Sex and Gender: The Science of Transgender Identity

gender identity and gendery equality

Possibly the most important part of the mental model humans construct is their mental model of themselves. This is what we call our identity. It takes all the beliefs we have about ourselves and attempts to put them together into an internally coherent whole. Some of our most cherished political, religious, racial, and gender thoughts about ourselves tells us who we are and how we ought to interact with the world.

Updated 2/2/2023

These beliefs about ourselves are not just thoughts, either. They are deeply held emotional states. They are how we relate to the world. Our identity regulates our preferences and how we react to situations. And our identity determines how we experience the world

We can have multiple sub-identities – my being a metal fan, a hip-hop fan, an atheist, an intellectual, a man, a brother, a son, etc. – but they all come together to form a single identity that we call the I. This is the fabric that holds together our mental model of the world into a single whole. I am a metal fan. I am a hip-hop fan. I am an atheist, and so on.

Our identity is formed in large part through what is called narrative identity. This is the story we tell ourselves about ourselves. As Wikipedia says in its opening:

The theory of narrative identity postulates that individuals form an identity by integrating their life experiences into an internalized, evolving story of the self that provides the individual with a sense of unity and purpose in life. This life narrative integrates one’s reconstructed past, perceived present, and imagined future. Furthermore, this narrative is a story – it has characters, episodes, imagery, a setting, plots, and themes and often follows the traditional model of a story, having a beginning (initiating event), middle (an attempt and a consequence), and an end (denouement).

These emotional states are not purely mental models we even choose to create, either. They can be shaped and formed through our thoughts and self-talk (narrative identity), as is proposed in cognitive behavioral theory, but much of it comes from our biology as well.

For instance, political affiliation has been associated with differential brain structure. An MRI study showed that political conservatives, contrasted with political liberals (in the American sense of the word), had more gray matter in the right amygdala. Another fMRI study of risk-taking behavior showed political conservatives have more activity in the right amygdala. The amygdala is important in processing emotions such as fear and threat. These results seem to suggest that there is a biological component in conservative resistance to change, seeing progress as a threat to the status quo.

Another instance of identity that has become important in our times is gender identity. There is strong evidence of a biological component to this as well. That binary sexes exist is a scientific fact. But even within this binary there is wiggle room. From occurrences of androgen insensitivity syndrome to XY gonadal dysgenesis to Klinefelter syndrome, and other forms of intersexuality, there are plenty of ways to genetically/chromosomally push the limits of the binary. But it’s also the case that genetically/chromosomally typical males and females can have a broad spectrum of masculinity and femininity, often, but certainly not always, connected to sexual orientation.

Going further, some males will identify as female and some females will identify as male in what is known as transgender identity. People with transgender identity experience what is known as gender dysphoria, or the distress a person experiences due to a mismatch between their gender identity—their personal sense of their own gender—and their sex assigned at birth (i.e., natal sex). Indeed, there is research showing that pre-hormone treatment transgender people have brain biochemistry and anatomy more similar to the gender they identify as than they do their natal sex, and that gender affirming treatments (e.g., hormone therapy) increases the quality of life for most people who identify as transgender. 

This post will give an overview of some of the literature on the neurobiology and neuroanatomy of transgender identity, the genetics of transgender identity, the affects of gender affirming hormone treatment, detransition, and so-called rapid-onset gender dysphoria (ROGD). I will begin with a few older(ish) studies, primarily from prior to the politicization of gender ideology, before going into newer studies. The newer studies are fine, in my opinion (though I do try to point out when there is dissent to a study’s findings or methodology), but I still want to avoid accusations of bias creeping into science.

Without further adieu, here are the papers.

 

Older Studies

The 2000 paper by Frank Kruijver et al and the 2008 paper by Garcia-Falgueras and Swaab both show that the number of neurons, as well as the receptor BSTc (bed nucleus of the stria terminalis, which is sexually dimorphic) in the male brain is the same as that in FtM transgender people, and vice versa for MtF transgender people (theirs is the same as cisgender females). This is regardless of whether they had begun hormone replacement therapy.

bed nucleus of stria terminalis BSTc transgender brain
BSTc numbers for a MtF transgender woman are the same as that for a cisgender woman as opposed to a cisgender male.

A 2007 paper by Ramachandran and McGeoch and a 2008 paper by Ramachandran and Mcgeoch discuss cisgender men who have had their penis amputated for various reasons report the sensation of a “phantom penis” while MtF transgender people who have had sex reassignment surgery report the sensation of a phantom penis significantly less often; FtM transgender people report the sensation of a phantom penis. Phantom limbs are known to occur because the feeling of your body does not happen in your body, but in the brain – the parietal region of the brain has our body “mapped” and all sensations actually occur there. The reduction in phantom penis reports in MtF transgender people, as well as the reporting of a phantom penis in FtM transgender people, suggests that the brains of these individuals has mapped their body in a way that corresponds to their gender identity as opposed to their birth sex.

For more on this notion of phantom limbs, brain-body representation incongruity, and transgender identity, see the following papers:

Gender Dysphoria and Body Integrity Identity Disorder: Similarities and Differences (2014)

Body Integrity Identity Disorder and Gender Dysphoria: A Pilot Study to Investigate Similarities and Differences (2014)

Altered White Matter and Sensory Response to Bodily Sensation in Female-to-Male Transgender Individuals (2017)

Phantom Penis: Extrapolating Neuroscience and Employing Imagination for Trans Male Sexual Embodiment (2020)

The 2009 paper by Luders et al and a 2016 review article by Kreukels and Guillamon both show that, independent of hormone replacement therapy, the neuroanatomy of transgender people matches more closely to the sex with which they identify in some key ways while also displaying morphology similar to the sex to which they were born – in other words, the brain structures of both MtF and FtM transgender people lie somewhere in between male and female, with some regions appearing more like the gender with which they identify and others appear more like the sex to which they were born.

transgender brain
Rametti et al (2010)

A 2009 study by Gizewski et al found significantly enhanced activation for men compared with women was revealed in brain areas involved in erotic processing, i.e., the thalamus, the amygdala, and the orbitofrontal and insular cortex, whereas no specific activation for women was found. When comparing MTF transsexuals with male volunteers, activation patterns similar to female volunteers being compared with male volunteers were revealed. Sexual arousal was assessed using standard rating scales and did not differ significantly for the three groups. In other words, the brains of MtF transgender women responded more like natal women to erotic simuli. Berglund et al (2007) had similar findings.

A 2013 paper by Milton Diamond show that monozygotic (identical) twins show a 33% concordance in transgenderism amongst FtM transgender people and 28% amongst MtF transgender people, as opposed to 4.76% and 0.34% for dizygotic (fraternal) twins respectively. In other words, if one person in a set of twins is transgender, there is a significant chance the other one will be as well, whereas in fraternal twins, the correlation is significantly decreased, indicating a biological cause.

Further Reading

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study (2010)

Increased Cortical Thickness in Male-to-Female Transsexualism (2012)

Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls—A Voxel Based Morphometry Study (2013)

 

Newer Studies

In the above I have purposefully used older studies. The reason for this is because some may argue that in our recent political climate that science may be compromised. But there are more recent papers that come to the same findings. Here are just a few of them:

A 2022 study by Kurth et al used MRI to examine the brains of 24 cisgender men, 24 cisgender women, and 24 transgender women before gender-affirming hormone therapy using a multivariate classifier that yields a continuous (rather than a binary) estimate for being male or female and found that the brains of transgender women ranged between cisgender men and cisgender women (albeit still closer to cisgender men), and the differences to both cisgender men and to cisgender women were significant (p = 0.016 and p < 0.001, respectively).

The estimated Brain Sex index was significantly different between the three groups (F(2,69) = 40.07, p < 0.001), with a mean of 1.00 ± 0.41 in cisgender men and of 0.00 ± 0.41 in cisgender women. The Brain Sex of transgender women was estimated as 0.75 ± 0.39, thus hovering between cisgender men and cisgender women, albeit closer to cisgender men (see also Figure 1). The follow-up post hoc tests revealed that transgender women were significantly more female than cisgender men ( Cohen’s d = 0.64, t(46) = 2.20, p = 0.016), but significantly less female than cisgender women ( Cohen’s d = 1.87, t(46) = 6.48, p < 0.001).
Kurth et al (2022)

A 2021 review article by Frigerio et al examines 39 studies on gender identity and 24 on sexual orientation and found that the neurometabolic features in transgender individuals resemble those of their experienced gender despite the majority resembling those from their natal sex.

A 2022 study by Uribe et al examined the effects of spontaneously occurring local activation (i.e., events) on global integration (Deco et al., 2015) through the intrinsic ignition framework (Deco & Kringelbach, 2017; Deco, Tagliazucchi, et al., 2017) of 29 trans men and 17 trans women with gender incongruence, 22 cis women, and 19 cis men and found that there were significant differences (FWE corrected p < .004) between all gender groups when the intrinsic ignition framework was computed across the whole-brain functional network in both mean-ignition and node-metastability measurements (Figure 2a and Table 1). There was a gradual progression in the mean-ignition, that is, cis men > cis women > trans men > trans women. On the other hand, the average node-metastability was the highest in the cis woman group, and the trans man group showed the lowest average.

Uribe et al (2022)

A 2020 study by Uribe et al examined the resting state functional connectivity of independent brain component networks, the intra- and inter-network connectivity strengths and global network large-scale characteristics in a homogeneous group of early onset TW [trans women] and TM [trans men]. In line with our predictions, there are three main findings: (i) TM, TW, and CW [cis women] had decreased connectivity in parietal regions compared with CM [cis men] as we predicted based on the cortical developmental hypothesis; (ii) similarly, TW and CW had less small worldness than CM, showing the existence of gender differences (considering the identification with the gender regardless of the assigned sex at birth) in this global network property; and (iii) TM had weaker connectivity in widespread regions mainly located in the frontal cortex and the majority of their significant connection nodes were part of the SN. Some of the regions that presented reduced functional connectivity in TM in comparison with CM were part of the own’s body perception hypothesis.

The graph-theory measurements showed that, like CW, the TW group had smaller small world coefficients than CM only when we kept the 7.5% of the strongest connections. They also had a lower clustering coefficient (also at 7.5% of the strongest connections) and modularity (when keeping the 5% of the strongest connections) than did CM. This possibly means that connectivity across the studied functional networks within the CM group follows a higher small-world organization due to a greater functional segregation of the brain. Functional segregation is the ability allowing specialized processing to occur within densely interconnected groups of brain regions and it is measured by the clustering coefficient and modularity properties. On the other hand, no significant differences at any sparsity threshold were found in characteristic path length as a measure for functional integration, i.e. the ability to rapidly combine specialized information from distributed brain regions (Rubinov and Sporns, 2010). Networks that keep a balance between functional integration and segregation are described as having a small-world structure (Sporns and Honey, 2006), meaning that the network has a high clustering coefficient and short path length, that is, global shortcuts across the network that allow fast transfer of information and low energy consumption at the same time (Bullmore and Sporns, 2009). The possible neural underpinnings of an increased/decreased small world network are not clear. Indeed, although a negative correlation is described between increasing age and decreased global connectivity measures in healthy aging studies, such effects are modest and more obvious local changes take place (Gong et al., 2009; Onoda and Yamaguchi, 2013).
In summary, similar to TM, TW showed reduced connectivity in the parietal lobe in comparison with CM. In addition, graph-theory measures are able to differentiate CM from TW and CW in both segregation and integration parameters.

Uribe et al (2020)

A 2014 study by Hahn et al found differences on lobar/hemispheric connectivity in transgender people, as well as total intracranial volume for MtF transgender people between those of male and female controls.

Hahn et al (2014)

A 2013 study by Zubiaurre-Elorza et al found similar CTh [coritical thickness] in androphilic MtF and female controls, and increased CTh compared with male controls in the orbito-frontal, insular and medial occipital regions of the right hemisphere. The CTh of FtM was similar to control women, but FtM, unlike control women, showed (1) increased CTh compared with control men in the left parieto-temporal cortex, and (2) no difference from male controls in the prefrontal orbital region.

Zubiaurre-Elorza et al (2013)

In a 2014 study by Burke et al they found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical.

Burke et al (2014)

A 2017 study by Clemens et al examined twenty‐eight MtFs (15 hormonally untreated), 21 male and 20 female healthy control participants for resting‐state functional connectivity (rs‐FC) measured by functional magnetic resonance imaging (fMRI) and found that MtFs exhibit patterns of rs‐FC which are different from both their assigned and their aspired gender, indicating an intermediate position between the two sexes. We suggest that the present study constitutes a starting point for future research designed to clarify whether the brains of individuals with GD are more similar to their assigned or their aspired gender.

In a 2019 study, Manzouri and Savic report multimodal magnetic resonance imaging data, including cortical thickness (Cth), subcortical volumes, and resting state functional magnetic resonance imaging, from 27 transgender women (TrW), 40 transgender men (TrM), and 80 heterosexual (40 men) and 60 homosexual cisgender controls (30 men). These data show that whereas homosexuality is linked to cerebral sex dimorphism, gender dysphoria primarily involves cerebral networks mediating self–body perception. Among the homosexual cisgender controls, weaker sex dimorphism was found in white matter connections and a partly reversed sex dimorphism in Cth. Similar patterns were detected in transgender persons compared with heterosexual cisgender controls, but the significant clusters disappeared when adding homosexual controls, and correcting for sexual orientation. Instead, both TrW and TrM displayed singular features, showing greater Cth as well as weaker structural and functional connections in the anterior cingulate-precuneus and right occipito-parietal cortex, regions known to process own body perception in the context of self.

A 2020 study by Flint et al looked to substantiate evidence that the brain structure of TIs [transgender individuals] differs from male and female, we use a combined multivariate and univariate approach. Gray matter segments resulting from voxel-based morphometry preprocessing of N = 1753 cisgender (CG) healthy participants were used to train (N = 1402) and validate (20% holdout N = 351) a support-vector machine classifying the biological sex. As a second validation, we classified N = 1104 patients with depression. A third validation was performed using the matched CG sample of the transgender women (TW) application sample. Subsequently, the classifier was applied to N = 26 TW. Finally, we compared brain volumes of CG-men, women, and TW-pre/post treatment cross-sex hormone treatment (CHT) in a univariate analysis controlling for sexual orientation, age, and total brain volume. The application of our biological sex classifier to the transgender sample resulted in a significantly lower true positive rate (TPR-male = 56.0%). The TPR did not differ between CG-individuals with (TPR-male = 86.9%) and without depression (TPR-male = 88.5%). The univariate analysis of the transgender application-sample revealed that TW-pre/post treatment show brain-structural differences from CG-women and CG-men in the putamen and insula, as well as the whole-brain analysis. Our results support the hypothesis that brain structure in TW differs from brain structure of their biological sex (male) as well as their perceived gender (female). This finding substantiates evidence that TIs show specific brain-structural alterations leading to a different pattern of brain structure than CG-individuals.

Flint et al 2020
Flint et al (2020)

A 2013 study by Ku et al found by means of functional magnetic resonance imaging, they found that the TXs [transgenders], as opposed to controls (CONs [cisgenders]), displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs.

A 2021 study by Mueller et al used MRI to examine the neurobiology of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity). They found that transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), they observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. They conclude that rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype. They do say that while this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites.

Further Reading

I highly recommend the following review article (a number of the above studies were discovered here): Neuroimaging Studies in People with Gender Incongruence (2016) by Baudewijntje P.C. Kreukels & Antonio Guillamon

Neural network of body representation differs between transsexuals and cissexuals (2014)

White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging (2014)

Female-to-Male Transsexual Individuals Demonstrate Different Own Body Identification (2016)

A Review of the Status of Brain Structure Research in Transsexualism (2016)

Intrinsic network connectivity and own body perception in gender dysphoria (2017)

Neural Systems for Own-body Processing Align with Gender Identity Rather Than Birth-assigned Sex (2020)

Cortical Gyrification in Transgender Individuals (2021)

Replication of Previous Findings? Comparing Gray Matter Volumes in Transgender Individuals with Gender Incongruence and Cisgender Individuals (2021)

 

Genetics Studies

The genetic component to transgender identity is still tenuous, but there is some tantalizing evidence that genetics may play a role in transgender identity. Some evidence, such as in Karamanis et al (2022) discussed below, indicates that the intrauterine environment, may play a larger role than genetics. When it comes to genetics and heritability (i.e., how much genetics explains variation in a particular trait) it’s often difficult to tease apart how much variation is due to genetics, how much is due to environment, and how much is due to the interaction of the two (many gene variants are known to increase a propensity for some behavior, but only if the person has grown up in a particular environment or are presented with particular situations). Furthermore, most traits, even something as seemingly straightforward as height, are enormously polygenic, i.e., there are hundreds of genes known to contribute to the trait (and often in ways that aren’t as straightforward as “alleles A, B, and C for genes P, Q, and R cause phenotype X”).

In what follows I will briefly go over a few studies concerning the genetics of transgender identity.

Cortés-Cortés et al (2017) found that XbaI-rs9340799 in ESR1 estrogen receptor gene is involved in FtM gender dysphoria in adults.

Fernández  et al (2014) examined sex hormone-related genes ERβ (estrogen receptor β), AR (androgen receptor), and CYP19A1 (aromatase) and found that FtMs differed significantly from control group with respect to the median repeat length polymorphism ERβ (P = 0.002) but not with respect to the length of the other two studied polymorphisms. The repeat numbers in ERβ were significantly higher in FtMs than in control group, and the likelihood of developing transsexualism was higher (odds ratio: 2.001 [1.15-3.46]) in the subjects with the genotype homozygous for long alleles.

Hare et al (2009) found a significant association was identified between transsexualism and the AR [androgen receptor] allele, with transsexuals having longer AR repeat lengths than non-transsexual male control subjects (p=.04).

Bentz et al (2008) examined 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls and found that the CYP17 gene to be a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism. Similarly, Fernández et al (2015) found that the CYP17 MspA1 polymorphism A2 allele frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887).

Ramirez et al (2021) found that global CpG methylation is different in transgender people (prior to gender-affirming hormone treatment) compared to cisgender people.

A 2022 twin study by Karamanis et al examined a total of 2592 full siblings from a large register-based population in Sweden over the period 2001–2016 where gender dysphoria (GD) cases were registered, of which 67 were twins; age at first GD diagnosis for the probands ranged from 11.2 to 64.2 years. No same-sex twins that both presented with GD were identified during the study period. The proportion of different-sex twins both presenting with GD (37%) was higher than that in same-sex twins (0%, Fisher’s exact test p-value < 0.001) and in non-twin sibling pairs (0.16%). The present findings suggest that familial factors, mainly confined to shared environmental influences during the intrauterine period, seem to contribute to the development of GD.

A 2019 study by Theisen et al examined rare variants in genes associated with sexually dimorphic brain development and exploring how they could contribute to gender dysphoria. They performed whole exome sequencing on the genomic DNA of 13 transgender males and 17 transgender females. Whole exome sequencing revealed 120,582 genetic variants. After filtering, 441 variants in 421 genes remained for further consideration, including 21 nonsense, 28 frameshift, 13 splice-region, and 225 missense variants. Of these, 21 variants in 19 genes were found to have associations with previously described estrogen receptor activated pathways of sexually dimorphic brain development. These variants were confirmed by Sanger Sequencing. Their findings suggest a new avenue for investigation of genes involved in estrogen signaling pathways related to sexually dimorphic brain development and their relationship to gender dysphoria.

 

Hormone Therapy

Hormone therapy is when someone takes the hormone of the sex they identify as in order to have their body conform to their internal identity (i.e., to develop the secondary sex characteristics of the sex they identify as). FtM transgender people take testosterone (known as masculinizing hormone therapy) while MtF transgender people take estrogen (known as feminizing hormone therapy). These can be administered through injection either intramuscular or subcutaneous. This is not without its health risks. See the following papers:

Sex Steroids and Cardiovascular Outcomes in Transgender Individuals: A Systematic Review and Meta-Analysis (2017)

The effects of oestrogens and their receptors on cardiometabolic health (2017)

Effects of Sex Hormone Treatment on the Metabolic Syndrome in Transgender Individuals: Focus on Metabolic Cytokines (2018)

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study (2018)

Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy (2019)

Gender-Affirming Hormone Therapy, Vascular Health and Cardiovascular Disease in Transgender Adults (2019)

Effects of Gender-Affirming Hormones on Lipid, Metabolic, and Cardiac Surrogate Blood Markers in Transgender Persons (2019)

Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People (2020)

Sex and Gender Differences in Clinical Pharmacology: Implications for Transgender Medicine (2021)

There are also what are called puberty blockers, which are meant to halt the onset of puberty. This is primarily done with gonadotropin-releasing hormone (GnRH) agonists. These desensitize the pituitary gland (by causing GnRH receptor downregulation) and thereby reducing the release of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in less testosterone/estrogen production. The purpose, as Anacker et al (2021) puts it, is:

The clinical purpose of GnRHa administration to transgender youth in early adolescence is: (1) to prevent further development of secondary sex characteristics consistent with sex assigned at birth, which risks increasing or perpetuating anatomic dysphoria and related social stigma; and (2) to gain time for (therapist-assisted) consideration of the transgender identity before starting hormone treatments that lead to irreversible development of secondary sex characteristics consistent with the individual’s gender identity.

Again, this treatment is not without its risks. See the following papers:

Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria (2015)

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents (2016)

Brain Maturation, Cognition and Voice Pattern in a Gender Dysphoria Case under Pubertal Suppression (2017)

Effect of Concurrent Gonadotropin-Releasing Hormone Agonist Treatment on Dose and Side Effects of Gender-Affirming Hormone Therapy in Adolescent Transgender Patients (2019)

The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort (2019)

Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones (2020)

Body Composition and Markers of Cardiometabolic Health in Transgender Youth on Gonadotropin-Releasing Hormone Agonists (2021)

Now I will give some summaries of studies on the use of hormone therapy as a treatment for gender dysphoria:

Smith et al (2014) describe the affects of cross-sex hormone therapy (CSHT) as: Within the first 6 months of CSHT, changes in transsexual females include breast growth, decreased testicular volume, and decreased spontaneous erections, and changes in transsexual males include cessation of menses, breast atrophy, clitoral enlargement, and voice deepening. Both transsexual females and males experience changes in body fat redistribution, muscle mass, and hair growth. Desired effects from CSHT can take between 3 and 5 years; however, effects that occur during puberty, such as voice deepening and skeletal structure changes, cannot be reversed with CSHT. Decreased sexual desire is a greater concern in transsexual females than in transsexual males, with testosterone concentrations linked to sexual desire in both. Regarding CSHT safety, bone mineral density is preserved with adequate hormone supplementation, but long-term fracture risk has not been studied. The transition away from high-dose traditional regimens is tied to a lower risk of venous thromboembolism and cardiovascular disease, but data quality is poor. Breast cancer has been reported in both transsexual males and females, but preliminary data suggest that CSHT does not increase the risk. Cancer screenings for individuals of both natal and transitioned sexes should occur as recommended. More long-term studies are needed to ensure that CSHT regimens with the best outcomes can continue to be prescribed for the transsexual population.

In 2015 Staphorsius et al found no significant effect of GnRHa [gonadotropin releasing hormone analogs] on ToL [Tower of London] performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD

In 2014 Zubiaurre-Elorza et al found that testosterone therapy increases CTh in FtMs. Thickening in cortical regions is associated to changes in testosterone levels. Estrogens and antiandrogens therapy in MtFs is associated to a decrease in the CTh that consequently induces an enlargement of the ventricular system. 

In 2021 Zubiaurre-Elorza et al found that testosterone produces structural changes in the brain [of FtM transsexual people] as detected by quantitative magnetic resonance imaging. Mainly, it induces an increase in cortical volume and thickness and subcortical structural volume probably due to the anabolic effects. Animal models, specifically developed to test the anabolic hypothesis, suggest that testosterone and estradiol, its aromatized metabolite, participate in the control of astrocyte water trafficking, thereby controlling brain volume.

In 2021 Skewis et al looked at people newly commencing standard full-doses of masculinising (n = 42; 35 = trans masculine, 7 = non-binary) or feminising (n = 35; 33 = trans feminine, 2 = non-binary) GAHT [gender affirming hormone therapy] and cisgender participants (n=53 male, n=50 female) found that in trans people initiating masculinising GAHT, there was a decrease in gender dysphoria with adjusted mean difference -6.80 (-8.68, -4.91), p < 0.001, and a clinically significant improvement in emotional well-being [adjusted mean difference 7.48 (1.32, 13.64), p = 0.018] and social functioning [adjusted mean difference 12.50 (2.84, 22.15), p = 0.011] aspects of QoL [quality of life] over the first 6 months of treatment relative to the cisgender female comparison group. No significant differences were observed in other QoL domains. In trans people initiating feminising GAHT, there was a decrease in gender dysphoria [adjusted mean difference -4.22 (-6.21, -2.24), p < 0.001] but no differences in any aspects of QoL were observed. They conclude that in the short-term, our findings support the benefit of initiating masculinising or feminising GAHT for gender dysphoria. Masculinising GAHT improves emotional well-being and social functioning within 6 months of treatment. Multidisciplinary input with speech pathology and surgery to support trans people seeking feminisation is likely needed. Further longitudinal studies controlled for other confounders (such as the presence of social supports) contributing to QoL are needed.

In 2021 Aldridge et al had participants (n = 178) complete a socio-demographic questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Multidimensional Scale of Perceived Social Support (MSPSS) and the Autism Spectrum Quotient-Short Version (AQ-Short) at pre-assessment (T0) and at 18 months after initiation of GAHT (T1) [gender affirming hormone therapy]. They found that from T0 to T1, symptomatology was significantly decreased for depression (P < .001) and non-significantly reduced for anxiety (P = .37). Scores on the MSPSS predicted reduction in depression, while scores on the AQ-Short predicted reduction in anxiety. GAHT reduces symptoms of depression which are predicted by having higher levels of social support. Although anxiety symptoms also reduce, the changes are not significant and high levels of anxiety still remain post-GAHT. They conclude that the results highlight the important mental health benefits of GAHT. Support services (professional, third sector or peer support) aiming at increasing social support for transgender individuals should be made available.

A 2022 study by Glintborg et al looked at the number of transgender people who go on to receive hormone therapy. They looked at the national register-based cohort study in Danish transgender persons followed from 2000 until 2018. The cohort included 2789 transgender persons (n = 1717, CGI-cohort [received a diagnosis of gender identity disorder] and n = 1072, CPR-cohort [received a legal sex change but without diagnosis of GID]). The median age (interquartile range) at study inclusion was 26.1 (17.7) years for persons assigned male at birth (n = 1447) and 22.5 (10.5) years for persons assigned female at birth (n = 1342). In the CGI-cohort, the event rate for GAHT [gender affirming hormonal treatment] in transgender women increased from 4.0 (95% confidence interval [CI]: [3.1; 5.2]) events per 100 person in year 2000-2005 to 20.6 (17.8; 23.7) between 2014 and 2018. In transgender men, the event rate of GAHT increased from 4.2 (2.8; 6.2) to 18.8 (16.4; 21.6). The rate of discontinuation of GAHT was 0.06 (95% CI 0.049; 0.071) per person year. They conclude that the event rate of GAHT increased during 2000-2018. Our data suggested high adherence to GAHT.

A 2018 review article by Nguyen et al found that although there are some conflicting data, GAHT overwhelmingly seems to have positive psychological effects in both adolescents and adults. Research tends to support that GAHT reduces symptoms of anxiety and depression, lowers perceived and social distress, and improves quality of life and self-esteem in both male-to-female and female-to-male transgender individuals. Clinically, prescribing GAHT can help with gender dysphoria-related mental distress. Thus, timely hormonal intervention represents a crucial tool for improving behavioral wellness in transgender individuals, though effects on cognitive processes fundamental for daily living are unknown. Future research should prioritize better understanding of how GAHT may affect executive functioning.

Further Reading

Puberty suppression in adolescents with gender identity disorder: a prospective follow-up study (2011)

Young adult psychological outcome after puberty suppression and gender reassignment (2014)

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents (2016)

Brain Maturation, Cognition and Voice Pattern in a Gender Dysphoria Case under Pubertal Suppression (2017)

Systematic Review of the Long-Term Effects of Transgender Hormone Therapy on Bone Markers and Bone Mineral Density and Their Potential Effects in Implant Therapy (2019)

Bone Mineral Density in Transgender Individuals After Gonadectomy and Long-Term Gender-Affirming Hormonal Treatment (2019)

Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence (2020)

Research gaps in medical treatment of transgender/nonbinary people (2021)

 

Detransition

The 2015 USTS report

The Report of the 2015 US Transgender Survey is an important starting point, because a lot of people cite it when discussing the number of transgender people and the number of detransitioners. The survey was accessed exclusively through a website created specifically for the promotion and distribution of the survey.3 Data was collected over a 34-day period in the summer of 2015,4 and the final sample included 27,715 respondents from all fifty states, the District of Columbia, American Samoa, Guam, Puerto Rico, and U.S. military bases overseas. The survey contained mainly closed-ended questions, but respondents were also offered the opportunity to provide write-in responses in fifty-three of the survey questions. Over 80,000 write-in responses were provided by respondents.

I also recommend the CDC Behavioral Risk Factor Surveillance System (BRFSS) and the associated paper by Kellan E. Baker (2019), which found that transgender individuals comprised an estimated 0.55% (95% CI, 0.51%-0.59%) of the sample, which is equivalent to 1.27 million transgender adults in the general US population. They also found that transgender adults were more likely to report diminished HRQOL [health related quality of life] in the previous 30 days as measured by greater odds of fair or poor health (adjusted odds ratio [AOR], 1.30; 95% CI, 1.03-1.62; P = .02) or severe mental distress (AOR, 1.66; 95% CI, 1.36-2.01; P < .001) (Table 2). They also reported more days of combined poor physical and mental health (adjusted mean [SE] difference: 1.20 [0.04] days; P < .001) and of activity limitation (1.34 [0.09] days; P < .001).

D’Angelo et al (2020) compare the above two surveys and say:

Table 1, which compares the demographic characteristics of the USTS participants [the 2015 report] to those of transgender participants from a high-quality probability sample collected by the Centers for Disease Control Behavioral Risk Factors Surveillance System (BRFSS) (Baker, ; CDC, –2017). As Table 1 illustrates, even after applying weighting to correct for known survey biases, the USTS participants were far more likely to be young (42% vs. 22% were 18–24 years old) and educated (47% vs. 14% had completed post-secondary education) than BRFSS participants. They were far less likely to own a home (16% vs. 55%) or to be married or coupled (18% vs. 46%). They were also much more likely to have a non-binary identity (38% vs. 22%) and a markedly different self-reported sexual orientation: Only 15% of the USTS participants reported a heterosexual orientation, compared to 69% of the BRFSS participants. (It is not clear if sexuality in either case was reported relative to one’s sex or gender identity.)

Other Papers on Detransition

Two studies, one by Call et al (2021) and the other by Tordoff et al (2022) say:

There is increasing evidence that gender-affirming interventions improve mental health outcomes for TGD youth. TGD youth report worse mental health outcomes in invalidating school and family environments and improved outcomes in affirming climates. TGD youth experience significant healthcare disparities, and intersectional clinical approaches are needed to increase access to affirmative care. Providers can best support TGD youth by considering ways they can affirm these youth in their healthcare settings, and helping them access support in schools, family systems, and communities. Understanding the intersection of multiple minority identities can help providers address potential barriers to care to mitigate the health disparities seen in this population. [Call et al (2021)]

And

This study found that gender-affirming medical interventions were associated with lower odds of depression and suicidality over 12 months. These data add to existing evidence suggesting that gender-affirming care may be associated with improved well-being among TNB youths over a short period, which is important given mental health disparities experienced by this population, particularly the high levels of self-harm and suicide. [Tordoff et al (2022)]

Yet there is growing concern about detransition, which is when someone who once identified as transgender stops identifying as transgender and ceases gender affirming therapies. This can occur before any sorts of medical interventions (e.g., puberty blockers, hormone therapy, mastectomy, vaginoplasty, etc.) but can also occur after such measures are taken. The latter case can result in permanent unwanted consequences, making it a touchy subject. This is even more concerning when it comes to children. In what follows I will post links and summaries to papers discussing detransition, and in particular how prevalent it is, since this is what a lot of the current debate is surrounding.

In general, those who advocate for affirmation only want to downplay the prevalence of detransitioners, or argue that the reasons for detransition have more to do with discrimination (external pressures) than from a person deciding they identify as their natal sex. This is because if detransition is common, and it is because people later on decide they identify as their natal sex (as opposed to detransitioning to avoid psychological or physical stress), then affirmation only would be an undesirable approach because it could cause harmful or unwanted consequences for more people. Those who advise caution against affirmation only, or who are against it altogether, want to emphasize the prevalence of detransitioners for the opposite reason: to show that caution towards (or even abstention of) gender affirmation approaches is warranted in order to reduce or avoid harm.

The following papers attempt to look at the issue of detransitioners, in particular their prevalence in the population.

In 2018 Wiepjes et al published a paper on their study of the medical files of all people who attended their gender identity clinic from 1972 to 2015. They found that 6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female) visited their gender identity clinic from 1972 through 2015. The number of people assessed per year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The percentage of people who started HT within 5 years after the 1st visit decreased over time, with almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were identified as experiencing regret.

In 2020 Turban et al performed a cross-sectional study, to study the affect of gender identity conversion efforts (GICE) [psychological interventions with a predetermined goal to change a person’s gender identity to align with their sex assigned at birth.]. A survey was distributed through community-based outreach to transgender adults residing in the United States, with representation from all 50 states, the District of Columbia, American Samoa, Guam, Puerto Rico, and US military bases overseas. Data collection occurred during 34 days between August 19 and September 21, 2015. Data analysis was performed from June 8, 2018, to January 2, 2019. Of 27 715 transgender survey respondents (mean [SD] age, 31.2 [13.5] years), 11 857 (42.8%) were assigned male sex at birth. Among the 19 741 (71.3%) who had ever spoken to a professional about their gender identity, 3869 (19.6%; 95% CI, 18.7%-20.5%) reported exposure to GICE in their lifetime. Recalled lifetime exposure was associated with severe psychological distress during the previous month (adjusted odds ratio [aOR], 1.56; 95% CI, 1.09-2.24; P < .001) compared with non-GICE therapy. Associations were found between recalled lifetime exposure and higher odds of lifetime suicide attempts (aOR, 2.27; 95% CI, 1.60-3.24; P < .001) and recalled exposure before the age of 10 years and increased odds of lifetime suicide attempts (aOR, 4.15; 95% CI, 2.44-7.69; P < .001). No significant differences were found when comparing exposure to GICE by secular professionals vs religious advisors.

D’Angelo et al (2021) take issue with the above Turban (2020) study here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878242/

See also Forsythe et al (2022) for a similar study to that of Turban (2020): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902682/

In 2021 Turban et al issued a cross-sectional nonprobability survey of 27,715 TGD adults in the United States. They found that a total of 17,151 (61.9%) participants reported that they had ever pursued gender affirmation, broadly defined. Of these, 2242 (13.1%) reported a history of detransition. Of those who had detransitioned, 82.5% reported at least one external driving factor. Frequently endorsed external factors included pressure from family and societal stigma. History of detransition was associated with male sex assigned at birth, nonbinary gender identity, bisexual sexual orientation, and having a family unsupportive of one’s gender identity. A total of 15.9% of respondents reported at least one internal driving factor, including fluctuations in or uncertainty regarding gender identity. They conclude that among TGD adults with a reported history of detransition, the vast majority reported that their detransition was driven by external pressures.

In 2021 Lisa Littman obtained information with a link to an anonymous survey that was shared on social media, professional listservs, and via snowball sampling. Sixty-nine percent of the 100 participants were natal female and 31.0% were natal male. Reasons for detransitioning were varied and included: experiencing discrimination (23.0%); becoming more comfortable identifying as their natal sex (60.0%); having concerns about potential medical complications from transitioning (49.0%); and coming to the view that their gender dysphoria was caused by something specific such as trauma, abuse, or a mental health condition (38.0%). Homophobia or difficulty accepting themselves as lesbian, gay, or bisexual was expressed by 23.0% as a reason for transition and subsequent detransition. The majority (55.0%) felt that they did not receive an adequate evaluation from a doctor or mental health professional before starting transition and only 24.0% of respondents informed their clinicians that they had detransitioned.

In 2022 MacKinnon et al conducted in-depth interviews with 28 people. Among the 28 participants, 18 (64%) were assigned female at birth and 10 (36%) were assigned male at birth; 2 (7%) identified as Jewish and White, 5 (18%) identified as having mixed race and ethnicity (which included Arab, Black, Indigenous, Latinx, and South Asian), and 21 (75%) identified as White. Participants initially sought gender-affirmation at a wide range of ages (15 [56%] were between ages 18 and 24 years). Detransition occurred for various reasons, such as an evolving understanding of gender identity or health concerns. Participants reported divergent perspectives about their past gender-affirming medical or surgical treatments. Some participants felt regrets, but a majority were pleased with the results of gender-affirming medical or surgical treatments. Medical detransition was often experienced as physically and psychologically challenging, yet health care avoidance was common. Participants described experiencing stigma and interacting with clinicians who were unprepared to meet their detransition-related medical needs.

Further Reading

A Typology of Gender Detransition and Its Implications for Healthcare Providers (2021)

Detransition Among Transgender and Gender-Diverse People—An Increasing and Increasingly Complex Phenomenon (2022)

The Gender Affirmative Treatment Model for Youth with Gender Dysphoria: A Medical Advance or Dangerous Medicine? (2022)

 

Rapid Onset Gender Dysphoria (ROGD)

This is a controversial notion, primarily put forward by Lisa Littman, that says that children, particularly girls, will take on a transgender identity due to social pressures and undiagnosed mental disorders (e.g., depression, anxiety, autism). There is now even a website for parents of children with ROGD. I will link to Lisa Littman’s papers, as well as countering papers, here.

Parent reports of adolescents and young adults perceived to show signs of a rapid onset of gender dysphoria (Littman, 2018)
             –     Correction: Parent reports of adolescents and young adults perceived to show signs of a rapid onset of gender dysphoria (Littman, 2018)

Formal comment on: Parent reports of adolescents and young adults perceived to show signs of a rapid onset of gender dysphoria (Costa, 2019)

In Support of Research Into Rapid-Onset Gender Dysphoria (Hutchinson, Midgen, and Spiliadis, 2020)

Methodological Critique of Littman’s (2018) Parental-Respondents Accounts of “Rapid-Onset Gender Dysphoria” (Arjee Javellana Restar, 2019)

The Use of Methodologies in Littman (2018) Is Consistent with the Use of Methodologies in Other Studies Contributing to the Field of Gender Dysphoria Research: Response to Restar (2019) (Littman, 2020)

Do Clinical Data from Transgender Adolescents Support the Phenomenon of “Rapid Onset Gender Dysphoria”? (Bauer, Lawson, and Metzger, 2022)

(June, 2022) Lisa Littman and Joanne Sinai respond to the above Bauer, Lawson, and Metzger (2022) paper: https://www.jpeds.com/article/S0022-3476(22)00183-4/pdf

(June, 2022) Bauer, Lawson, and Metzger respond to Lisa Littman and Joanne Sinai: https://www.jpeds.com/article/S0022-3476(22)00184-6/pdf

Alison Clayton (2022) brings up the issue of possible placebo effect in gender-affirming treatment in children experiencing gender dysphoria. She says:

In the field of GD youth medicine, there is a combination of features that seems to create a perfect storm setting for placebo effect. Thus, we have a population of vulnerable youth presenting with a condition, which has no objective diagnostic tests, and that is currently undergoing an unexplained rapid increase in prevalence and marked change in patient demographics. The treatment response is mainly based on patient-reported outcomes (yes, this can be the case for other conditions but remember we are considering the combination of features, not just a feature in isolation). Some clinicians, who may be affiliated with prestigious institutions, enthusiastically promote GAT, including on the media, social media, and alongside celebrity patients. Some make overstated claims about the strength of evidence and the certainty of benefits of GAT, including an emphasis on their “life-saving” qualities, and under-acknowledge the risks. Alternative psychosocial treatment approaches are sometimes denigrated as harmful and unethical conversion practices or as “doing nothing.” This combination of features increases the likelihood that there will be a complex interplay of heightened placebo and nocebo effects in this area of medicine, with significant implications for research and clinical practice.

 

Standards of Care

Regardless of where you stand as far as what treatment should be used for gender dysphoria, you should definitely check out the following for what is considered the standard of care for transgender people (as of 2022)

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (2022)

 

Transgender and Queer People in Science

The following are articles that popped up in my literature search for this post. They are here for your consideration.

Rajkovic et al (2022) sought to understand the perspectives of TGD (transgender and genderdiverse) individuals about trans-associated genetic research (TAGR). Eighteen semi-structured interviews were conducted with members of the TGD community to explore how TGD individuals view TAGR. Through inductive content analysis, five major themes were emergent: (1) TAGR could affect self-perception of identity; (2) TAGR could affect external views of TGD people; (3) TAGR could affect access to gender-affirming services; (4) TAGR could contribute to the pathologization and elimination of TGD identities; and (5) researchers should consult TGD community members and consider ethical concerns before conducting research. Participants highlighted concerns about TAGR being used as a tool for discrimination. Those who identified potential advantages of TAGR gave warning that TAGR would be unlikely to solely have positive effects. It is important for genetic researchers to prioritize the perspectives and concerns of TGD people highlighted in this study. Research about the TGD community needs to include TGD individuals as core members of the research team. Moreover, due to the serious ethical issues outlined in this study, TAGR should be reconsidered altogether.

Casper et al (2022) interviewed students with queer genders to understand the messages about sex, gender, and orientation they encountered in biology and the impact of these messages on them. They found five overarching themes in these interviews. Students described two narratives about sex, gender, and orientation in their biology classes that made biology implicitly exclusionary. These narratives harmed students by impacting their sense of belonging, career preparation, and interest in biology content. However, students employed a range of resilience strategies to resist these harms. Finally, students described the currently unrealized potential for biology and biology courses to validate queer identities by representing the diversity in sex and orientation in biology. We provide teaching suggestions derived from student interviews for making biology more queer-inclusive. 

Eric Llaveria Caselles (2021) examines instances of epistemic injustice that combine scientific deficiencies and the exclusion of relevant bodies of knowledge. The results of a content analysis show how the ignoring of biosocial, developmental, mosaicist, contextualist, and depathologizing approaches leads to internal conceptual inconsistencies, hermeneutical deficiencies and the upholding of questionable paradigms in the research field. Interviews with researchers involved in these brain studies reveal targeted and diffuse forms of testimonial injustice against alternative approaches, promoted by the hierarchical arrangements of research teams in combination with the careerist and economic logic of research. The analysis points to the exclusion of critical epistemologies of science and the historical oppression of trans people as epistemic agents as the underlying hermeneutical deficiencies. 

Concluding Remarks

What is sex besides biochemistry? Besides chromosomes? Biology is dictated by chemicals and those chemicals can be administered exogenously. Anatomy can be surgically altered. With gene editing systems like CRISPR/Cas9, it is even theoretically possible to alter someone at the genetic level. Do these people still contain some essence of their former sex? None of this is to say how gender dysphoria ought to be treated medically/therapeutically, but there is compelling evidence that it is a real phenomenon and that it may have a significant biological/neurological component.

The logical next step for this post would be to discuss probably the two most controversial issues surrounding transgender people: (1) whether or not children can reliably identify as transgender and what parents, doctors, therapists, and lawmakers ought to do about this; and (2) whether transgender athletes, primarily MtF transgender athletes, have an advantage over their opponents in sports and whether they should be allowed to compete in leagues that align with their gender identity as opposed to their natal sex. Both of these are hot-button issues, so in this post I am going to punt on those topics. Perhaps I will make separate posts for them in the future, but suffice to say that for (1) I understand the arguments on both sides, though I lean more towards a policy of caution than affirmation only; but for (2) I think it’s fairly clear that MtF transgender women have a distinct advantage over cisgender women in most sports, on account of having developed with high levels of testosterone (essentially having steroids for a significant portion of their life), and any discussion about whether or not they should be permitted in women’s leagues needs to begin from there.