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The Transgender Brain

Neurobiology: The Human Gender Identity System

Niko Rosen Storment

California Institute of Integral Studies

Neurobiology: BSPSY-1111-01

Mordecai Cohen Ettinger, MA

April 16, 2022


Neurobiology: The Human Gender Identity System

Introduction

Although the term “transgender” is a relatively new advent within the last century, people who identify outside of the binary sexes they were assigned at birth have existed forever (Transgender People Have Always Existed, 2021). Transgender people have existed across cultures, colors, and creeds, although how that is culturally manifested has varied. In Siberia, the Chuckchi are a nomadic, shamanic people who have embraced a third gender. In the Dominican Republic, a heritable hermaphroditic trait was discovered by ethnographers in the 1970s, where these individuals usually choose to identify with a third gender called guevedoche or machi-embra. In North America, the Zuni accept a two-spirit tradition where an individual lives as both genders simultaneously; their social role is considered sacred. In Hawaii, the Mahu are biological males or females that inhabit gender roles between or encompassing the masculine and feminine (A Map of Gender-Diverse Cultures | Independent Lens | PBS, 2022).

As westernization spread, so did Eurocentric conceptions of gender. Binary puritanical values–of which have an entire history within themselves–have thus created the illusion that this is a new phenomenon, but nothing could be further from the truth (Transgender People Have Always Existed, 2021).

In this paper, I will explore the biological basis for gender identity in the brain, as well as the existing trends in “treatment” for transgender individuals and how those treatments may affect the brain and alter its phenotype. I will also explore the bottom line in terms of brain health for transgender individuals living within a westernized society, and the best approaches for future research.

Gender Identity and the Brain

Although gender (what someone identifies with) and sex (biologically manifested sex traits) are separate constructs, there is some overlap when discussing neurobiology. This is due to the self-identifying principle of gender having a structural basis within the brain, making way for the question; what makes someone feel like a particular gender? Because gender is a social construct, this definition cannot be unlinked from cultural context (similarly, human brains cannot be fully separated from the environments they exist within), however certain sex differences in neurobiology may account for an individual’s alignment with one gender or another, as explored below in more depth by Nguyen, et al. wherein transgender individuals’ brain patterns without Gender Identity Disorder (GID) “treatment” already resemble their gender identity more closely than their assigned sex at birth (2019). For the purposes of this paper, the term gender identity will serve as a functional definition of what an individual feels is authentic to them, not separate from the brain structures within its makeup. However, this is not to be confused with gonadal sex.

Gender identity is a term made up of two separate concepts - gender and identity. Although one would hope to locate one central point for ease of studying transgender individuals, neurobiology is hardly ever that clear cut. Gender in the brain relies on several varied factors - chromosomal makeup (“bottom-up” approach [Karalexi et al., 2020]), pre-natal exposure to in vitro androgens, and gonadal hormones secreted throughout the development of an organism (“top-down” approach [Karalexi et al., 2020]). These three factors together determine the makeup of an individual’s gender expression biologically, which may result in varying manifestations of sex, and/or gender identity.

Chromosomes are a blueprint for the body’s proteins. These proteins have special instructions for protein synthesis that fabricate the rest of your body. Over the lifespan, these proteins continue to follow the chromosomal blueprint to cue the bodily changes that manifest. These manifested blueprints are your phenotype. Typically, each cell in the body has 23 pairs of chromosomes (46 in total) - half from the parent who contributed the sperm, and half from the parent that contributed the egg.

Two of these chromosomes are the X and the Y chromosome. It is famously taken for granted that XX will result in female and XY will result in male. In reality, many other combinations are possible, including XXY (Klinefelter syndrome), XXX (Trisomy X syndrome), and other variations of the manifested phenotype within XX and XY individuals. X chromosomes are associated with feminization of the organism while Y chromosomes result in masculinization. X and Y chromosomal dosages are determined by various mechanisms to ensure balance between the two. This includes X upregulation (in which the X chromosome is overly expressed to restore autosome balance, i.e., heightened RNA stability, increased frequency of transcriptional bursts), and X inactivation (random silencing of extra X chromosomes during “female” embryogenesis). This process begins before gonadal differentiation. In other words, the process of DNA sex differentiation begins prior to the development of gonadal regions on a cellular level - creating “female” and “male” cell body replication throughout the organism. This patterning in chromosomal manifestation creates so-called “mosaic” tissues and can differ among tissues themselves. The body - and the brain - are a “gender mosaic.” To further the variability of this phenomenon, some genes escape X inactivation solely in the brain. Epigenetic modifications also differ between individuals, adding additional layers of variability among phenotypes (Raznahan et al., 2020).

Classically, the field of sex-differentiated brain studies has focused on differences in the “male” and “female” brain, however the gender mosaic model paints a different picture entirely, in that it reflects the actual variation potential for gender identity. Despite this, brain structures can be affected by circulation of gonadal hormones, specifically over the course of development, and during critical periods of development. The accompanying structures reveal trends in brain structure within the estrogen circulated brain, versus the testosterone circulated brain.

“Male” “Female” In Utero Testosterone and its aromatization to estrogen cause masculinization of the fetal brain Absence of androgen production and estrogen-binding activity of alpha-fetoprotein cause feminization of the fetal brain Adolescence More between- network connectivity, larger grey matter volume, lower grey matter density More within-network connectivity, less grey matter volume, higher grey matter density Adulthood More total brain volume, more grey matter volume, more white matter volume, more cerebrospinal fluid volume, higher proportion of white matter, larger volume of the central subdivision of the bed of nucleus stria terminals, better visuospatial and mathematical ability, weaker right-hand preference Less total brain volume, less grey matter volume, less white matter volume, less cerebrospinal fluid volume, higher proportion of grey matter, thicker cortex, higher global cerebral blood flow, better perceptual speed and fine manual dexterity, stronger right-hand preference

(Nguyen, et al., 2019)

Estradiol, testosterone, and progesterone greatly affect neurotransmitter levels and receptors, as well as glial architecture and function (Nguyen, et al., 2019). Therefore, fluctuation of circulating gonadal hormones predictably has extensive effects on brain structure and function.

To circle back to the second part of the concept of gender identity–identity – neuroscientists have identified three brain regions that are critical for self-awareness; the insular cortex, anterior cingulate cortex, and the medial prefrontal cortex (all areas identified as sex-differentiated regions [Macey, 2016]). However, like most things in the brain, the entire concept of identity cannot be confined to these three areas. Rather, identity lies heavily in the diffuse patch work of pathways between brain regions (The roots of human self-awareness, 2015). These networks and pathways compose of grey and white matter, another category of the brain highly dependent on sex-differentiated development (Nguyen, et al., 2019).

When pairing knowledge of identity with knowledge of gender, we can see that the human gender identity system is in actuality a very complex and variable mechanism dependent on several factors of development, with highly variable results. It’s a wonder anyone has a cohesive gender at all! Perhaps that assumption is taken for granted.

The Transgender Brain

Given the high variability of gender identity of the brain, being transgender hardly has one definition. However, colloquially, a transgender individual is someone who’s social/personal identity is in misalignment with the sex they were assigned at birth. Though recorded rates of transgender individuals are rising (Nguyen, et al., 2019), we have no way of estimating how much of this is due to cultural acceptance of gender individuality, or changes in cultural perception of gender roles; and therefore, changes in individual relation to gender identity. Additionally, there may be other epigenetic factors that are contributing to this rise, yet to be identified.

Regardless, it is an increasing phenomenon that various fields have tried their hands at defining and analyzing. Specifically, the field of psychology has done what it usually does when something it does not understand emerges - it has pathologized it (as with Intersex [without a clear binary sex phenotype] individuals in chromosomal science). Gender Identity Disorder (GID) arose in the DSM 2nd and 3rd editions as a way of describing someone who believes they were “born in the wrong body” --a popular and controversial interpretation of transgenderism–and therefore needed treatment through sexual reassignment. The DSM 5 has departed from such definitions of transgender individuals, however, there is still much debate on the issue, and oftentimes this diagnosis is simply necessary for access to gender-affirming treatments, though they may not be entirely accurate (Nguyen, et al., 2019).

Among the treatments for GID is Hormone Replacement Therapy (HRT). This is a therapy that aims to feminize or masculinize an individual’s secondary sex characteristics accordingly to their preferred gender. Brain structure is one of these targeted areas, and HRT aims to assimilate areas that are incongruent within the gender mosaic, and remedy GID’s characteristic gender dysphoria (discomfort experienced due to differences in gender identity and sex assigned at birth).

In Nguyen, et al.’s article “What has sex got to do with it? The role of hormones in the transgender brain,” brain structures were not uniformly influenced by HRT. However, the largest affected areas of the brain after HRT were the amygdala, putamen, corpus callosum, medial temporal lobe, nucleus accumbens, 3rd ventricle, hypothalamus, white matter, and grey matter (2019). These findings further evidence variability based on sex-differentiated chromosomal phenotypes and substantiate the claim that HRT does change brain structure to be more in line with an individual’s preferred gender expression.

Changes in brain structure are hypothesized to result in differing behavioral phenotypes as well. In transgender women treated with HRT, three months of estrogen addition and testosterone suppression resulted in a decline in anger and aggression proneness, sexual arousal, and spatial ability; as well as an increase in verbal fluency. In transgender men treated with HRT, three months of testosterone treatment was associated with increase in aggression proneness, sexual arousal, and spatial ability performance; and a deteriorating effect on verbal fluency (Pol, et al., 2006). Despite these findings, it is hard to tease apart cultural values from brain structure influences, as behavioral changes may have resulted from changing positionality within society. However, findings associated with structural change are not to be ignored, nor are the observed changes in spatial ability and verbal fluency; a well-recorded and studied trend in sex-differential phenomena (Nguyen, et al., 2019).

The complexities of the human gender identity system are highlighted when neurobiologists observe differences in transgender individuals that have not undergone HRT. Although a quarter of studies to date have conflicting findings (as to be expected with something as variable as the gender mosaic model, and given small sample sizes), most neuroimaging research found that brain morphology and activation patterns at rest and during cognitive performance are more closely congruent with gender identity rather than sex assigned at birth. Similarly, gray matter volume and white matter microstructure of transgender individuals not undergoing HRT are more similar to cisgender control subjects of their preferred gender. When measuring conceptual styles, transgender people perform in congruence with their gender identity - suggesting an “innate quality” originating in brain development rather than exogenous hormonal intervention. Furthermore, cerebral processing was found to be more similar to gender identity than natal sex in transgender individuals not undergoing HRT, as well as with neural activation patterns in the superior frontal gyrus. (Nguyen, et al., 2019).

Literature Review

Nguyen, H. B., Loughead, J., Lipner, E., Hantsoo, L., Kornfield, S. L., & Epperson, C. N. (2019). This article focuses on understanding the developmental and structural differences between transgender and cisgender individuals before and after hormone replacement therapy and aims to develop an understanding of the origins of gender identity and sex difference. It provides an overview of sex differences in utero, adolescence, and through adulthood. They make the case for hormones affecting brain structures across the lifespan. Nguyen, et al also addresses the brain as a gender mosaic, an interesting framing to neurobiological understanding. They explore transgender sex differences prior to HRT, as well as HRT effects on brain structures.

Karalexi, M. A., Georgakis, M. K., Dimitriou, N. G., Vichos, T., Katsimpris, A., Petridou, E. T., & Papadopoulos, F. C. (2020). Shows improvement in mental health for transgender individuals who experience gender dysphoria after hormone treatment and notes no adverse effects. It provides an in-depth exploration of methodology and control for factors usually not addressed in other studies such as the fact that individuals “naive” to HRT typically still operate more closely to their gender rather than their biologically assigned sex, and how this effects study results and ability to study changes before and after HRT.

Holmes, D. (2016). Article describes specific brain changes in transgender individuals after hormone therapy. Specifically, MtF individuals (male-to-female) had reduced hippocampal volume and a global increase in ventricular structures. Additionally, reductions in grey matter in the right hippocampus and right caudate.

Pol, H. E. H., Cohen-Kettenis, P. T., Van Haren, N. E. M., Peper, J. S., Brans, R. G. H., Cahn, W., Schnack, H. G., Gooren, L. J. G., & Kahn, R. S. (2006). Treatment of transgender individuals with hormone replacement therapy provides rare opportunity to study effects of sex steroids on brain morphology. For male to female individuals, brain volumes decreased, whereas female to male individuals experienced total brain and hypothalamic volume increase. Gonadal hormones provide essential maintenance to sex-specific differences in human brain. Old article – can contrast tone with newer studies that do not value maintaining sex differences as positive, and do not objectify trans persons for study (hopefully).

Raznahan, A., & Disteche, C. (2020). Humans show sex-differences in cognition and psychopathology that may be influenced by gonadal sex-steroids and/or sex chromosomes on regional brain development. This article highlights specific sex-chromosome genes that could drive developmental sex-differences through sex-based expression and functionality (“bottom up”) and contrasts it with MRI studies on sex differences in regional brain anatomy (“top down”).

Kaczkurkin, A.N., Raznahan, A. & Satterthwaite, T.D. (2019). Youth often undergo rapid changes that result in neuropsychiatric conditions with sex differences. Sex differences emerge during development such as differences in brain structure, white matter organization, and perfusion during development. Normative differences may be indicative of sex differences. Kackurkin, et al provide insights into cerebral gray matter, white matter volume, regional differences, gray matter density, cortical thickness, cortical surface area, cerebral blood flow, and more. It also includes a section on the relevance for psychopathology (depression, anxiety, psychosis, ADHD), as well as future research suggestions

Conclusion

We are highly variable organisms living within the highly variable environments of our cultures. As such, our relation to the outer world is constantly changing; and therefore, how we hold the truths of identity within the structures of our brains is also constantly changing. Despite this variability, we do find a reasonable amount of certainty in studying the positive effects of transitioning for transgender individuals. Sex hormones and chromosomes change brain structure, but so does trauma (Kaczkurkin et al., 2019). We can borrow from psychoanalysis and hypothesize that transgender individuals crave the development of their full selves, selves many current societal structures do not allow for, and historically have not. The trauma of being unable to be your most honest self, paired with the cultural violence transgender people endure throughout development has detrimental effects on many brain structures, and can often lead to higher levels of depression, anxiety, and other psychological conditions (Kaczkurkin et al., 2019).

There are concerns regarding long-term HRT for the overall health of transgender individuals. Studies of post-menopausal cisgender females have shown that cognitive decline may be a concern with long-term estrogen deprivation in individuals assigned female at birth. Similarly, there are many studies exploring the negative effects of testosterone deprivation in cisgender males. However, studies also show that trauma and adversity during childhood may change the need for and/or effect of gonadal hormones on the brain, and oftentimes hormonal treatment has proved beneficial (Nguyen, et al., 2019). Rather than pause on gender-affirming care, the field should seek to create more longitudinal studies within this underrepresented population to anticipate roadblocks in brain health for transgender individuals undergoing HRT. Given the current societal trauma impressed upon transgender people, and the unrealistic romanticization of a complete societal change towards pre-western conceptions of gender, this seems the only logical step, albeit a step without total certainty; and a necessary step considering the detrimental effects of gender dysphoria on brain health.

The bottom line–transgender people exist in many ways, and access to social transition and/or gender-affirming care may be lifesaving, if not at the very least resulting is drastic improvements in the quality of life.


References

Holmes, D. Cross-sex hormones alter grey matter structures. Nat Rev Endocrinol 12, 686 (2016). https://doi.org/10.1038/nrendo.2016.177

Kaczkurkin, A.N., Raznahan, A. & Satterthwaite, T.D. Sex differences in the developing brain: insights from multimodal neuroimaging. Neuropsychopharmacol 44, 71–85 (2019). https://doi.org/10.1038/s41386-018-0111-z

Karalexi, M. A., Georgakis, M. K., Dimitriou, N. G., Vichos, T., Katsimpris, A., Petridou, E. T., & Papadopoulos, F. C. (2020). Gender-affirming hormone treatment and cognitive function in transgender young adults: a systematic review and meta-analysis. Psychoneuroendocrinology, 119, 104721. https://doi.org/10.1016/j.psyneuen.2020.104721

Kolb, B., Whishaw, I. Q., & Teskey, C. G. (2019b). An Introduction to Brain and Behavior (Sixth ed.). Worth Publishers.

Nguyen, H. B., Loughead, J., Lipner, E., Hantsoo, L., Kornfield, S. L., & Epperson, C. N. (2019). What has sex got to do with it? The role of hormones in the transgender brain. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 44(1), 22–37. https://doi.org/10.1038/s41386-018-0140-7

Macey, P. M. (2016). Sex Differences in Insular Cortex Gyri Responses to the Valsalva Maneuver. Frontiers. https://www.frontiersin.org/articles/10.3389/fneur.2016.00087/full#:%7E:text=Sex%20differences%20in%20spatial%20organization,females%20(16%2C%2048)

A Map of Gender-Diverse Cultures | Independent Lens | PBS. (2022, March 19). Independent Lens. https://www.pbs.org/independentlens/content/two-spirits_map-html/

Pol, H. E. H., Cohen-Kettenis, P. T., Van Haren, N. E. M., Peper, J. S., Brans, R. G. H., Cahn, W., Schnack, H. G., Gooren, L. J. G., & Kahn, R. S. (2006). Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure, European Journal of Endocrinology eur j endocrinol, 155(suppl_1), S107-S114. Retrieved Mar 24, 2022, from https://eje.bioscientifica.com/view/journals/eje/155/suppl_1/1550107.xml

Raznahan, A., & Disteche, C. (2020). X-chromosome regulation and sex differences in brain anatomy. Neuroscience and Biobehavioral Reviews. https://doi.org/10.1016/j.neubiorev.2020.10.024

Transgender People Have Always Existed. (2021, May 11). ACLU of Ohio. https://www.acluohio.org/en/news/transgender-people-have-always-existed



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