THE MODERN PROBLEM OF IDENTITY

Highlighting pertinent information from each and every scientific study currently available on transgenderism, sexual dimorphism of the brain, and the efficacy of gender reinforcement, cross sex hormones and surgery as a treatment option. This was a very short list with over 90% of the studies done within the last decade. Presented information widely differs from that which is propagated by the Transgender lobbies as unquestionably true. The “science” agrees with transgender ideology as much as any severely limited, small, inconsistent, inconclusive, insufficient, scientific study could support, or discredit, anything, ever. The medical negligence on the behalf of the AMA, APA, and wide range of other medical associations needs to be addressed. Conclusions reached from each study are not congruent with what is being pushed as a matter of fact on their websites.

Human sexuality is an objective biological binary trait: “XY” and “XX” are genetic markers of male and female, respectively – not genetic markers of a disorder. The norm for human design is to be conceived either male or female. Human sexuality is binary by design with the obvious purpose being the reproduction and flourishing of our species. This principle is self-evident. The exceedingly rare disorders of sex development (DSDs), including but not limited to testicular feminization and congenital adrenal hyperplasia, are all medically identifiable deviations from the sexual binary norm, and are rightly recognized as disorders of human design. Individuals with DSDs (also referred to as “intersex”) do not constitute a third sex.

No one is born with a gender. Everyone is born with a biological sex. Gender (an awareness and sense of oneself as male or female) is a sociological and psychological concept; not an objective biological one. No one is born with an awareness of themselves as male or female; this awareness develops over time and, like all developmental processes, may be derailed by a child’s subjective perceptions, relationships, and adverse experiences from infancy forward. People who identify as “feeling like the opposite sex” or “somewhere in between” do not comprise a third sex. They remain biological men or biological women.

A person’s belief that he or she is something they are not is, at best, a sign of confused thinking. When an otherwise healthy biological boy believes he is a girl, or an otherwise healthy biological girl believes she is a boy, an objective psychological problem exists that lies in the mind not the body, and it should be treated as such. These children suffer from gender dysphoria. Gender dysphoria (GD), formerly listed as Gender Identity Disorder (GID), is a recognized mental disorder in the most recent edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM- 5).5 The psychodynamic and social learning theories of GD/GID have never been disproved.

Puberty is not a disease and puberty-blocking hormones can be dangerous. Reversible or not, puberty- blocking hormones induce a state of disease – the absence of puberty – and inhibit growth and fertility in a previously biologically healthy child.

According to the DSM-5, as many as 98% of gender confused boys and 88% of gender confused girls eventually accept their biological sex after naturally passing through puberty.

Pre-pubertal children diagnosed with gender dysphoria may be given puberty blockers as young as eleven, and will require cross-sex hormones in later adolescence to continue impersonating the opposite sex. These children will never be able to conceive any genetically related children even via articifial reproductive technology. In addition, cross-sex hormones (testosterone and estrogen) are associated with dangerous health risks including but not limited to cardiac disease, high blood pressure, blood clots, stroke, diabetes, and cancer.

Rates of suicide are nearly twenty times greater among adults who use cross-sex hormones and undergo sex reassignment surgery, even in Sweden which is among the most LGBTQ – affirming countries. What compassionate and reasonable person would condemn young children to this fate knowing that after puberty as many as 88% of girls and 98% of boys will eventually accept reality and achieve a state of mental and physical health?

Conditioning children into believing a lifetime of chemical and surgical impersonation of the opposite sex is normal and healthful is child abuse. Endorsing gender discordance as normal via public education and legal policies will confuse children and parents, leading more children to present to “gender clinics” where they will be given puberty-blocking drugs. This, in turn, virtually ensures they will “choose” a lifetime of carcinogenic and otherwise toxic cross-sex hormones, and likely consider unnecessary surgical mutilation of their healthy body parts as young adults.

Prevalence estimates suggest that MF transsexualism is more common than FM transsexualism although a few studies have found a 1:1 ratio.

Prevalence estimates range from 1:10,000 to 1:100,000 for MF and 1:30,000 to 1:400,000 for FM.

Studies examining the biological causes of gender identity disorder have typically examined the effects of prenatal hormones on prenatal brain development. During normal prenatal development, the presence of testosterone leads to the development of external male genitalia and to a male differentiated brain. It is hypothesized that for individuals with gender identity disorder, a discrepancy may exist between prenatal genital differentiation and brain differentiation such that the external genitals develop, for example, as male while the brain develops as female. The evidence to support this hypothesis is mixed.

Genetic females exposed to high levels of testosterone in utero (e.g., congenital adrenal hyperplasia), rarely develop gender identity disorder.

Similar prenatal exposure to antiandrogenic, androgenic, and estrogenic drugs rarely leads to gender identity disorder in either genetic females or males although some of these individuals display abnormal gender role behavior.

Zhou et al. (1995) found that the central subdivision of the bed nucleus of the stria terminalis (a region of the hypothalamus) was smaller in MF transsexuals compared to normal males but similar in size to normal females, a difference that was not accounted for by hormone therapy. These findings however, showed only small portion of brain feminization and the rest of their brain was different, or that similar to a male.

Recent studies indicate that, compared to controls, MF transsexuals have more older brothers (but not more older sisters) and a later birth order (Blanchard et al., 1995; Zucker et al., 1997). Conversely, FM transsexuals are more likely to have several younger sisters but not brothers compared to controls (Zucker et al., 1998).

Birth order is implicated in the cause of homosexuality as well.

Childhood gender identity disorder may, in some cases, predict adult gender identity disorder. Fifty-five feminine boys with gender identity disorder were followed into early adulthood. Five of the feminine boys were diagnosed with gender identity disorder, one as a transvestite, 21 as homosexual, 14 as heterosexual, and 14 that were not rated. This suggests that childhood gender identity disorder reflects a high likelihood of either adult gender identity disorder or homosexuality (Green, 1987).

Gender Identity Disorder definition included homosexuals, and gender nonconforming individuals, which is why it was revised to Gender Dysphoria. The ‘disorder’ itself, as identified by diagnostic criteria in the DSM, was not removed. Gender Dysphoria, and Gender Identity Disorder, are essentially the same thing. The purpose for removing the moniker was because it brought unnecessary stigma and shame to those suffering from gender dysphoria. The criteria hasn’t changed folks, and you absolutely do need to experience gender dysphoria in order to correctly identify oneself as transgender. If Gender Dysphoria is nonexistent, the individual is plainly only a gender-nonconforming, gender-bending, gender-fluid, dresser.

A review of sex reassignment surgery outcome studies suggests that in most cases, surgery resolves the gender identity disorder. Depending on the study, between 71% and 97% of subjects were successfully treated with surgery and less than 1% later took steps to reverse the sex reassignment. Factors that predict a poor outcome include: misdiagnosed transvestism, poor surgery outcome, poor social or work functioning, suicidal tendencies, and sex reassignment surgery late in life. This suggests that the current procedure for determining appropriateness of sex reassignment surgery is effective, when applied strictly (Cohen-Kettenis & Gooren, 1999).

Outdated, incorrect statistics.

Male to female transsexuals who are attracted to men (MF homosexuals) seem to have a better post-surgery outcome compared to MF transsexuals who are attracted to women (MF heterosexuals).

Obviously Gender Identity was often used as conversion therapy in the past, and unfortunately still persists in this to this day with modern day gender ideology.

MF heterosexuals may have a poorer post-surgery outcome because of the added stigma of becoming homosexual after surgery, and because they typically present for surgery much later in life than MF homosexuals and thus are likely to have more male-role investments (e.g., husband, father).

This is mainly who we are bending language and twisting reality for. They still highly retain their male socialization, combined with higher rates of narcissism, and entitlement. Not all, but this is the more problematic group.

Existing literature demonstrates that there is no solid evidence for the differences in the function/structure of the brain between children and adolescents with and without GD. Indeed, there is no comprehensive selfness and understanding of sexual issues in childhood and adolescence. The cultural and sociocultural contexts and specific cultural environment based behaviors have not yet fully developed in this period. In fact, these contexts are emerging and developing in this period of life. Therefore, it seems reasonable to expect that at this age, major behavioral changes have not formed at the social level and, consequently, the brain has not undergone significant changes.

After adolescence and over time, the subject becomes more familiar with gender and sexual issues and faces transsexualism (or even homosexuality) due to lack of proper selfness, lack of appropriate parenting or his/her childhood background. New ideas and beliefs form for the subject inappropriate for his/her biological sex, and subject tries to avoid right and normal culturally contextual behaviors. Subject instead imagines themselves in their preferred identity rather than biological sex, and tries to adapt the values/lifestyle/behaviors to their gender identity. Depending on how much the subject with GD persists in changing his/her gender (i.e., positive, neutral or negative transgenders) and the extent to which he/she has experienced gender identity, we will observe brain changes and, as a result, related culturally voluntary behaviors. Perhaps this is why the results of brain studies in transgender people are largely contradictory.

However, for instance, when a person with GD whose biological gender is male, regulates his lifestyle based on his preferred gender identity (i.e., the female), we should expect, according to the CBB loop model, the brain to adapt to this belief and this lifestyle with time, and consequently changes in function and then the structure of the brain occur.

Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females.

Homosexual MtFs and female controls had less gray matter volume in the left somatosensory and primary motor cortices as well as the posterior cingulate and calcarine gyri and the precuneus than male controls and FtMs. These findings suggest that homosexual MtFs have a feminine cortical pattern. However, the results should be taken cautiously because of the small sample size and the brain statistical maps showing significance were at an uncorrected level (p < .001).

In girls, more grey matter volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex.

Our findings thus indicate that neural grey matter distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.

Overall, in vivo MRI studies indicate that the main morphological parameters of the brain (ICV, GM, WM, and CSF) are congruent with their natal sex in untreated homosexual MtFs. However, some cortical regions show feminine volume and thickness and it should be underscored that CTh presents an F > M morphological pattern. Nevertheless, with respect to CTh, this feminine cortical pattern is not the same as the one shown by control females.

The main white matter fascicles in MtFs are demasculinized, while others are still masculine. Most of the differences appear to be located in the right hemisphere. So far, the studies on the white matter, like those above on gray matter, strongly suggest that MtFs have their own brain phenotype that mainly affects the right hemisphere.

All we know about the morphology of the brain of nonhomosexual MtFs comes from a single VBM study (Savic & Arver, 2011). Nonhomosexual MtFs have the same total intracranial volume as control males. They also show a larger gray matter volume in cortical regions in which the male and female controls did not differ in the study. These regions were the right parieto-temporal junction, the right inferior frontal, and the insular cortices. It was concluded that their data did not support the notion that the nonhomosexual MtF brain was feminized.

NONHOMOSEXUAL TRANSGENDER MALES WERE FOUND TO HAVE A BRAIN THAT IS IN ACCORDANCE WITH THEIR BIOLOGICAL SEX.

Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus. The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.

DOES NOT SUPPORT THE NOTION THAT BRAINS OF MTF ARE FEMINIZED

Just wanted to make sure that those results are heard and understood.

Blanchard categorized trans women into two groups:

Homosexual Transsexuals who are attracted exclusively to men, and who seek sex reassignment surgery because they are feminine in both behavior and appearance; And Autogynephillic Transsexuals who are sexually aroused at the idea of having a female body.

Untreated heterosexual MtFs had a relatively smaller putamen and thalamus than male and female controls although these two latter groups did not show sex differences in the two structures (Savic & Arver, 2011). In summary, the cortex of nonhomosexual MtFs presents morphological peculiarities in regions in which male and female controls do not differ.

In FtMs, the gross morphological parameters correspond to their natal sex; their cortex is generally feminine but differs from males in different regions than do control females (compare Fig. 2a and c). Furthermore, some brain bundles are masculinized (Fig. 3b). All these findings suggest that homosexual FtMs have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure. Moreover, these changes are mostly seen in the right hemisphere.

With regard to treating gender dysphoria in patients with serious mental illness, there is a dearth of published literature, posing a challenge in offering evidence-based recommendations or tailored treatments. A systematic review of serious mental illness among lesbian, gay, bisexual, and transgender populations found only 27 articles between 1990 and 2015, and none included randomized controlled trials or pre-post intervention outcome evaluations.

>>Only 27, in twenty-five years. Even less that focused on transgender individuals, mental illness, and gender-reaffirming therapy.

Clinicians treating patients with serious mental illness may wonder whether a patient is experiencing gender dysphoria or is instead experiencing gender-related delusions that will disappear after a psychotic episode. Published reports indicate a tendency toward withholding gender-affirming medical treatments in the setting of psychosis, due to fear of misdiagnosis leading to irreversible interventions. Recent case series, however, suggest that gender dysphoria is separate from psychosis and often predates the onset of psychotic symptoms.

>>Which recent case studies? The nonexistent ones?

It is not uncommon for transgender people to first disclose their gender identity during an acute psychotic episode, but this can be due to a disinhibited state rather than to delusions. In these instances, people who have spent their lives hiding their gender identity may feel less concerned about antitransgender stigma, rejection, and abandonment during a psychotic episode and may therefore exhibit a less filtered expression of gender identity.

Gender dysphoria and desire to transition are often disclosed in late adolescence or early adulthood, which overlaps with the period of vulnerability for first-break psychosis. Concurrent psychosis may delay a diagnosis of gender dysphoria.

Literally anything but Gender Identity and ideology is questioned if it occurs during a psychotic episode. Insufficient evidence was therefore obviously provided to justify the revision of “gender identity disorder.”

Findings revealed over two thirds were undergoing hormone reassignment, suggesting a commitment to the real-life cross-gender process. One quarter had had problems with substance abuse prior to entering treatment, but less than 10% evidenced problems associated with mental illness, genital mutilation, or suicide attempts. Those completing the MMPI demonstrated profiles that were notably free of psychopathology.

Studies comprised of over two thirds on hormones undergoing the cross-gender process wouldn’t be applicable as you have to be mentally stable to start transitioning.

Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits.

Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization.

Abnormalities in genes related to gonadal hormone synthesis and action have been found in these individuals, suggesting that GID/GD is a disorder of sexual brain differentiation caused by exposure to altered hormone levels during a sensitive period; however, evidence for such a viewpoint has not been consistently found, and it fails to account for patients with late-onset GID who have few or no symptoms during childhood.

GID has been conceptualized as a disorder of cortical representation of sex-specific bodily features, particularly the genitalia, but such a proposal does not account for the other behavioural changes seen in this condition.

An influential model of GID, briefly alluded to above, posits that this condition is due to a disorder of sexual development which specifically involves the brain, but spares the internal and external genitalia. This theory has gained some support from brain imaging studies in which sexually dimorphic brain regions resemble those of the desired rather than the anatomical gender in subjects with GID.

There is evidence that some brain structures may show a similar variation in schizophrenia, with men showing a “feminized” pattern and women showing a “masculinized” pattern, leading to the proposal that schizophrenia itself may be related to gender-atypical brain development, perhaps caused by prenatal hormonal imbalances.

However, there are important differences in brain structure across the two disorders: most importantly, the thickness of the cerebral cortex is increased in male-to-female transsexuals, while schizophrenia has been consistently associated with decreased cortical thickness, irrespective of gender. This suggests that even if both disorders are related to common neurodevelopmental pathways, the changes seen in GID are less severe and more region-specific than those seen in schizophrenia.

Apart from the direct evidence of brain imaging studies, indirect evidence of prenatal hormonal influences can be obtained by studying the ratio of the length of the second and fourth digits (the 2D : 4D ratio) in adults; higher ratios indicate a more “feminized” pattern. In persons with GID, evidence of an altered 2D : 4D ratio has been reported in several studies, though some researchers have found a specific association only in men or women. These alterations are generally in the direction of individual's self-identified sex, with female-to-male subjects showing a more “masculinized” pattern than control women, and male-to-female subjects showing a more “feminized” ratio. Very similar alterations in the 2D : 4D ratio have been reported in schizophrenia, more specifically in male patients where a reversal of normal sexual dimorphism has been documented. Similar abnormalities are also found in schizotypal disorder, a condition which is genetically and clinically related to schizophrenia. This alteration, especially in male patients with schizophrenia, has also been tentatively linked to abnormalities in prenatal testosterone exposure, a mechanism relevant to GID.

Besides indicating sexual dimorphism, the finger length ratio is also an indicator of cerebral lateralization. Alterations in cerebral lateralization may result in an excess of atypical hand dominance patterns, such as left-handedness or mixed laterality.

A meta-analysis of 40 published studies found that schizophrenia was consistently associated with increased atypical hand dominance, particularly left-handedness. Similarly, both male and female transsexuals have higher rates of non-right-handedness than healthy controls, and this has been documented even in young boys with childhood GID. These findings suggest an altered pattern of lateralization, presumably of developmental origin and at least partly linked to genes involved in neurodevelopment.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays a key role in brain development, as well as in the maintenance of neural plasticity in adult brains. The activity of BDNF can be influenced by several factors, including sex hormones such as oestrogen and testosterone. A meta-analysis of studies conducted in patients with schizophrenia has identified a consistent, moderate decrease in blood BDNF levels compared to healthy controls. A recent study has found evidence of decreased serum BDNF levels in patients with GID. The authors of this paper have suggested that these changes may be due to childhood adversity or stress related to the patients' “minority” status. Yet, it is equally probable that low BDNF levels may signal a defect or deviation in normal brain development in this patient group, in the light of what is already known about the role of this molecule in the sexual differentiation of the brain.

More recent research has also found high rates (25%) of childhood maltreatment in male-to-female transsexuals; patients with a history of maltreatment had greater dissatisfaction with their body and worse mental health.

A study of individuals with ASD identified deviations in gender typicality, particularly lower overall levels of masculinity in both genders and higher levels of “tomboyism” in women with ASD. Individuals of both biological sexes with ASD and comorbid GID/GD have also been reported in the literature. Conversely, studies of individuals with GID have identified high levels of autistic traits and comorbid ASD, though some of these results appear to be gender-specific. Deficits in empathising, a feature of ASD, are also associated with GD, especially in female-to-male subjects.

It has been found by some researchers that individuals with female-to-male GID have deficits in empathising. This leads to difficulties in interacting with people of their own sex, who use empathising as a preferential mode of interaction, and may cause them to identify more readily with males, who use “systemizing” more prominently than empathizing. Though this possibility was raised in the context of autistic traits, it may also be relevant to the schizoid or schizophrenia-like personality traits seen in individuals with GID/GD and provides a further pathway by which a neurodevelopmental vulnerability can lead to the development of this disorder.

Findings suggest that testosterone treatment resulted in increased levels of psychological functioning on multiple domains in transgender men relative to nontransgender controls.

Research tends to support the evidence that hormone therapy reduces symptoms of anxiety and dissociation, lowering perceived and social distress and improving quality of life and self-esteem in both male-to-female and female-to-male individuals. Instead, compared to female-to-male individuals, hormone-treated male-to-female individuals seem to benefit more in terms of a reduction in their body uneasiness and personality-related psychopathology and an amelioration of their emotional functioning. Less consistent findings support an association between hormonal treatment and other mental health-related dimensions. In particular, depression, global psychopathology, and psychosocial functioning difficulties appear to reduce only in some studies, while others do not suggest any improvement in these domains. Results from longitudinal studies support more consistently the association between hormonal treatment and improved mental health. On the contrary, a number of cross-sectional studies do not support this evidence.

Affirmed males reported greater depression and anxiety at baseline, but these differences were small (P < .01). Youth reported large improvements in body dissatisfaction (P < .001), small to moderate improvements in self-report of depressive symptoms (P < .001), and small improvements in total anxiety symptoms (P < .01). No demographic or treatment-related characteristics were associated with change over time. Lifetime and follow-up rates were 81% and 39% for suicidal ideation, 16% and 4% for suicide attempt, and 52% and 18% for NSSI, respectively.

Although strong recommendations have been made for invasive and potentially irreversible interventions, high-quality scientific data on the effects of this approach are generally lacking. Limitations of the existing transgender literature include general lack of randomized prospective trial design, small sample size, recruitment bias, short study duration, high subject dropout rates, and reliance on “expert” opinion.

Existing data reveal significant intervention-associated morbidity and raise serious concern that the primary goal of suicide prevention is not achieved. In addition to substantial moral questions, adherence to established principles of evidence-based medicine necessitates a high degree of caution in accepting gender-affirming medical interventions as a preferred treatment approach.

Patients who experience a gender identity that is discordant with biological sex have an alarmingly high incidence of serious psychosocial morbidity including depression, anxiety, eating disorders, substance abuse, HIV infection, and homelessness (Connolly et al. 2016).

Most concerning, nearly half of all affected individuals will contemplate suicide and a third will attempt suicide (Adams, Hitomi, and Moody 2017).

Despite ideologically influenced efforts to portray sex along a continuum, reproductive biology is inherently binary. Specifically, there are only two gonads (testes and ovaries) that contribute to the conception of new human life. The existence of individuals with disorders of sexual development (DSDs) does not alter this basic biological reality (Eid and Biason-Lauber 2016).

In many individuals with DSDs, fertility is absent or severely impaired (Lee et al. 2006, 2016). When genital ambiguity is present, there are established clinical pathways involving hormonal, genetic, and imaging studies to assist clinicians in determining the sex of the affected child (Lee et al. 2016). In these rare cases, which affect <0.02 percent of all infants, the physician must make a tentative sex assignment at the time of birth. For the remaining 99.9% of infants, sex is not “assigned” at birth but rather is correctly recognized by the observation of the appearance of the external genitalia.

Nearly all patients who present to medical establishments for the treatment of gender dysphoria have normally formed and functioning sexual anatomy and function prior to hormonal or surgical intervention.

There is evidence that male to female ratio of individuals with sex–gender identity discordance has reversed, with more recent estimates showing that much of the observed increase is due to biological females who identify as male (Zucker 2017)

It is frequently claimed, without documented scientific evidence, that this increase is driven by an increase in existing patients coming forward for treatment rather than a change in overall incidence or change in rates of persistence among affected youth. The degree to which social affirmation of transgendered identity has affected these epidemiologic trends is unknown.

The phenomenon of adolescent girls with no prior expression of gender dysphoria presenting as having a transgendered identity in social networks has been reported (aka rapid onset gender dysphoria; Littman 2018).

There is no available blood test or imaging procedure that can be used to determine a person’s self-perceived gender identity. Evaluation relies exclusively in the domain of patient report of internally held feelings and beliefs. There are, however, published data that provide potential clues to influencing factors (Saleem and Rizvi 2017)

This includes several reports of structural and functional differences between brains of individuals with sex-discordant gender identity compared to brains from people with gender identity that matches sex (Burke et al. 2014; Luders et al. 2009; Kruijver et al. 2000).

The existing data on brain structure and function do not account for the known phenomenon of neuronal plasticity (i.e., environmental stimuli can alter brain structure; Ismail, Fatemi, and Johnston 2017). Thus, it is not clear whether changes in brain structure are the cause or effect of transgendered identity and behavior.

It is known that prenatal and perinatal hormone exposure can alter sexual phenotype (i.e., the physical appearance of the body; Jost et al. 1973). The degree to which these hormones influence gender identity remains an area of active investigation. (Berenbaum and Beltz 2016).

Female infants born with congenital adrenal hyperplasia (CAH), a condition that exposes the developing baby to high levels of male hormones (androgens), often exhibit typical male preferences and behaviors. Several potential explanations for this phenomenon that are independent of prenatal male hormone exposure have been proposed (Jordan-Young 2012). Importantly, the vast majority of affected children with CAH historically did not experience self-perceived transgender identity or gender dysphoria (Zucker et al. 1996).

Limited data also suggest a role of genetics in gender identity. This includes investigation of identical twins (Heylens et al. 2012). Because identical twins have exactly the same genes, if gender identity is exclusively determined by genetics, one would predict that there would be 100 percent concordance in identical twin pairs (i.e., if one twin experienced transgender identity, the other twin would also share this experience). However, the observed concordance is closer to 40 percent of affected twins.

There are ongoing efforts to sequence the genomes of individuals with sex-discordant gender identity to find a specific gene (or genes) that contribute(s) to this experience (Yang et al. 2017). The data published to date addressing this question provide potential clues, but similar to the limitations of with brain structures, there is considerable overlap between affected and nonaffected individuals (Foreman et al. 2019). Thus, it is likely that influences, whether primary or secondary, are polygenetic (i.e., the genetic differences are many, with each contributing only a small fraction of the observed phenotype).

Several reports have found high co-occurrence of autism in children with gender dysphoria (Glidden et al. 2016).

Despite the endorsement of gender affirmation approaches by several medical organizations including the Endocrine Society (Hembree et al. 2017) and the World Professional Alliance for Transgender Health (WPATH; Coleman et al. 2012), it is important to recognize the low quality of scientific evidence used in generating these treatment recommendations.

With the publication of both the initial treatment guidelines by the Endocrine Society guidelines in 2009 and revised guidelines in 2017, the Grading of Recommendations, Assessment, Development and Evaluations system was used to assess data quality (Guyatt et al. 2008). This system ranks evidence into four categories (strong, moderate, low, and very low). Nearly all of the recommendations made were based upon “low” or “very low” quality evidence. By definition, these designations mean that there is a high likelihood that the attainment of new data will necessitate changes to the guidelines provided. The only data that reached the level of “moderate” quality were related to adverse medical outcomes.

The limitations of the published studies in the growing field of transgender medicine are many. They include a general lack of randomized controlled trial design, small sample sizes, high potential for recruitment bias, questions regarding the precision of measured parameters, nongeneralizable population groups, relatively short follow-up, high numbers of patients lost to follow-up, and frequent reliance upon “expert opinion” alone. While such deficiencies are not unique to this field of investigation, the strength of the recommendations made on the basis of this type of evidence is, in many respects, disproportionate. In other areas of medicine, much greater caution is generally applied to advancing a single treatment approach over other potential interventions.

The pioneering work of Zucker established that many but not all patients who received psychological counseling and support were able to manage and resolve conflicts arising from discordant gender identity, particularly in affected children (Zucker et al. 2012).

Since the widespread adoption of interventional strategies directed toward affirming transgender identity, efforts to identify psychological approaches to mitigate dysphoria, with or without desistance as a desired goal, have largely been abandoned. The WPATH has rejected psychological counseling as a viable means to address sex–gender discordance with the claim that this approach has been proven to be unsuccessful and is harmful (Coleman et al. 2012). Yet the evidence cited to support this assertion, mostly from case reports published over forty years ago, includes data showing patients who benefited from this approach (Cohen-Kettenis and Kuiper 1984).

Although largely unstudied, cognitive behavioral therapy in particular may have significant benefit to this patient population by reducing social anxiety (Busa, Janssen, and Lakshman 2018). To date, there have been no randomized controlled trials investigating the risks and benefits of social transition.

There have been studies that report positive effects of nonmedical interventions: cross-sectional data on preferred name use have reported significant short-term improvement in self-reported sense of well-being (Russell et al. 2018). Furthermore, children who have undergone social transition with parental support have reported reduced levels of dysphoria (Durwood, McLaughlin, and Olson 2017; Olson et al. 2016). Limitations of these data include small sample size, restriction of study subjects to those with mild dysfunction, reliance on parental report, and lack of long-term follow-up.

Long-acting gonadotropin-releasing hormone (GnRH) agonists (aka “puberty blockers”) have been recommended to halt pubertal progression when this process occurs prematurely in children (Carel et al. 2009). Purported justification of this intervention for children with persisting dysphoria includes overall safety of these medications, allowance of more time for a child to explore their gender identity, reversibility upon treatment cessation for desisting individuals, and prevention of irreversible changes in secondary sexual characteristics for patients with persistent gender discordance. Yet the use of this intervention remains controversial (Vrouenraets et al. 2015; Giovanardi 2017).

There are a few relatively small studies that have demonstrated improved sense of well-being and reduced dysphoria in adolescent transgendered youth who receive puberty-blocking drugs (de Vries et al. 2011, 2014), but there are also significant concerns related to associated risks (Hruz, Mayer, and McHugh 2017). First, there are limited data specifically assessing the long-term safety of delaying normally timed puberty (Schagen et al. 2016). This class of medication has not been approved by the US Food and Drug Administration for use in halting normally timed puberty for gender-dysphoric youth (AbbVie 2018). Risks include osteopenia (low bone density), altered adult height, and impaired special memory (de Vries et al. 2011; Hough et al. 2017). Rather than merely providing more time for the exploration of gender identity, there is a concern that most if not all children exposed to this intervention will proceed to cross-sex hormone therapy (de Vries et al. 2011). While cessation of GnRH agonist administration will allow resumption of the signals that direct gonadal maturation, the interruption of a normal developmental process, which is time-dependent, cannot be “reversed.”

In the peer-reviewed literature on individuals who have undergone gender-affirming medical procedures to change bodily appearance, relatively low rates of regret and desire to “de-transition” to a gender role corresponding to biological sex have been observed (Wiepjes et al. 2018). Due to limitations in available data, questions remain regarding long-term satisfaction, particularly when initiated in adolescent children (Mahfouda et al. 2019). Most reports are from retrospective chart review or longitudinal study design.

None of the available studies include matched randomized prospective control groups. There is a deficiency of scientific study systematically assessing this patient population to understand factors that are correlated with and may contribute to failure to achieve lasting relief of dysphoria following the affirmation of discordant gender identity.

Affected individuals who desire to transition back to a gender role concordant with biological sex have reported negative social stigma similar to or in some cases exceeding that encountered prior to their initial medical intervention to support transgendered identity (Heyer 2018).

The available data on the long-term effects of gender affirmation in this patient population indicate that the most serious concern, suicide, remains significantly elevated above the background population after medical intervention to alter sexual appearance. Specifically, a thirty-year follow-up study in Sweden on patients who had undergone medical transition showed a rate of completed suicide that was nineteenfold above the backgrounds population (Dhejne et al. 2011). Because this was not a controlled study, it is not possible to assess the impact of the medical treatments themselves on outcomes.

Further indicating a lack of efficacy of this approach is a recent meta-analysis in North American patients, where suicidal ideation was assessed over the course of an individual’s lifetime and within the past year (Adams, Hitomi, and Moody 2017). In this report, suicide rates were similar in both groups. The few studies that examined suicidal ideation before and after gender transition found suicidal ideation to be increased.

The infertility that results can be irreversible, particularly where this intervention is undertaken prior to full gonadal maturation (Hembree et al. 2017).

Androgen levels achieved in female patients given testosterone exceed those observed in women with polycystic ovarian syndrome and frequently reach levels seen in androgen-secreting tumors with associated cardiovascular risk (Macut, Antić, and Bjekić-Macut 2015).

Males receiving estrogen have a fivefold increase in the incidence of thromboembolic stroke (Getahun et al. 2018).

Adverse metabolic effects that increase the risk of cardiovascular disease have also been reported (Irwig 2018; Maraka et al. 2017).

The influence of cross-sex hormones on cancer risk remains unclear. Potential risks for cancer development include exposure to cross-sex hormones, effects of sexually transmitted diseases (i.e., some sexually transmitted diseases increase risk of some cancers), and failure to obtain recommended screening in patients presenting to medical facilities with a gender that does not match biological sex. Further research is needed to adequately address this serious concern (Braun et al. 2017).

Physicians who deliver this care can also remain mindful of the long history of the harms that have been done to patients from the use of unproven medical interventions (Johnson 2014).

Just over 20 years ago, a publication reported the first observed neurobiological difference between cisgender and transgender individuals (Zhou et al., 1995). In particular, the bed nucleus of the stria terminalis (BNST) was found to have a smaller average size in male-to-female (MtF) transgender individuals, with a size more similar to that of an average cisgender female than cisgender male.

Interpretation of the BNST results at that time thus focused on the size difference rather than the function. As MtF transgender individuals had a size more similar to their desired gender than assigned gender, these data supported the theory that distress in gender dysphoria was due to an anatomic incongruence between brain and body sex. The incongruence was then specifically stated to be that transgender individuals have brain sex opposite to their gender assigned at birth.

Today, the BNST is no longer a black box but has several identified functions. For example, the BNST is a key component of the fear/distress network (Lebow and Chen, 2016; Tillman et al., 2018). Although chronic distress is a defining characteristic of gender dysphoria, the connection between the functional role of the BNST and its association with gender dysphoria appears to have received little consideration.

The connection between anatomic changes in the body ownership network and gender dysphoria has been a focus of several recent studies (Burke et al., 2017; Manzouri et al., 2017; Manzouri and Savic, 2019). The results on both the distress and body ownership networks suggest a theory in which each aspect of gender dysphoria is explained by the functional significance of known neuroanatomical differences.

Cortical thickness(CTh) maps showed control females have thicker cortex than control males in the frontal and parietal regions. In contrast, males have greater right putamen volume. FtMs had a similar CTh to control females and greater CTh than males in the parietal and temporal cortices. FtMs had larger right putamen than females but did not differ from males. MtFs did not differ in CTh from female controls but had greater CTh than control males in the orbitofrontal, insular, and medial occipital regions. In conclusion, FtMs showed evidence of subcortical gray matter masculinization, while MtFs showed evidence of CTh feminization. In both types of transsexuals, the differences with respect to their biological sex are located in the right hemisphere.

Postmortem studies identified the following two regions of the social behavioral network being altered in MtF transgender individuals: the third interstitial nucleus of the hypothalamus (INAH3), part of the anterior hypothalamus, and the BNST (Zhou et al., 1995; Garcia-Falgueras and Swaab, 2008).

The involvement of the body-ownership network (Tsakiris, 2010) in gender dysphoria can best be described by first considering how this network is studied in other contexts. The network has often been examined using the rubber hand illusion, whereby an individual is made to feel ownership over a rubber hand by time-locked visual and tactile stimulation to both the observed rubber hand and the unobserved real hand. Time-locked visual and tactile stimulation have also been used to create the illusion of ownership of an entire body that is not one’s own. The illusion even persists if the individual shakes hands with what looks like their actual body (Petkova and Ehrsson, 2008). The illusion involves subconscious processing, which is closely connected with other systems. For example, causing one to feel ownership of a more obese body can cause activation of the distress network, particularly the insula and anterior cingulate cortex (Preston and Ehrsson, 2016), whereas the illusion of being invisible can reduce subjective and objective social stress measures (Guterstam et al., 2015). Ownership of an artificial limb has also been induced in amputees by replacing the tactile stimulus with electrical stimulation (Collins et al., 2017). The body-ownership network is considered (Grivaz et al., 2017) to include the insula (particularly the left anterior insula), the right ventral premotor cortex, and portions of the posterior parietal cortex (specifically the right and left intraparietal sulci and left superior parietal lobule; see also discussion in Manzouri et al., 2017; Fig. 1).

The literature based on human data, which connects gender dysphoria with the body-ownership network and body perception, has been continually growing over the last decade. Some early work identified the involvement of the cingulate and insula but failed to associate them with their roles in body perception or distress (Nawata et al., 2010; Zubiaurre-Elorza et al., 2013), having their interpretation instead focused on cerebral dimorphism. Savic and Arver (2011) recognized the involvement of body perception networks in gender dysphoria as early as 2011 and have since published a stream of articles further reinforcing its relevance. Some studies focused purely on anatomic measurements (Burke et al., 2017; Manzouri et al., 2017; Manzouri and Savic, 2019). Other studies used images of the bodies of research subjects morphed to look more like the opposite gender (Feusner et al., 2016, 2017; Burke et al., 2019).

The effect of sexual orientation was also found to be a major confounding factor, in that some changes in earlier work thought to be associated with gender dysphoria were found to be explained better by the sexual orientation of the subjects (Burke et al., 2017; Manzouri and Savic, 2019). However, regions of the body-ownership network remained significant even after controlling for sexual orientation (Burke et al., 2017; Manzouri and Savic, 2019).

One of the regions identified in these studies (Nawata et al., 2010; Zubiaurre-Elorza et al., 2013; Manzouri et al., 2017), the anterior insula, is a common node in both the distress and body-ownership networks, and is interconnected with the central extended amygdala and periaqueductal gray (Kong et al., 2010; Tillman et al., 2018). Beyond the work of Savic (Feusner et al., 2016, 2017; Burke et al., 2017, 2018, 2019; Manzouri et al., 2017; Manzouri and Savic, 2019; Kilpatrick et al., 2019), results from a task-based study focused on the body representation network in transgender individuals, which included changes in the postcentral gyrus and superior parietal lobule (Lin et al., 2014). Lin et al. (2014) motivated that study by claiming that the involvement of the body-ownership network is a consequence of “dissonance between their biological sex and gender identity.” However, all available relevant data are correlational and do not constrain whether changes in body ownership cause, or are caused by, the perception of dissonance.

Xenomelia is a condition in which individuals feel a given body part is not their own, feel distress, and desire to have it removed. Changes have been observed in the body-ownership network using MRI data (Hilti et al., 2013) and cellular activation measured by MEG (McGeoch et al., 2011). Similar changes in MEG activation have been observed in transgender individuals.

Sensory perception related to body ownership and both gray and white matter in the body-ownership network (particularly the anterior insula, intraparietal sulcus, and superior parietal lobule) are directly linked with transgender individuals.

While a variety of neuroanatomical changes have been noted (for review, see Smith et al., 2015; Guillamon et al., 2016; Altinay and Anand, 2019), my view specifically addresses the functional significance of the observed changes in the distress network, social behavioral network, and body-ownership network, including the neuronal substrates of the BNST, anterior hypothalamus (encompassing the INAH3), anterior insula, intraparietal sulcus, superior parietal lobule, and orbitofrontal cortex.

For a number of sexually dimorphic brain structures or processes, signs of feminisation or masculinisation are observable in transsexual individuals, which, during hormonal treatment, partly seem to further adjust to characteristics of the desired sex. Still, it appears the data are quite inhomogeneous, mostly not replicated and in many cases available for male-to-female transsexuals only. As the prevalence of homosexuality is markedly higher among transsexuals than among the general population, disentangling correlates of sexual orientation and gender identity is a major problem. To resolve such deficiencies, the implementation of specific research standards is proposed.

The present review focuses on the brain structure of male-to-female (MtF) and female-to-male (FtM) homosexual transsexuals before and after cross-sex hormone treatment as shown by in vivo neuroimaging techniques. Cortical thickness and diffusion tensor imaging studies suggest that the brain of MtFs presents complex mixtures of masculine, feminine, and demasculinized regions, while FtMs show feminine, masculine, and defeminized regions. Consequently, the specific brain phenotypes proposed for MtFs and FtMs differ from those of both heterosexual males and females. These phenotypes have theoretical implications for brain intersexuality, asymmetry, and body perception in transsexuals as well as for Blanchard’s hypothesis on sexual orientation in homosexual MtFs. Falling within the aegis of the neurohormonal theory of sex differences, we hypothesize that cortical differences between homosexual MtFs and FtMs and male and female controls are due to differently timed cortical thinning in different regions for each group.