diagnosis, access to care, including insurance coverage for SRS, would be threatened. The
argument that GID is a nonpsychiatric medical condition [e.g., a neural, central nervous system
(CNS)-limited intersex condition] (Meyer-Bahlburg 2011) was considered, but it was deemed that
the evidence for this was far from clear and could not be justified.
To retain the diagnosis in the DSM-5, a reconceptualization was articulated in which “identity”
per se was not considered a sign of a mental disorder. Rather, it was the incongruence between
one’s felt gender and assigned sex/gender (usually at birth) leading to distress and/or impairment
that was the core feature of the diagnosis. As a result, the subworkgroup argued for a change in
name from GID to GD in order to better reflect this incongruence. Once a consensus within the
subworkgroup was reached with regard to retention, five substantive changes were proposed and
implemented:
1. The diagnostic criteria for adolescents and adults moved to a more detailed polythetic format
(Table 1), replacing the rather vague criteria that were used in the DSM-IV. The threshold
of two symptoms (out of six) was based, in part, on secondary data analyses, which indicated
that the presence of at least two indicators yielded a sensitivity rate of 94.2% and a specificity
rate of 99.3%.
2. A lower-bound six-month duration criterion was introduced based on clinical consensus,

but, unfortunately, without formal empirical evidence. The inclusion of a duration criterion
was, however, deemed important for clinical reasons, namely, to caution against a hasty
diagnosis with the potential unintended consequence of inappropriate treatment for clients
in which the symptoms might well prove to be transitory.
3. Whether or not individuals with a physical intersex condition, now termed a disorder of sex
development (DSD), should be diagnosed with GD has had a back-and-forth history since
the DSM-III (Kraus 2015; Meyer-Bahlburg 1994, 2010, 2015). Since the publication of the
DSM-IV, considerable evidence has accumulated that some individuals with a DSD expe-
rience GD and may wish to change their assigned gender (Berenbaum & Meyer-Bahlburg
2015, Meyer-Bahlburg 2010, Pasterski et al. 2015, Richter-Appelt & Sandberg 2010). Al-
though the percentage of DSD patients who develop GD is DSD syndrome dependent,
such patients express a phenomenology that is both similar to and different from patients
with GD with no known DSD, and similarities and differences also exist in developmental
trajectories. Because the presence of a DSD suggests a specific causal mechanism that may
not be present in individuals without a DSD, it was included as a specifier in the DSM-5.
4. For adolescents and adults, the DSM-IV specifier for sexual attraction (to males, to female,
to both, to neither) was removed in the DSM-5. This was an issue that was debated intensely
by the subworkgroup. On the one hand, there is considerable evidence, particularly for na-
tal males, that sexual orientation in adults with GD is related to a whole host of variables,
including developmental phenomenology and trajectories, and is likely related to somewhat
distinct causal mechanisms. Indeed, sexual orientation (or sexual attraction) fits well with the
DSM-IV definition of a subtype (“mutually exclusive and jointly exhaustive phenomenolog-
ical subgroupings”), and there is considerable evidence for its validity as a subtype (Lawrence
2010). On the other hand, it can be argued that sexual orientation per se does not, in and of
itself, constitute a symptom of GD (“symptom expression”), which is a cornerstone of the
meaning of a specifier in DSM-5. As a result, the subworkgroup recommended that sexual
attraction be removed as a specifier but described in the text as an important component of
variations in developmental trajectories and with regard to research on causal mechanisms.
5. A posttransition specifier was added to the GD criteria for adolescents and adults. The addi-
tion of this specifier was deemed necessary because there are many individuals who, after a
gender transition (social and/or biomedical), no longer meet the criteria set for GD; however,
they continue to undergo chronic hormone treatment, further gender-confirming surgery,
or intermittent psychotherapy/counseling to facilitate the adaptation to life in the desired
gender and the social consequences of the transition. Although the concept of posttransition
was modeled on the concept “in [partial or full] remission” as used for mood disorders, “re-
mission” has implications in terms of symptom reduction that do not apply directly to GD.
Cross-sex hormone treatment of gonadectomized individuals could, of course, be coded as
treatment of hypogonadism, but this would not apply to individuals who have not undergone
gonadectomy but receive hormone treatments. In the DSM-5 text, it is noted that the course
specifier of “full remission” in its original meaning does apply to a small number of adults.
Gender Dysphoria and the ICD-11

The World Health Organization intends to publish the eleventh revision to its International Clas-
sification of Diseases and Related Health Problems (ICD-11) in 2018. Advisory groups have been
assembled for the Mental and Behavioural Disorders section (First et al. 2015). Two members
of the DSM-5 Work Group on Sexual and Identity Disorders, Cohen-Kettenis and Drescher,
served on a subgroup of three. A general proposal has been made to move the ICD-10 diagnoses
pertaining to GD, the sexual dysfunctions, and the paraphilic disorders out of the Mental and Be-
havioural Disorders section to a new section provisionally entitled Conditions Related to Sexual
Health (Drescher 2013, 2015; Drescher et al. 2012), with the DSM-5 “gender dysphoria” label
replaced with the label of “gender incongruence.” This proposal appears to be based in part on
the argument that such a section would be agnostic with regard to whether or not gender incon-
gruence is best conceptualized as a psychiatric or nonpsychiatric medical condition. Retention in
the ICD-11 in this new section would, in theory, allow national health care systems or private
insurance companies to continue to provide coverage and thereby not threaten access to care for
clients unable to pay for medical care out of pocket.
ASSESSMENT
Psychological Assessment
Psychological assessment of GD, particularly dimensional evaluation, can be used to complement
a detailed clinical history, including an appraisal of the symptoms that constitute the DSM-5 diag-
nosis. For example, the gender-related scales [masculinity-femininity, masculine gender, feminine
gender (Mf, GM, and GF, respectively)] of the Minnesota Multiphasic Personality Inventory-2
(MMPI-2) (Martin & Finn 2010) provide objective measures of clients’ gender-typical or atypical
attitudes and interests (Gómez-Gil et al. 2008). The Feminine Gender Identity Scale for Males
(Freund et al. 1977) and the Masculine Gender Identity Scale for Females (Blanchard & Freund
1983) were developed, in part, to provide dimensional assessment of some indicators of transsex-
ualism (both historic and concurrent) during the period when the diagnosis was either about to
appear in the DSM-III or shortly thereafter.
More recently, the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and
Adults (GIDYQ-AA) has been developed (Deogracias et al. 2007). The GIDYQ-AA consists of
27 items that pertain to gender identity and GD and are designed to capture multiple indicators
of gender identity and GD, including subjective (n = 13 items), social (n = 9 items), somatic (n = 3
items), and sociolegal (n = 2 items) parameters. The GIDYQ-AA has parallel male and female
versions. Each item is rated on a 5-point response scale ranging from 1 (never) to 5 (always) based
on a time frame of the past 12 months. A total score is calculated by summing scores on the
completed items and dividing by the number of marked responses.
The psychometric properties of the GIDYQ-AA were examined by Deogracias et al. (2007) with
a sample of 462 participants that included both university students and gender identity patients.
A principal factor analysis indicated a one-factor solution was the best fit, accounting for 61.3%
of the total variance. The measure successfully discriminated gender identity patients from both
heterosexual and nonheterosexual controls, with large effect sizes. Using a cut-point of ≤3.00,
selected on the basis of visual inspection of the frequency distributions of mean scores, Deogracias
et al. (2007) found the scale to have excellent sensitivity (90.4%) and specificity (99.7%). Similarly,
using clinical controls, Singh et al. (2010) found a specificity rate of 100% and sensitivity rates of
93.3% and 87.3% for adolescents and adults with GID, respectively. These findings suggest that
the GIDYQ-AA can be used to identify ‘‘caseness” in patients referred to a specialized gender
identity clinic and that the questionnaire does not simply identify clinical problems in general. It
has also been used to identify potential “cases” in patient groups for whom it has been surmised
contain an overrepresentation of individuals with GD, such as women with borderline personality
disorder (Singh et al. 2011). Other contemporary dimensional measures of GD include the Utrecht
Gender Dysphoria Scale (Schneider et al. 2015); however, one advantage of the GIDYQ-AA is
that it uses a specific time frame and has parallel items for males and females, whereas the Utrecht
Gender Dysphoria Scale does not have identical items for the two sexes.
An important component of GD pertains to body image and body dissatisfaction. Although
signs of body image dissatisfaction, including anatomic dysphoria, can be detected in some pre-
pubertal children with GD, this becomes much more salient with the onset of puberty, which
accentuates the incongruence between one’s felt gender and somatic sex with the emergence of
secondary sex characteristics (Feusner et al. 2015).
Several measures have been used to assess this body image dissatisfaction, including the Body
Image Scale (Lindgren & Pauly 1975, van de Grift et al. 2015), the Body Uneasiness Test (Bandini
et al. 2013), and the Hamburg Body Drawing Scale (Becker et al. 2015). Becker and colleagues
found the expected elevation in body image dissatisfaction with regard to sex-specific body features,
but they also found some elevations in more general aspects of body image. Along similar lines,
Vocks et al. (2009) reported that gender-dysphoric adults showed impairment in body image
related to eating disorders (e.g., restrained eating behavior). Body image is an important variable
to assess because a reduction in dissatisfaction is an important metric in identifying improvement

in psychosocial well-being following a gender social transition and corresponding biomedical
treatments (Kraemer et al. 2008).
Biological Assessment
Physical examination and laboratory testing are generally viewed as having limited value for pa-
tients with GD. For adults who have a co-occurring DSD, this has invariably been documented
prior to an assessment for GD. Almost all patients with GD have a normal sex chromosome kary-
otype (Auer et al. 2013a). Nonautosomal positive findings in males most commonly indicate the
presence of Klinefelter syndrome (47,XXY) or an XYY karyotype (Auer et al. 2013a, Buhrich &
McConaghy 1978). Only a few case reports in the literature have identified a sex chromosomal
abnormality in females with GD (Auer et al. 2013a, Khandelwal et al. 2010).
ASSOCIATED PSYCHOPATHOLOGY
Understanding the nature and prevalence of psychopathologic conditions that occur in association
with GD can potentially improve diagnostic precision, inform treatment planning, and provide
insights into the causes and consequences of GD. A review of existing research in this area,
however, reveals a wide range of inconsistent, confusing, and at times seemingly contradictory
results. Many studies have significant limitations. These include the use of small and potentially
unrepresentative samples and reliance on brief self-report measures rather than structured clinical
interviews. Some investigators have combined male-to-female (MtF ) and female-to-male (FtM)
persons for purposes of analysis, and subtypes based on sexual orientation or age of onset have
rarely been taken into consideration.
Increased Prevalence of Associated Psychopathology

Comorbid psychopathology is significantly more prevalent in adults with GD than in the general
population. Mood and anxiety disorders are especially likely to occur in association with GD.
Two large, recently published, methodologically strong studies illustrate these points; they also
provide a standard against which the results of other investigations can be compared. These two
reports are summarized in the first two rows of Supplemental Table 1 (follow the Supplemental
Material link in the online version of this article or at http://www.annualreviews.org).
Dhejne et al. (2011) reported the results of a longitudinal, population-based follow-up study
of all persons who underwent SRS in Sweden between 1973 and 2003, a cohort consisting of
191 MtF and 131 FtM transsexuals. Data were obtained from several Swedish national reg-
istries, which contain information about births, deaths, hospital discharges and diagnoses, criminal
records, etc. Each patient was compared with 10 randomly selected, age-matched persons of both
their birth sex and their reassigned or final sex. Dhejne et al. (2011) found that 19% of MtF
patients and 17% of FtM patients had been hospitalized for psychiatric problems other than
GD prior to undergoing sex reassignment, compared to only 3–4% of both birth-sex and final-
sex matched controls. After SRS, patients with GD were 2.8 times more likely than controls to
have been hospitalized for a psychiatric problem other than GD, even after adjustment for prior
psychiatric comorbidity; they were 4.2 times more likely prior to this adjustment. After SRS,
transsexual patients were 4.9 times more likely to have made a suicide attempt and 19.1 times
more likely to have died from suicide, again after adjusting for prior psychiatric comorbidity.
The prevalence of these conditions was similar in MtFs and FtMs. The multiple strengths of this
study—longitudinal design, absence of selection bias, well-chosen control groups, and unusually
long follow-up times—suggest that its findings are likely to be highly reliable.
Heylens et al. (2014a) described the prevalence of current and lifetime comorbid psychopathol-
ogy in 305 patients with GD (182 MtFs, 123 FtMs) seen from 2007 through 2010 in gender clinics
in Belgium, Germany, the Netherlands, and Norway that participated in the European Network
for the Investigation of Gender Incongruence. Data were collected using the Mini International
Neuropsychiatric Interview-Plus and the Structured Clinical Interview for DSM-IV Axis II Per-
sonality Disorders. Approximately 38% of patients had a current Axis I disorder and about 69%
had a lifetime Axis I disorder, with similar prevalence figures in MtFs and FtMs. The most com-
mon Axis I conditions were mood disorders (27% current, 60% lifetime) and anxiety disorders
(17% current, 28% lifetime). Although this study did not employ a formal control group, these
figures substantially exceed prevalence rates of comorbid psychopathology in the general popula-
tion in Western European countries. For example, Alonso & Lépine (2007) used the Composite
International Diagnostic Interview and found that, in a representative sample of adults from six
European countries, only 26% reported a lifetime prevalence of any mental disorder. About 30%
of both MtFs and FtMs had either attempted suicide or reported recent suicidal ideation. About
15% of GD patients had one or more DSM-IV Axis II disorders, a prevalence similar to that of
the general population in the countries that participated in the European Network for the Inves-
tigation of Gender Incongruence. There were no significant differences in comorbid conditions
between early-onset and late-onset GD groups, except for a higher prevalence of Axis II disorders
in late-onset FtMs.
Eight other studies that used structured clinical interviews for data collection (Colizzi et al.
2015; Gómez-Gil et al. 2009; Guzmán-Parra et al. 2015; Haraldsen & Dahl 2000; Hepp et al.
2005; Madeddu et al. 2009; Mazaheri Meybodi et al. 2014a,b) reported generally similar results
(see Supplemental Table 1): Most found about a 30–40% prevalence of current comorbid psy-
chopathology and about a 50–80% prevalence of lifetime comorbid psychopathology in adults
with GD, including a 20–60% prevalence of personality disorders. Another large study by Landén
et al. (1998), which used data from Swedish national registries—the same method that Dhejne
et al. (2011) subsequently employed—reported similar results, as did three smaller studies by
Miach et al. (2000) and De Cuypere et al. (1995, 2006), all of which found a high prevalence
of associated psychopathology despite the use of unstructured clinical interviews. The studies by
Dhejne et al. (2011) and Heylens et al. (2014a) and these 12 other studies, summarized in the first
14 rows of Supplemental Table 1, probably provide the most reliable estimates of the prevalence
of associated psychopathology in adults with GD.
Four other studies have used self-report screening instruments to assess current depression,
anxiety, and psychological distress in large cohorts of US transgender adults, some of whom
probably would not have met full diagnostic criteria for GD (Bockting et al. 2013, Budge et al.
2013, Clements-Nolle et al. 2006, Nuttbrock et al. 2013). All of these studies found that current
depression and anxiety were significantly more prevalent in adults with GD than in the general
population: about a 45–60% prevalence of current depression and about a 35–40% prevalence of
current anxiety. The results of these studies are summarized in the final four rows of Supplemental
Table 1.
Studies that Find Little or No Increased Prevalence

of Associated Psychopathology
Some studies have identified no or little increased prevalence of associated psychopathology. These
reports are sometimes cited to support the idea that GD is “usually an isolated diagnosis” (Cole
et al. 1997, p. 13) or one that is “associated with a low level of psychopathology” (Fisher et al.
2013, p. 417). Few of these studies, however, employed structured clinical interviews. Hoshiai
et al. (2010) observed that investigations that use structured clinical interviews typically report
higher comorbidity rates than investigations that do not, and they suggested that the latter studies
could easily underestimate the prevalence of comorbid conditions:
Studies using the structured clinical interview revealed a relatively high comorbidity rate of Axis I
disorders (30–67%), while studies without a structured interview showed a lower comorbidity rate of
Axis I disorders (4–19%). The possibility that clinical diagnosis without a structured interview missed
psychiatric comorbidity among GID patients cannot be denied. (p. 517)
Some reports that found a relatively low prevalence of comorbid psychopathology also have
other methodological limitations that render their conclusions questionable.
Five studies that found little or no increased prevalence of associated psychopathology in adults
with GD are summarized in Supplemental Table 2 (follow the Supplemental Material link
in the online version of this article or at http://www.annualreviews.org). The report by Fisher
et al. (2013) is arguably the most detailed and methodologically sound; the prevalence figures it
found for current and lifetime associated psychopathology (approximately 15–20% current, and
approximately 30% lifetime) are lower than most of the studies listed in Supplemental Table 1
and are not greatly different from general population estimates in Western countries. Fisher et al.
found an especially low prevalence of personality disorders—lower than in the general population.
The report by Colizzi et al. (2014) described the same patient cohort as the report by Colizzi
et al. (2015) in Supplemental Table 1 but found much lower prevalence figures for associated
psychopathology; the reasons for this difference are unclear, although it was noted that there were
“several patients with substantial functional impairment that did not receive a standard diagnosis
based on the DSM-IV-TR criteria due to an insufficient number/duration of symptoms” (p. 71).
The final three studies listed in Supplemental Table 2 are methodologically less strong
and may have underestimated the prevalence of comorbid psychopathology. The low prevalence
figures reported by Hoshiai et al. (2010) are especially puzzling, given the very high prevalence
of suicidal ideation, suicide attempts, and self-harm among their participants. Reports by Terada
et al. (2011, 2012), which examined subsets of the larger patient cohort described by Hoshiai
et al. and which are not included in the table, found almost identical results: Comorbid psychiatric
diagnoses were uncommon, but approximately three-quarters of patients reported suicidal ideation
or suicide attempts.
Self-Report Measures of Associated Psychological Symptoms

Several investigators have used self-report measures, including the Symptom Checklist-90-Revised
(SCL-90-R), MMPI, and MMPI-2, to examine psychiatric symptoms in adults with GD. Reports
using the SCL-90-R have generally found that GD patients—at least prior to treatment—have
significantly higher mean scores than healthy control subjects (Auer et al. 2013b, Davey et al. 2014,
Haraldsen & Dahl 2000, Heylens et al. 2014b, Simon et al. 2011). Haraldsen & Dahl (2000) also
found, however, that the GD patients had significantly lower mean scores than clinical patients with
personality disorders. Differences between the mean SCL-90-R scores of GD patients and healthy
control subjects, although statistically significant, were typically small and in most cases clinically
unimportant. Unfortunately, investigators have not systematically examined differences in the per-
centages of clinically elevated SCL-90-R scores between GD patients and healthy control subjects.
Several studies have used the MMPI or MMPI-2 to assess psychopathology in adults with GD.
Most investigations conducted prior to 2000, however, involved small numbers of participants,
and their results have been inconsistent or contradictory (for reviews, see Gómez-Gil et al. 2008,
Miach et al. 2000). In one of the larger pre-2000 studies, which involved 93 MtFs and 44 FtMs,
Cole et al. (1997) found that mean MMPI clinical scale scores were in the normal range for both
MtF and FtM participants, but more than 20% of participants had T scores ≥70 on at least one
clinical scale, excluding the Gender Identity Scale (Mf ). Miach et al. (2000) and Gómez-Gil et al.
(2008) found similar results using the MMPI-2: Patients with GD had mean clinical scale scores
in the normal range, but 28% of MtFs and 27% of FtMs had T scores ≥65 on one or more
clinical scales (excluding Mf ), especially those measuring depressive, psychopathic, paranoid, or
schizophrenic traits.
Increased Prevalence of Suicidality and Self-Harm

Supplemental Table 3 (follow the Supplemental Material link in the online version of this ar-
ticle or at http://www.annualreviews.org) summarizes the results of 13 studies that investigated
suicidality and self-harm in adults with GD. These studies suggest that about one in three adults
with GD has experienced suicidal ideation, attempted suicide, or engaged in suicidal or nonsui-
cidal self-harm. The results described by Dhejne et al. (2011)—a greatly increased likelihood of
attempted and completed suicide a decade or more after completion of SRS—are particularly dis-
concerting. Prevalence figures for suicide attempts, which usually reflect self-reports, vary widely
between studies—probably a result of varying standards for what constitutes an attempt. Dhejne
et al. (2011) found a 9.0% prevalence of documented suicide attempts in adults with GD over
a minimum 10-year follow-up period, compared to a 1.4% prevalence in age- and sex-matched
control subjects.
Explanations of Associated Psychopathology

Mental health professionals who agree that GD is a genuine mental disorder would probably
consider the increased prevalence of associated psychopathology in adults with GD unsurprising,
given that different types of mental disorders are significantly correlated with each other and that
having one mental disorder greatly increases the probability of having one or more other mental
disorders (Caspi et al. 2014, Newman et al. 1998). Mental health professionals who doubt that
GD is a genuine mental disorder generally invoke other explanations to account for the increased
prevalence of associated psychopathology; these include the psychological consequences of gender
incongruence and especially the effects of minority stress (Meyer 2003), a term that refers to the
stressful consequences of the prejudice, discrimination, and victimization that persons with GD
often experience.
Meta-analytic reviews (Pascoe & Smart Richman 2009, Pieterse et al. 2012) demonstrate that
perceived prejudice and discrimination are associated with an increased prevalence of mental
health problems in minority groups, although effect sizes are small to medium: typical correlations
are about 0.20. Moreover, direction of effect cannot be conclusively determined (i.e., whether
prejudice and discrimination lead to a greater likelihood of developing mental health problems,
or whether mental health problems lead to a greater likelihood of experiencing—or perceiving—
prejudice and discrimination).

Several studies have investigated the relationship between psychosocial variables and associated
psychopathology or related symptoms (suicidality or self-harm) in persons with GD. Perceived
prejudice and discrimination have been found to be positively associated with general mental health
symptoms (Bockting et al. 2013), depression (Nuttbrock et al. 2013), suicidality (Clements-Nolle
et al. 2006), and self-harm (Claes et al. 2015). One study with implications for direction of effect
(Nuttbrock et al. 2013) found that gender-related abuse that had been experienced a year earlier
was associated with current depression in MtFs age 30 or younger—but not in MtFs older than
age 30. Bauer et al. (2015) found that greater social support was associated with less suicidality.
A number of studies have found that receiving treatment for GD, especially hormone treat-
ment, is associated with lower levels of psychopathology (Colizzi et al. 2014, 2015; Gorin-Lazard
et al. 2013; Heylens et al. 2014b; Murad et al. 2010; Newfield et al. 2006) and suicidality (Bauer
et al. 2015). Conversely, anxiety and depression are more prevalent early in the transition pro-
cess (Budge et al. 2013). Patients who have completed at least a year of hormone therapy and
cross-living and are applying for SRS demonstrate less psychopathology than patients undergoing
evaluation for hormone therapy (Gómez-Gil et al. 2008). In contrast to many of these findings,
Dhejne et al. (2011) reported that even after successful completion of SRS—and after adjust-
ment for pretreatment psychopathology—transsexuals exhibited much higher prevalence rates
for psychopathology and suicidality than age- and sex-matched control groups.
Investigators have also reported a few findings that are not easy to reconcile with the hy-
potheses that gender incongruence and minority stress are causally related to a higher prevalence
of psychopathology in adults with GD. For example, Bockting et al. (2013) found no signifi-
cant association between self-reported GD (as a symptom, not a formal diagnosis) and symptoms
of psychopathology in transgender adults. Moreover, Heylens et al. (2014a) and Terada et al.
(2012) found no significant relationship between age of onset of GD and prevalence of comorbid
psychopathology, which seems contrary to the expectation that an earlier onset of GD and a con-
sequent lengthier exposure to experiences of prejudice and discrimination ought to be associated
with more prevalent psychopathology. Interestingly, Terada et al. (2012) found that nonhomosex-
ual orientation in MtFs and analloeroticism (lack of attraction to either men or women) in FtMs
was positively associated with comorbid psychopathology.
CAUSAL MECHANISMS
Understanding the genesis of GD has relied on some general principles about “normative” or sex-
typical psychosexual development. A simple model is that the mechanisms involved in normative
sex-dimorphic psychosexual differentiation (including gender identity itself ) are inverted in the
development of GD. Thus, a normative sex differentiation model, not only as used in human
studies but also in scores of animal studies (Wallen 2009), has guided much of the causal mechanism
research on the development of GD, whether such research is biological or psychosocial. It is,
however, important to note that within-sex models have also been utilized; such models involve
the identification of mechanisms that might explain a within-sex difference in a sex-dimorphic

trait. An example of this would be the fraternal birth order effect, namely, the finding that gay
men have more older brothers than do heterosexual men. Although there is an enormous sex
difference in sexual orientation, the hypothesized mechanism regarding the fraternal birth order
effect applies only to males (Blanchard 2004).
Biological Processes
In this section, we summarize research on biological mechanisms in two areas: genetics and the
role of prenatal sex hormones, including their effects on putative sex-dimorphic neural structures.
Genetics. Family and twin studies have examined whether genetic factors contribute to the de-
velopment of gender identity, GD, and related phenomena (Burri et al. 2011, Gómez-Gil et al.
2010, Heylens et al. 2012, Loehlin et al. 2005). Loehlin et al. (2005) examined the heritability of
gender diagnosticity, a scale that predicts whether an individual is masculine or feminine based on
gender-related interests: 25% to 47% of the total variance was explained by genetic factors. Re-
called gender nonconformity was studied in adult twins, with heritability estimates ranging from
0.50 to 0.57 in men and from 0.37 to 0.40 in women (Bailey et al. 2000). Burri et al. (2011) ex-
amined recalled childhood gender typicality, sexual orientation, and adult gender identity. Herit-
ability for the Adult Gender Identity Scale was only 0.11. A study in twins of which one was diag-
nosed with GID showed that 39.1% of the monozygotic twins were concordant for GID, whereas
none of the dizygotic twins were concordant (Heylens et al. 2012).
Genes that are involved in either sex steroid biosynthesis or action have been investigated
because it is known that sex steroids contribute to the sexual differentiation of the brain. Complete
loss of function of the androgen receptor in XY individuals with complete androgen insensitivity
syndrome almost invariably results in a female gender identity; therefore, it may be a candidate
gene that affects gender identity development. In MtFs, a polymorphism of CAG repeat length in
the androgen receptor was found (Hare et al. 2009), but another study with a larger sample failed
to replicate this finding (Fernández et al. 2014b). Estrogen receptor (ER) genes have also been
studied. The prevalence of a long CA repeat in ERβ was found to be higher in MtF transsexuals
than in control men (Henningsson et al. 2005). Because the CYP19 is important for aromatization
of androgens into estrogens, this gene may be another candidate, but none of the studies found
support for this gene’s involvement in the development of GD (Fernández et al. 2014b, Hare et al.
2009, Henningsson et al. 2005, Ujike et al. 2009). In FtMs, there was a link to the CYP17 gene
(Bentz et al. 2008) and to polymorphism of the ERβ gene (Fernández et al. 2014a), but another
study did not find any associations with these polymorphisms (Ujike et al. 2009).
At present, no strong candidate gene has been found that can account for the development
of GD. Many human traits and diseases have a polygenic architecture, where the phenotype is
determined by variation in many genes. This is plausibly the case for GD, and future studies
should determine if the architecture is polygenic or if there are specific loci with larger effects.
In addition, gender identity is most likely a complex trait that results from a combination of
multiple genetic and environmental factors. In twin, adoption, or family studies, these factors
can be dissected. Furthermore, phenotypes should be carefully defined, and homogeneous groups
should be compared. In neuroimaging studies (see below), attention has now been drawn to the
importance of describing the phenotypes and taking into account sexual orientation and age of
onset.
Prenatal sex hormones. Sexual differentiation of all somatic tissues has long been ascribed to
exposure of testicular hormones in the fetus (Bocklandt & Vilain 2007), resulting in masculine
phenotypes in the presence of testicular hormones and feminine phenotypes in the absence of
these hormones. These early effects of sex hormones on the brain are denoted as organizing
effects, as opposed to effects of circulating hormones later during life on the already organized
neural system (Phoenix et al. 1959). It is hypothesized that feelings of gender incongruence may
arise from atypical sexual differentiation of the brain under the influence of prenatal hormones
(Swaab & Garcia-Falgueras 2009). Time windows for prenatal development of genitals and the
brain are believed to differ; thus, exposure to atypical levels of prenatal hormones during a certain
gestational period may have an effect on the brain but not the body.
Sex-dimorphic neural structures. In the search for neurobiological underpinnings of GD, brain
structure and function have been studied to determine whether the brains of transgender indi-
viduals show atypical sexual differentiation. A series of Dutch studies fueled this line of research
by showing female-typical hypothalamic nuclei in MtF transsexuals (Garcia-Falgueras & Swaab

2008, Kruijver et al. 2000, Zhou et al. 1995). The aim of subsequent imaging studies was to deter-
mine whether the brains of people with GD would show more resemblance to their experienced
gender than their natal sex. Supplemental Table 4 (follow the Supplemental Material link
in the online version of this article or at http://www.annualreviews.org) summarizes imaging
studies in adults with GD before the start of cross-sex hormone treatment.
Gray matter is one of the main components of the CNS and largely consists of neuronal cell bod-
ies. Studies of nonhomosexual MtFs have shown that gray matter volumes were largely in line with
their natal sex (Luders et al. 2009, Savic & Arver 2011). For homosexual MtFs, some differences
have been observed: Like control women, homosexual MtFs showed larger gray matter volumes in
comparison with male controls and FtMs in several cortical regions (Simon et al. 2013). Another
measure of gray matter volume is cortical thickness (CTh). CTh is generally higher in women
than in men. Homosexual MtFs showed CTh similar to that of female controls but increased
CTh compared with male controls in the orbito-frontal, insular, and medial occipital regions of
the right hemisphere (Zubiaurre-Elorza et al. 2013). Using this measure, nonhomosexual MtFs
also showed higher CTh compared with control men (Luders et al. 2012).
The putamen, a nucleus that is part of the basal ganglia and mainly associated with motor
regulation, is the only subcortical structure that has shown differences, although the findings are
diverse: The right putamen of nonhomosexual MtFs was larger than that of control men and was
in the female range in one study (Luders et al. 2009), but relatively smaller than that of male and
female controls in another study (Savic & Arver 2011). In homosexual MtFs, the volume of the
putamen was comparable to that of male and female controls (Zubiaurre-Elorza et al. 2013).
White matter mainly contains myelinated nerve fibers. Diffusion tensor imaging (DTI) is a
technique that is used to visualize white matter microstructure. One DTI study found that homo-
sexual MtFs had a pattern that was significantly different from control men and control women
(Rametti et al. 2011b) and the values were in between male and female controls. A similar picture,
but with another DTI measure, was found in MtFs (in both homosexual and nonhomosexual sub-
groups): Mean diffusivity values were increased compared to control males (Kranz et al. 2014b).
Structural connectivity networks were also examined in the same participants (Hahn et al. 2014).
A decreased hemispheric connectivity ratio in subcortical/limbic regions was found in mainly
nonhomosexual MtFs compared to control men and women, which seemed to be related to an
increased interhemispheric lobar connectivity.
With regard to the sexual differentiation hypothesis, the following picture now emerges, taking
sexual orientation into account: Homosexual MtFs are dissimilar to their natal sex in gray matter
volume (Simon et al. 2013), CTh (Zubiaurre-Elorza et al. 2013), and white matter microstruc-
ture (Rametti et al. 2011b). For nonhomosexual MtFs, the picture is less clear: Their gray matter
volumes were in line with their natal sex (Luders et al. 2009, Savic & Arver 2011), but they do
show differences in white matter microstructure compared to control men (Kranz et al. 2014b).
However, all groups in the Kranz et al. study were mixed with regard to sexual orientation, which
may have affected the results. Overall, evidence supports the sexual differentiation hypothesis in
homosexual MtFs, but not in nonhomosexual MtFs. Natal women with GD are more homoge-
neous with regard to sexual orientation (most are homosexual). FtMs (like control men) had larger
gray matter volumes than female controls and MtFs in several areas (Simon et al. 2013), and similar
CTh to control women (Zubiaurre-Elorza et al. 2013). Like male controls, they had a larger vol-
ume of the putamen than female controls (Zubiaurre-Elorza et al. 2013). White matter FA values
of FtMs were significantly greater than those of female controls but similar to those of male con-
trols in several fascicles (Rametti et al. 2011a). In one of the fascicles, the corticospinal tract, FtMs
had values in between male and female controls. Kranz et al. (2014b) found a significant decrease
in mean diffusivity values in FtMs compared with control females. Intrahemispheric connectivity
between the right subcortical/limbic and right frontal and temporal lobes was decreased in FtMs
compared with male and female controls and MtFs (Hahn et al. 2014). All structural studies in
adult FtMs thus far render support for atypical sexual differentiation of their brains.
Neural functioning. Functional connectivity is a method to evaluate interactions between re-

gions while performing a task (task-related functional connectivity) or while not performing a
particular task (resting-state connectivity). While viewing erotic and nonerotic interactions of
male-female couples, the functional connectivity of MtFs and FtMs (as a group) showed an in-
crease between the ventral tegmental area and the anterior cingulate cortex subregions compared
to controls (men and women together) (Ku et al. 2013). It was argued that because the ventral
tegmental area is associated with dimorphic genital representation and the anterior cingulate cor-
tex is central in conflict monitoring and social processing, the pattern could be a substrate of the
psychological distress of transgender individuals. These findings should thus not be viewed in
the realm of the sexual differentiation hypothesis, but rather are more suggestive of the brain’s
substrate for incongruence between body and identity.
Functional studies that focus on homosexual MtFs do not exist, nor are there studies that com-
pare homosexual with nonhomosexual MtFs. In nonhomosexual MtFs, a female-like response in
hypothalamic activation while smelling odorous steroids (Berglund et al. 2008) and brain activity
while viewing erotic videos (Gizewski et al. 2009) were detected, arguing for sex-atypical reactions
in these groups. Brain activation patterns during voice perception of a sexual-orientation mixed
group of MtFs differed from those of men and, partly, also of women ( Junger et al. 2014). Dif-
ferences were shown in brain activation during a visuospatial task in MtFs with unknown sexual
orientation in comparison with controls of their natal sex (Schöning et al. 2010).
While processing positive affective images, FtMs under gonadal suppression showed less acti-
vation in the right superior temporal lobe compared to control women (Soleman et al. 2014). The
findings may well be related to their GD instead of the gonadotropin-releasing hormone (GnRH)
treatment because no associations with hormonal levels were found.
Kranz et al. (2014a) studied the hemispheric asymmetry in the cerebral serotonin transporter
system in males, females, and MtF transsexuals because lateralization of emotional processing
has been shown. Serotonin is known to play an important role in emotional processing, and
hemispheric asymmetry of the serotonin system has been reported as well. MtFs differed from
male controls in the midcingulate cortex (rightward asymmetry for male controls but not for MtFs
and female controls) and from female controls in the calcarine gyrus. It was concluded that MtFs
show asymmetries of the serotonin transporter system “that relate to both genetic sex, gender and
a special feature of gender dysphoria” (p. 180).
In sum, findings indicate structural as well as functional alterations in the brains of transgender
individuals, either as a consequence of atypical sexual differentiation or as a result of a mismatch
between their anatomical sex characteristics and their gender identity. Brain changes may also be
triggered by psychological distress. Future studies should carefully consider the phenotypes of
participants, ideally combining genetic profiles with neuroimaging measures.
Psychosocial Processes
Nascent markers of gender identity emerge very early in development (Martin et al. 2002). To
the extent that gender identity is a stable trait, psychosocial factors—to truly merit causal status—
should be able to account for the emergence of a cross-gender identity in the first few years of life,
when it is first expressed. Otherwise, psychosocial factors would be better conceptualized as having
a perpetuating role. If psychosocial factors can also account for instances of a cross-gender identity
that first manifest in adolescence or even later (the late-onset form of GD discussed previously),
they should also be operative prior to the time of onset.
Given these assumptions, it is obvious that the study of causal psychosocial factors in adults
with GD faces methodological barriers because it largely relies on retrospective methods, which
are subject to many interpretive problems. As an example, Cohen-Kettenis & Arrindell (1990)
had both MtF and FtM adult patients rate their parents on the Egna Minnen av Barndoms Uppfos-
tran (My Memories of Upbringing) questionnaire with regard to three dimensions of behavior:
rejection, emotional warmth, and overprotection (e.g., intrusiveness, strictness). Compared to a
volunteer sample of male community controls, the MtF patients did not differ significantly in their
recollection of maternal behavior; however, fathers were rated as significantly more rejecting, less
warm, and more overprotective. The FtM patients rated their mothers as significantly more re-
jecting, less warm, and more overprotective than the female controls. They also rated their fathers
as more rejecting and less warm.
Regarding the MtF data, it could be argued that there was no support for the maternal over-
closeness hypothesis theorized to play a role in the development of GD (Stoller 1968); however,
ratings of the fathers could be interpreted as support for a distance hypothesis (Green 1987).
Regarding the FtM data, it could be argued that there was support for a maternal undercloseness
hypothesis that has been theorized (Stoller 1975), but there was no support for an overcloseness
hypothesis with the father, since the fathers were also rated as more rejecting and less warm.
Consider three challenges in interpreting these kinds of data. First is the direction-of-effect
conundrum. For example, perhaps fathers of MtF patients were more rejecting because they them-
selves were alienated by feminine-gendered behaviors of their son in childhood, so the direction of
effect was from son to father, not father to son (Freund & Blanchard 1983). Second, the commu-
nity controls were volunteers, so it is conceivable that this was a source of bias (e.g., perhaps they
were more likely than a truly random sample to come from families that were more harmonious).
Third, the study lacked a clinical control group. A control group would have been desirable to
determine whether the adult patients with GD recalled patterns of parental behavior that were
unique or simply characteristic of clinical populations in general (Garber & Hollon 1991).
One conceptual issue is the extent to which gender identity is a stable, within-person trait,
almost impervious to external influences once it has become internalized. An ideal study would be
to sample a representative cohort of young children who have a clear-cut identity as a boy or as
a girl and to assess their gender identity again much later in development (e.g., in adolescence or
adulthood) in order to examine its stability. Although the data are limited, some evidence suggests
that gender identity is likely a very stable trait. In Green’s (1987) study of very feminine boys, a
control sample of boys, who were all behaviorally masculine in childhood and presumably had a
male gender identity, all had a male gender identity at follow-up in late adolescence. Steensma
et al. (2013b) used data from a longitudinal study of 879 Dutch children to assess the stability in
gender identity at two time points: any time between 4 and 12 years of age and then 24 years later
(mean ages, 7.5 years and 30.9 years, respectively). On the Child Behavior Checklist, 818 parents
indicated that their child did not express a wish to be of the other gender or to behave like the
other gender. At follow-up, 98.8% of these now grown-up children did not self-report a desire to
be of the other gender.
In clinical populations of children with GD, however, gender identity stability is less certain.
A number of studies have shown that the majority of these children do not persist in their desire
to be of the other gender when followed up in late adolescence or adulthood (Drummond et al.
2008, Green 1987, Singh 2012, Wallien & Cohen Kettenis 2008), particularly in samples in which
a social transition to living as the desired gender has not occurred prior to puberty (Steensma et al.
2013a).
If children with GD shift their gender identity in a direction that is more congruent with
their natal sex, and if there are some adults who initially identify as a sexual orientation minority
(Diamond & Butterworth 2008) but then shift their gender identity so that it is no longer congru-
ent with their natal sex, then it becomes important to understand the proximal factors that might
contribute to this change. One such factor may involve an iterative matching process between sur-
face expressions of gender role behavior and identity. Many children with GD show a diminution
of their cross-gender role behavior over time, which may lead to a shift in their underlying gender
identity or identification. Conversely, adults with a minority sexual identity and who have a his-
tory of marked gender-nonconforming behavior may eventually settle on a cross-gender identity
that is more comfortable for them, as noted by Diamond & Butterworth (2008). Taken together,
these data suggest that, for at least some individuals, gender identity may be a more dynamic, fluid
process than previously thought.
THERAPEUTICS
The treatment of adults with GD is now largely standardized in developed countries, reflecting the
influence of clinical guidelines promulgated by professional associations. The Standards of Care
for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7 (SOC-7;
Coleman et al. 2011) is the best known and most influential guideline; similar recommendations
have been published by the Royal College of Psychiatrists (Wylie et al. 2014), a task force of
the American Psychiatric Association (Byne et al. 2012), the Endocrine Society (Hembree et al.
2009), and other professional groups (for reviews, see Gooren & Asscheman 2014, Lawrence 2014,
Monstrey et al. 2014). These guidelines represent the views of experienced clinicians and scholars,
but many of their recommendations reflect a low quality of evidence (i.e., case-series reports and
expert opinion) (Byne et al. 2012).
The following subsections examine recent developments and controversies related to the treat-
ment of adults with GD. Two broad themes underlie these analyses. First, the contemporary
emphasis on reducing barriers to care and promoting client autonomy and self-determination is
not easily reconciled with some elements of current treatment guidelines. Second, the increasing
diversity of adults who qualify for a GD diagnosis has not been matched by an expanded range of
treatment options addressing this diversity.
Diagnosing GD and Comorbid Conditions and the Role

of Mental Health Professionals
The SOC-7 rescinded the longstanding requirement that the diagnosis of GD and any associated
psychopathology be made by mental health professionals (MHPs). Now, any “health professional
who is appropriately trained in behavioral health and competent in the assessment of gender
dysphoria” (Coleman et al. 2011, p. 181) may make these diagnoses and any contingent treatment
recommendations. This change, intended to reduce barriers to care, may unintentionally result in
underdiagnosis of comorbid psychopathology. As noted previously, even experienced MHPs tend
to underdiagnose comorbid psychopathology unless they employ structured clinical interviews.

MHPs have historically served as gatekeepers as well as diagnosticians for adults with GD,
because eligibility for hormone therapy and SRS has traditionally been contingent on assessments
that only MHPs were considered qualified to make. Some clinicians believe that such gatekeeping
functions are unnecessarily time consuming and potentially undermine individuals’ autonomy
and choice (Bouman & Richards 2013). The SOC-7 and other guidelines have deemphasized
the role of MHPs in recommending hormone therapy: Physicians are now allowed to prescribe
hormones without a MHP’s recommendation, particularly for patients using hormones without
medical supervision (Coleman et al. 2011, pp. 187, 191–192; Wylie et al. 2014, pp. 176–177). This
approach to prescribing is sometimes referred to as the informed consent model (Coleman et al.
2011, Deutsch 2012).
This liberalized approach reflects contemporary clinical realities, particularly the widespread
use of nonprescribed hormones by persons with GD. Gómez-Gil et al. (2009) reported that
approximately 60% of Spanish MtFs applicants for sex reassignment had taken hormones without
medical supervision (see also Simonsen et al. 2015). Interestingly, some evidence indicates that
adults with GD who disregard traditional treatment guidelines and undergo hormone therapy
without the recommendation of a psychiatrist achieve psychosocial outcomes similar to those of
more compliant patients and achieve them more quickly (Pimenoff & Pfäfflin 2011).
It is not always clear what the informed consent model means. Deutsch (2012), who surveyed
12 clinics that claimed to prescribe hormones using this model, found that whereas “only four of
the 12 sites required any contact with a mental health provider” (p. 141), the average time patients
spent with MHPs during the intake process was 2.4 hours. Five clinics required a minimum
number of visits or imposed specified waiting periods before prescribing, suggesting a belief that
meaningful informed consent cannot be obtained quickly. It remains unclear whether informed
consent prescribing requires a formal diagnosis of GD or whether any transgender adult who is
able to give consent can receive hormones, regardless of diagnosis. It is similarly uncertain whether
informed consent requires that any comorbid psychopathology be satisfactorily controlled. A close
reading of the SOC-7 suggests that the latter is required—and that the informed consent model
is not very different from the standard model:
The difference between the Informed Consent Model and SOC, Version 7, is that the SOC puts greater
emphasis on the important role that mental health professionals can play in alleviating gender dyspho-
ria . . . In the Informed Consent Model, the focus is on obtaining informed consent as the threshold
for the initiation of hormone therapy . . . Less emphasis is placed on the provision of mental health
care . . . unless significant mental health concerns are identified that would need to be addressed before
hormone prescription. (Coleman et al. 2011, p. 188)
It appears that what one might intuitively consider “informed consent prescribing”—offering
medically supervised hormone therapy without preconditions or delay to any transgender person
who requests it, is competent to consent (i.e., not psychotic or grossly mentally impaired), and
has received basic information about risks and benefits—is not yet widely available. Given the
prevalence of unsupervised hormone use, such a development is arguably overdue.
Counseling and Psychotherapy for Adults with Gender Dysphoria

In past decades, helping adults with GD find greater acceptance and comfort with their natal sex
and assigned gender was considered a legitimate goal of counseling and psychotherapy, especially
when undertaken at the client’s request. Current guidelines, however, describe such efforts as both
futile and unethical. According to the SOC-7:
Treatment aimed at trying to change a person’s gender identity and lived gender expression to become
more congruent with sex assigned at birth has been attempted in the past (Gelder & Marks 1969;
Greenson 1964), yet without success, particularly in the long-term (Cohen-Kettenis & Kuiper 1984;
Pauly 1965). Such treatment is no longer considered ethical. (Coleman et al. 2011, p. 186)
The citations allegedly demonstrating that such treatment efforts are “without success” date from
30 to 50 years ago, when adults with GD were much less prevalent and diverse than today. It is
recognized that GD can remit in some cases (Marks et al. 2000); perhaps psychotherapy could
facilitate such remission—or a reduction in GD symptoms, with greater congruence between
gender identity and expression and assigned sex—in some subset of the diverse group of adults
whose gender problems now qualify for a diagnosis of GD. Unfortunately, these possibilities have
not yet been investigated, and such investigations are strongly discouraged in the SOC-7. If a
client with GD decided that overt cross-gender expression carried too great a risk of unacceptable
consequences and requested a psychotherapist’s help in trying to make their gender identity
and gender expression more congruent with their assigned sex, would the therapist’s participation
always be unethical, as the SOC-7 seems to assert? If so, the SOC’s position would seem to conflict
with the client’s right to autonomy and self-determination. Perhaps the overarching treatment
goal of psychotherapy for GD—“long-term comfort in . . . gender identity expression, with realistic
chances for success in . . . relationships, education, and work” (Coleman et al. 2011, p. 184)—could
sometimes best be achieved by supporting clients in a decision to forego gender transition or
overt public cross-gender expression. This psychotherapeutic aim, which was explicitly set forth
in version 6 of the SOC [i.e., “acceptance of the need to maintain a job, provide for the emotional
needs of children, honor a spousal commitment, or not to distress a family member as currently
having a higher priority than the personal wish for constant cross-gender expression” (Meyer et al.
2001, pp. 19–20)], was expunged from the SOC-7.
These issues assume greater importance in light of recent evidence that sex reassignment is
associated with more serious psychological sequelae and more prevalent regret than had previously
been supposed. Two large population-based studies from Sweden (Dhejne et al. 2011, 2014)
are particularly relevant. The 2011 study, discussed previously, described the greatly elevated
prevalence of comorbid psychopathology, death by suicide, and suicide attempts in the cohort of
patients who underwent SRS between 1973 and 2013. The 2014 study examined the prevalence of
“regret applications” (applications for reversal of legal sex reassignment) in patients who underwent
SRS during the 1960–2010 period. Only 2.2% of these patients submitted regret applications, over
one-quarter of which came from the small cohort of patients who underwent SRS before 1972. But
regret applications were made a median of eight years after SRS, so some patients who underwent
SRS recently may yet submit such applications. Moreover, whereas only 10 patients who underwent
SRS between 1972 and 2000 submitted regret applications, 10 others who underwent SRS between
1973 and 2003 died by suicide, and another 29 made documented suicide attempts (Dhejne et al.
2011). This suggests that regret applications underestimate the prevalence of genuine regret
or dissatisfaction after sex reassignment. Moreover, 3.3% of applications for SRS were denied,
sometimes due to comorbid psychopathology or failure to meet diagnostic criteria; had these
applicants undergone SRS under more liberal standards, they might have contributed to a still
greater prevalence of regret. Although a 2.2% prevalence of regret after SRS thus represents a
conservative estimate, it substantially exceeds figures previously reported by Pfäfflin (1992; 1.0–
1.5%) and Weitze & Osburg (1996; 0.4%). As Dhejne et al. (2014) noted, “This [difference] might
be explained by the extensive follow-up time in the present study and by the fact that virtually all
cases of regrets are captured in the Swedish registry system” (p. 1543).
A recent meta-analysis by Murad et al. (2010), examining outcomes of sex reassignment in 1,833
participants, confirmed both the benefits and limitations of this treatment. About 86% of FtMs
and 71% of MtFs reported improvement in GD symptoms after sex reassignment; about 84% of
MtFs and 78% of FtMs reported improvement in quality of life. Thus, it appears that about 20%
of patients do not experience significant benefit from sex reassignment. Many adults with GD
who now undergo sex reassignment would have been considered unsuitable or risky candidates in
years past (Dhejne et al. 2014). Smith et al. (2005) observed that factors predictive of less satisfac-
tory functioning after sex reassignment included nonhomosexual orientation relative to natal sex,
greater dissatisfaction with secondary sex characteristics, and more comorbid psychopathology,
yet adults with late-onset GD and nonhomosexual orientation, physical characteristics that are
highly incongruent with the desired sex, and significant comorbid psychopathology increasingly
request and undergo sex reassignment. Perhaps the SOC should reinstate its endorsement, at least
in certain cases, of psychotherapy that aims to increase comfort with assigned sex and gender role
and discourages sex reassignment.
Real-Life Experience in the Preferred Gender Role

It is now accepted that not all persons with GD will want or need all of the treatment elements
available to them. Accordingly, the SOC-7 endorses hormone therapy, real-life experience (RLE),
and SRS without psychotherapy; hormone therapy and RLE without SRS; and even RLE and SRS
without hormone therapy in certain cases. The ordinary eligibility requirements in the SOC-7,
however, do not allow SRS without a 12-month, full-time RLE, even when the client does not
desire a RLE. This exception to the principle of client autonomy and self-determination has never
been seriously challenged, despite a dearth of evidence supporting the value of RLE as an eligibility
criterion for SRS (Lawrence 2013, Levine 2009). Recognizing that SRS has significant risks, the
SOC-7 does not require adults with GD to undergo SRS if they can achieve satisfactory relief of
GD with hormone therapy and RLE alone. But RLE also carries significant psychosocial risks,
including loss of employment, impaired relationships with family and friends, and gender-based
discrimination and physical and mental abuse. Given these risks, the SOC arguably should not
require adults with GD to undertake a RLE if they can achieve satisfactory relief of GD with
hormone therapy and SRS alone.
This issue will probably soon become moot in light of language in the DSM-5 specifying
that adults with “a strong desire for the primary and secondary sex characteristics of the other
gender” can qualify for a diagnosis of GD on the basis of “a strong desire to be of the other
gender (or some alternative gender different from one’s assigned gender)” (Am. Psychiatr. Assoc.
2013, p. 452). Consequently, adults with GD who want to undergo SRS to achieve the primary
sex characteristics of the other gender but who identify with an “alternative gender” comprising
both male and female elements could theoretically satisfy the eligibility requirement of living for
12 months in a gender role that is congruent with one’s gender identity (Coleman et al. 2011) by
living part-time in their original gender role (e.g., in public) and part-time in the gender role of
the other sex (e.g., in private). When this option becomes more widely appreciated, the RLE will
be recognized as no longer meaningful and will cease to be an eligibility requirement for SRS.
Hormone Therapy
Recent investigations have largely confirmed the opinion that hormone therapy is an effective and
reasonably safe treatment in adults with GD. As noted previously, Murad et al. (2010) found that
cross-sex hormone treatment, usually accompanied by SRS, was associated with improvement in
GD, other psychological symptoms, and quality of life in about 80% of MtFs and FtMs. Cross-
sectional studies have also shown that hormone-treated MtFs and FtMs who have not undergone
SRS demonstrate significantly better quality of life (Gorin-Lazard et al. 2012), greater self-esteem,
better mood (Gorin-Lazard et al. 2013), and less psychological distress (Heylens et al. 2014b) than
persons who have not yet begun hormone treatment. But hormone therapy can be associated with
significant medical complications. Wierckx et al. (2012) found that, in 50 MtF patients who had
used feminizing hormones for a mean of 9.2 years, there were 3 (6%) thromboembolic events and
3 (6%) other cardiovascular complications, including 2 myocardial infarctions; moreover, about
one-quarter of MtF patients had significant osteoporosis. Wierckx et al. (2012) could not, however,
document any significant cardiovascular events or other serious complications in 50 FtM patients
who had used masculinizing hormones for a mean of approximately 10 years. In a subsequent
prospective study of 53 MtFs and 53 FtMs who received cross-sex hormone therapy for one year,
Wierckx et al. (2014) found no evidence of serious complications.
Hormone therapy for adult males with GD has traditionally included testosterone suppression
with spironolactone, cyproterone acetate (not available in the United States), or GnRH agonists.
Although both the SOC-7 (Coleman et al. 2011) and the Endocrine Society guidelines (Hembree
et al. 2009) mentioned the use of GnRH agonists in adult males with GD, the SOC-7 deempha-
sized GnRH agonists because of their expense and administration by injection or subcutaneous
implantation; it described cyproterone and spironolactone as more cost effective. In contrast, the
recent Royal College of Psychiatrists guidelines (Wylie et al. 2014) emphasized the problems
associated with spironolactone and cyproterone acetate and recommended GnRH agonists as an
“alternative and preferable” means of testosterone suppression in adult males with GD. GnRH
agonists may soon supersede traditional antiandrogens in this role.
Sex Reassignment Surgery

Few controlled studies have examined the psychosocial outcomes of SRS per se. Mate-Kole et al.
(1990) compared 20 MtFs who underwent vaginoplasty on an expedited basis with 20 wait-list
control patients; SRS patients were more socially active and displayed less anxiety, depression, and
obsessionality. Barrett (1998) examined psychological and social functioning in 40 FtMs who had
undergone phalloplasty an average of four years previously and 23 FtMs who had been approved
for, but were still awaiting, phalloplasty; there were no significant between-group differences in
SCL-90-R scores. Udeze et al. (2008) studied 40 MtFs who completed the SCL-90-R before
and six months after undergoing SRS, with each patient acting as her own control; no significant
differences in pre- and post-SRS scores were found. In a study discussed previously, Heylens et al.
(2014b) compared SCL-90-R scores in 46 MtFs and 11 FtMs before treatment, after hormone
therapy, and after SRS. Before treatment, patients’ mean subscale scores were significantly higher
than those of general population controls. After hormone therapy, patients’ scores no longer dif-
fered from those of controls, but no further improvement was observed after SRS. Contemporary
outcome studies of SRS are therefore consistent with earlier ones: Although the great majority
of adults with GD report improved subjective satisfaction, objectively measured psychological
symptoms neither improve nor worsen after SRS.
SUMMARY
In this article, we have provided an overview of GD in adults, including terminology and phe-
nomenology, epidemiology, diagnosis and assessment, associated psychopathology, causal mech-
anisms, and therapeutics. As transgender adults have attained increasing recognition, modern
cultures have undergone a remarkable change with regard to acceptance and support of people
with GD, including legal recognition and better access to health care. As more transgender adults
“come out,” we hope that this article will provide the contemporary clinician with a greater un-
derstanding of the research and clinical issues that will inform best practice in working with this
underserved population.
DISCLOSURE
Dr. Zucker was the Chair of the DSM-5 Workgroup on Sexual and Gender Identity Disorders.
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CP12CH20-Zucker ARI 8 January 2016 11:55

Review in Advance first posted online

still occur before final publication

Gender Dysphoria in Adults

Kenneth J. Zucker,1,∗ Anne A. Lawrence,2

Canada; email: [email protected]

Annu. Rev. Clin. Psychol. 2016. 12:20.1–20.31 Keywords

Sex Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.6

Psychological Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.9

20.2 Zucker · Lawrence · Kreukels

TERMINOLOGY AND PHENOMENOLOGY

www.annualreviews.org • Gender Dysphoria in Adults 20.3

Criteria for gender dysphoria in children

20.4 Zucker · Lawrence · Kreukels

Prevalence and Incidence

www.annualreviews.org • Gender Dysphoria in Adults 20.5

20.6 Zucker · Lawrence · Kreukels

Placement in the Nomenclature

Substantive Changes in the DSM-5

www.annualreviews.org • Gender Dysphoria in Adults 20.7

2. A lower-bound six-month duration criterion was introduced based on clinical consensus,

Gender Dysphoria and the ICD-11

20.8 Zucker · Lawrence · Kreukels

www.annualreviews.org • Gender Dysphoria in Adults 20.9

to assess because a reduction in dissatisfaction is an important metric in identifying improvement

Increased Prevalence of Associated Psychopathology

20.10 Zucker · Lawrence · Kreukels

www.annualreviews.org • Gender Dysphoria in Adults 20.11

Studies that Find Little or No Increased Prevalence

20.12 Zucker · Lawrence · Kreukels

Self-Report Measures of Associated Psychological Symptoms

Increased Prevalence of Suicidality and Self-Harm

Explanations of Associated Psychopathology

www.annualreviews.org • Gender Dysphoria in Adults 20.13

prejudice and discrimination).

20.14 Zucker · Lawrence · Kreukels

the identification of mechanisms that might explain a within-sex difference in a sex-dimorphic

www.annualreviews.org • Gender Dysphoria in Adults 20.15

by showing female-typical hypothalamic nuclei in MtF transsexuals (Garcia-Falgueras & Swaab

20.16 Zucker · Lawrence · Kreukels

Neural functioning. Functional connectivity is a method to evaluate interactions between re-

www.annualreviews.org • Gender Dysphoria in Adults 20.17

20.18 Zucker · Lawrence · Kreukels

www.annualreviews.org • Gender Dysphoria in Adults 20.19

Diagnosing GD and Comorbid Conditions and the Role

to underdiagnose comorbid psychopathology unless they employ structured clinical interviews.

20.20 Zucker · Lawrence · Kreukels

Counseling and Psychotherapy for Adults with Gender Dysphoria

www.annualreviews.org • Gender Dysphoria in Adults 20.21

Real-Life Experience in the Preferred Gender Role

20.22 Zucker · Lawrence · Kreukels

Sex Reassignment Surgery

www.annualreviews.org • Gender Dysphoria in Adults 20.23

20.24 Zucker · Lawrence · Kreukels

www.annualreviews.org • Gender Dysphoria in Adults 20.25

20.26 Zucker · Lawrence · Kreukels

Kreukels, TD Steensma, ALC de Vries, pp. 277–97. New York: Springer

www.annualreviews.org • Gender Dysphoria in Adults 20.27

20.28 Zucker · Lawrence · Kreukels