Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists

Animal research has established that sex differences in the phenotype of both body and brain as well as behaviors are the result of multiple, sex-biasing factors. These include hormonal, sex-chromosomal (41), genetic, and epigenetic contributions (42). The sensitivity of brain tissues to organizational effects of sex hormones appears to be particularly high at prenatal/perinatal stages of development and gradually declines toward young adulthood (43). The timing of hormonal secretions in the course of development, however, gives the impression of three discrete sensitive periods: (1) pre/perinatal; (2) pubertal (44); and (3) for females, the first pregnancy (45).

In humans, statistical sex differences in brain structure are well documented (46), and findings of sensitive periods for sexual differentiation of the brain appear to parallel those seen in other mammals (47, 48). The evidence for brain/behavior effects of prenatal androgenization is particularly strong (49–51), much of which derives from studies of individuals with somatic intersex conditions and varying degrees of functional androgen exposure (51–53).

Androgenization of the brain depends not only upon the level of androgen to which a fetus is exposed but also upon numerous other factors, including the presence of enzymes to convert androgens to the specific metabolites required by particular brain cells, their steroid receptors, and their postreceptor mechanisms that are involved in the full response to androgens. Receptor structure, which can influence sensitivity, is genetically determined, while the activity of genes for receptors and postreceptor mediators is subject to epigenetic modulation (54).

As the period of genital differentiation largely precedes the sexual differentiation of the brain (55), it is conceivable that GD in individuals without somatic intersex conditions could reflect a brain-limited intersex condition (i.e., a lack of concordance between the sexually differentiated state of the brain and body). That hypothesis has been tested in a variety of ways, including searching for features of the brain in individuals with GD that more closely match their experienced gender than their birth-assigned gender (56). Investigations in this regard have included postmortem morphometric and stereological studies (57), as well as in vivo morphometric (58), functional magnetic resonance imaging (59), and diffusion tensor imaging studies of the brain (60–62), and examination of otoacoustic emissions (63).

As reviewed elsewhere (53, 56, 64), while some positive findings in the predicted direction have been reported (56, 64), inferences are currently limited. This is because few findings have been replicated and few studies have adequately controlled for potentially confounding variables such as age, sexual orientation, transition status (including history of gender-affirming hormonal treatment, if any), and hormonal status at the time of study (or of death in the case of postmortem studies) (53).

Much of what is known about the role of early hormonal exposure on the development of gender identity in humans derives from studies of gender outcomes in individuals with somatic intersex conditions. Early guidelines for initial gender assignment for such infants relied heavily on the surgical potential to achieve concordance between the gender assigned and the appearance and functional potential of the external genitalia, in particular, the capacity of penile-vaginal intercourse (9). Current guidelines, however, emphasize what is known about the longterm gender outcomes of individuals with intersex conditions on a syndrome by syndrome basis (52).

Overall, these data suggest that regardless of genetic constitution, or gonadal or genital development at birth, individuals prenatally exposed to a full complement of masculinizing hormonal influences (i.e., androgen exposure and the cellular mechanisms for responding fully to androgens as described above) have an increased likelihood of GD when assigned female (51, 52). Conversely, most reported 46,XY individuals with complete androgen insensitivity syndrome (and hence no functional androgenization of the brain) have developed a female gender identity, despite having a Y chromosome as well as normally developed and functioning testes (51, 52). To date, however, no brain marker of sexual differentiation has been validated to guide the initial gender assignment of infants with intersex conditions.

In mammals, and particularly in humans, psychological and social factors have a major additional influence on behavioral outcome (65). In humans, these psychosocial processes include verbal labeling (e.g., ‘‘boy’’ and ‘‘girl’’) and nonverbal gender-cuing (e.g., gender-specific clothing and haircuts) of children by parents and others in their social environment, as well as the shaping of children’s gendered behavior by positive and negative reinforcement and later by explicit statements of gender-role expectations. Related processes in developing children include gender-selective observational learning/imitation, the formation of gender stereotypes and of related self-concepts, and self-socialization. The effects on gender development have been documented in a vast body of research in developmental psychology (65).

The impact of such psychosocial factors, however, is not determinative. This is evidenced by individuals in whom gender identity is discordant with the initial gender assignment and gender of rearing, for example, transgender individuals and a higher than expected proportion of individuals with particular intersex conditions (i.e., 46,XY individuals with high degrees of somatic hypomasculinization and 46,XX individuals with high degrees of somatic hypermasculinization) (66, 67).

Systematic data on gender identity development are much more limited than those on gendered behavior. Yet, the data available, especially for those with intersex conditions, lead to the conclusion that, while early androgenization plays a role, a definitive biological predetermination of gender identity seems unlikely. Not a single biological factor, but multiple factors (i.e., biological, psychological, and social) appear to influence the development of gender identity (50).

The need to transition gender is even less understood in individuals without, compared to those with, intersex conditions (68). Along with the dramatically increased referrals of gender-variant individuals to specialized clinics in Western Europe and North America over the last two decades (69, 70), there has been a diversification of presentations beyond the original ‘‘transsexual’’ who sought (or was perceived by providers to seek) change to the ‘‘other’’ gender through treatment with gender-affirming hormones and genital surgeries. Currently, many transgender people seek chest, but not genital surgery, or only gender-affirming hormones, or only a social transition without any medical changes. Others may simply desire flexibility in gender expression without transition to ‘‘the other gender,’’ identifying, for example, as nonbinary or genderqueer (71, 72).

Prospective follow-up studies of children, who before puberty had met criteria for the DSM-IV diagnosis of GID, showed that the majority of those diagnosed with GID in early or early middle childhood ‘‘desisted,’’ meaning that they subsequently identified as their birth-assigned gender and did not meet criteria for GID. As adults, many identified as lesbian, gay, or bisexual (73–75). Some ‘‘desisters,’’ however, subsequently transitioned later in life (73).

The data available do not allow a clear prediction before puberty of which child will persist and transition permanently, and which child will not (75). With the introduction of stricter criteria for the diagnostic category of Gender Dysphoria in DSM-5, the persistence rate likely will be higher (73), but this needs to be tested by future long-term follow-up studies. For example, the degree of gender nonconformity and whether a child believes they are, as opposed to wishes to be, ‘‘the other’’ gender have been proposed as predictors of persistence (76, 77). Those in whom GD persists from childhood into adolescence are likely to experience an exacerbation of dysphoria with the emergence of (or with the anticipation of) undesired secondary sexual characteristics at puberty, in which case pubertal suspension should be considered (10).

Regardless of their initial sexual orientation, during and after transitioning to express their experienced gender, some individuals retain their pretransition sexual attraction patterns, while others change (7). In some transgender women, the desire to transition gender is preceded by fantasizing themselves as women, sometimes with sexual arousal (78). This phenomenon has been controversially interpreted by some as fetishism (79). Importantly, neither a history of fetishistic arousal nor one’s sexual orientation precludes one from meeting the criteria for the diagnosis of GD (27) or eligibility for gender transition services (7, 80).

Treatment should be patient centered and tailored to the needs and individuality of each patient. Patients should be asked what names and pronouns they use and should be addressed by those names and pronouns regardless of their stage of transition. Those who transitioned many years ago and are seeking treatment for another problem typically need much less focus on gender history than those who are questioning their gender identity, just beginning gender transition, or exploring options for gender expression. When gender is not the primary concern, devoting the appropriate amount of attention to gender-related issues is important, balancing against an overemphasis on gender that can feel inadvertently stigmatizing to the patient or distract from adequate focus on the chief complaint.

While it is important to avoid the assumption that coexisting psychiatric symptoms are due to gender variance, the impact of past and present gender-related stigma should be considered in the biopsychosocial evaluation. This is particularly important in light of the stress diathesis model of psychiatric illness and its exacerbations (8, 92). Suicidality should always be assessed, as should protective factors such as social and family supports (93). Suicidal ideation (3, 94) and completed suicide (90) are dramatically increased in this population and GD may be a risk factor for suicidality, independent of other psychiatric conditions (94, 95). Up to 47% of transgender adults have considered or attempted suicide (93). Assessment of suicide risk is especially important during periods of heightened vulnerability, such as when transgender identity is disclosed to family and more broadly (9, 83).

The gender assessment should include the age and circumstances when the patient first became aware of a sense of difference from peers of the same sex assigned at birth as well as experiences of negative affect or self-perception related to that sense of difference (8, 20). Any history of peripubertal and/or pubertal distress due to the anticipation and/or emergence of unwanted secondary sex characteristics should also be explored, as should past experiences of gender-related stigmatization, discrimination, harassment, and violence (8, 20).

The patient’s history of coping mechanisms and support systems should also be examined (8, 20). Gender expression (e.g., pronoun use, name changes, manner of dress, and bodily modifications) over time should be explored as well as what has and has not been helpful in improving the sense of well-being. It is important to clarify each patient’s goals and plans for social and/or medical transition, degree of commitment, and expectations (7, 96). For those who do not wish to transition, assessing current psychosocial challenges and formulating with the patient how to best address them (e.g., psychotherapy, group therapy, and social support) should not be neglected.

Recommendations regarding psychiatric assessment of individuals with GD have focused largely on assessment of eligibility for and decision-making capacity related to medical and surgical gender transition services (7, 8, 10) Eligibility for both gender-affirming hormone therapy and surgeries requires persistent gender dysphoria, a documented diagnosis of GD based on DSM-5 criteria, and the capacity to give informed consent (7). In addition, any significant medical or psychiatric concerns must be sufficiently controlled so that they do not interfere with the patient’s ability to safely adhere to the treatment regimen. The current standard of care in major clinics, the WPATH SOC7, and insurance requirements for reimbursement of services follow a flexible progression of transition steps, which may begin with completely reversible steps (e.g., change of pronouns, name, and manner of dress), followed by partially reversible changes (e.g., gender-affirming hormones), and then irreversible gender-affirming surgeries (7, 10–14, 97). There is flexibility in this process given that some people do not pursue all of these interventions or may prefer to do so in a different sequence. For example, transgender men may wish to undergo mastectomy or male breast construction before initiating masculinizing hormones (7).

Before gonadectomy, 12 months of continuous hormone therapy consistent with the patient’s gender goals are recommended, unless hormones are clinically contraindicated for the individual. The aim of hormone therapy before gonadectomy is primarily to allow the individual to experience a period of gender-affirming hormones, before irreversible surgical intervention (7). Before masculinizing or feminizing genital reconstructive surgeries, the WPATH SOC7 also recommend 12 continuous months of living in a gender role that is congruent with the patient’s gender identity (7).

Statements in this section are based on the cited studies supplemented by the authors’ cumulative clinical experience treating patients with GD. Psychotherapy can be useful for patients with GD; however, many successfully transition or decide against transition with little or no psychotherapy. Psychotherapy may be helpful at different times and for different reasons across the lifespan (7). Many transgender people seek mental health treatment on an intermittent basis, while contemplating gender transition, at key points in the transition process, or post-transition if symptoms recur or worsen.

Participation in transgender support groups, including peer-led groups, and other interactions with transgender individuals or the transgender community are often useful in clarifying the goals of those who experience ambivalence about transition. With patients who are otherwise eligible for transition treatments, but express ambivalence about transition, the therapist should maintain a stance of neutrality, creating a safe therapeutic space in which the patient can weigh all options and arrive at a decision in their own time. Many transgender adults need some combination of hormonal treatment and/or surgical procedures for relief of GD, but some experience relief with a change in gender expression without any medical treatment (7). Strengthening resilience factors identified in the transgender population (93) should be a focus, particularly, in patients with suicidal ideation.

Although treatment with exogenous estrogen or testosterone carries a risk for medical side effects (10), both have been associated with improvement with respect to anxiety, mood, and mood stability, as well as overall satisfaction and quality of life for both transgender women and transgender men (101–104). Similarly, review of the available literature (9) demonstrates the benefits of surgery in alleviating GD and the rarity of postsurgical regret. Emotional changes may occur with use of either androgen or estrogen supplementation, although these are usually subtle (9). An increase in libido usually occurs with androgen use with female to male transition (10). Although decreased libido due to antiandrogen and/or estrogen treatment in individuals transitioning male to female is common (10), some may experience a stronger interest in sex, perhaps due to the affirming aspects of attaining desired bodily changes.

Safer sex information and instruction in self-protective negotiation in sexual settings should be provided and tailored to the anatomy, needs, and experiences of transgender persons (9). Masculinizing hormones have been associated with a possible destabilization of psychotic and bipolar disorders, especially with supraphysiological blood levels of testosterone (7) in both cisgender and transgender men (105–106). The likelihood of such episodes can, therefore, be minimized by careful dosing and monitoring.

Detailed information on specific gender-affirming surgical procedures can be found elsewhere (7, 107). Psychiatrists should collaborate with other providers (e.g., endocrinologists, surgeons, psychotherapists, primary care providers, social workers, and other mental health professionals) to ensure that patients have the knowledge required to adequately evaluate the benefits, risks, and limitations of desired treatments and their alternatives. This is necessary not only for informed consent but also to ensure adequate preparation for surgery and postsurgical needs (e.g., convalescent period, period of sexual abstinence, and vaginal dilatation in the case of vaginoplasty).

Helping the patient anticipate and prepare for psychosocial impacts of treatment (e.g., impact on social relationships and employment) is also essential. Importantly, transition treatments target GD, not coexisting psychiatric diagnoses, and coexisting diagnoses are likely to require ongoing attention after transition, although symptom severity may be ameliorated (98, 100, 102).

Whether the initial evaluation for hormones is done by the hormone prescriber or by a mental health professional, criteria for starting hormones are the same: the presence of persistent GD, the ability to give informed consent, and relative mental health stability (7). Insurance carriers and surgeons require mental health evaluation before transition-related surgeries to assess and document eligibility, readiness, and medical necessity of the requested procedure (7, 10–14).

The specific requested content of referral letters varies among surgical providers and insurance plans. To avoid unnecessary delays in treatment, letter writers should be aware of such differences and ensure that their letters meet the requirements of all relevant parties. The content requested by most providers and insurance carriers is similar to that outlined in the WPATH SOC7. Genital and gonadal surgeries usually require documentation from two licensed mental health professionals, while chest surgeries generally require just one evaluation and referral (7, 108). Although not requirements of WPATH SOC7, some insurers require one letter from a psychiatrist or other doctoral level mental health provider, or may specify a minimal duration of mental healthcare (13). Such requirements vary by health system, insurance carrier, and state, and raise challenges for those without access to reimbursement for mental healthcare.