The Intersex Brain

Posted by Catie Profaci on July 2, 2020 in Uncategorized | Leave a comment

In June, J.K. Rowling – author of the beloved Harry Potter novels – tweeted, “If sex isn’t real, the lived reality of women is globally erased. I know and love trans people, but erasing the concept of sex removes the ability of many to meaningfully discuss their lives.” In the context of previous tweets, her words held the implication that transgender women are not women. (Apparently, to her, “real” means perfectly binary and exclusionary.) It is not the first time that Rowling has been accused of a TERF (“trans-exclusionary radical feminism”) agenda. In 2019, she explicitly expressed solidarity with Maya Forstater, a woman who had lost her job over anti-trans statements such as “men cannot change into women.” 

Rowling states that she fully supports the rights of transgender people ­– she just seems to have an issue with the concept of sharing womanhood with those not assigned as female from birth. Sadly, Rowling is far from alone in this thought. Although society has made strides towards accepting that gender identity can fall on a spectrum, and although respect for chosen pronouns is becoming more widespread, there is still strong pushback to the idea that biological sex is not fixed or binary. 

So… what does science say? Is biological sex binary and fixed from birth? Decidedly, no.

Sex Determination

In order to begin to answer these questions, we first must define sex and differentiate it from gender. While gender is how a person identifies in the sense of cultural norms, sex is biological. For example, the pronouns a person uses would give insight into their gender, whereas their chromosomes and reproductive systems would give insight into their sex. But just because sex is biological does not mean it is binary or fixed. In fact, even in terms of chromosomes and reproductive systems – two of the simplest and most-used methods of sex categorization – a large number of people do not fall into strictly binary categories.

In high school biology textbooks, the concept of sex determination is often extraordinarily oversimplified. We learn that women have XX chromosomes, a vagina, and ovaries while men have XY chromosomes, a penis, and testes. Perhaps there is also a brief mention of people with Klinefelter syndrome (males with XXY chromosomes) or Turner syndrome (females with only one full X chromosome). But chromosomes aren’t everything. When a human embryo is about five weeks old, a group of cells start forming a clump destined to become ovaries or testes. The SRY gene on the Y chromosome starts a signal cascade that pushes that clump towards testicular identity [1]. In the absence of that signal cascade, the clump becomes ovaries; people born with XY chromosomes but with a missing SRY gene develop female sex characteristics. 

Even if high school students understand that chromosomes and sex characteristics don’t always match, they are not usually taught about the spectrum of sexual characteristics that naturally exist. The term “intersex” is used to describe any condition in which genetic, gonadal, hormonal, and genital characteristics do not perfectly match those “typical” of the binary male or female. It has been estimated that up to 1 in 50 live births falls into this intersex category [2], although doctors vary widely on what they might consider as intersex.

Chromosomes and genitalia are not the only biological expressions of sex. The development of primary (e.g., internal and external genitalia) and secondary (e.g., breasts or facial hair) sex characteristics is heavily influenced by hormone levels. For example, people with XY chromosomes whose bodies are unable to respond to androgens (a type of sex hormone) can have mostly female external sex characteristics but male internal sex organs (undescended testes). Given the crucial role of hormones, if sex were truly binary, you might expect there to be little variation among males and females in terms of hormone levels, but that is not the case. Remarkably, even though males on average have a testosterone level 6x higher than that of females, there is so much variation among individuals that a male and female can have the same natural testosterone level (Figure 2) [3]. Not only are hormone levels variable, but they are also far from fixed and can change in response to a person’s age or environment, such as in response to stress [4]. Gender-affirming hormone treatment in transgender men and women can alter not only sex characteristics such as breast size and hair growth, but also other characteristics thought to be male or female, including facial structure [5].

Thus, it is evident that male and female sex characteristics exist on a spectrum, and treating them as fully binary categories invalidates the bodies and experiences of those who express a range of biological sex characteristics. There are devastating legal and medical ramifications to this invalidation. 

But… what about the brain? Are there differences between the male brain and the female brain?

The Intersex Brain

The answer is yes… but no. Yes, there are countless brain regions in which several characteristics (size, neuronal composition, neurotransmitters, etc.) have shown to be on average different between males and females [reviewed in 6]. Importantly, however, most of these characteristics are so variable that there is plenty of overlap between males and females rather than two distinct male and female forms. Furthermore, any one individual might be in a different place on the male-female spectrum for any particular brain characteristic. Thus, while one might be able to predict the sex of an individual via MRI with decent accuracy based on an algorithm accounting for many features, it would be nearly impossible to predict an individual’s specific brain characteristics based solely on their sex [6]. Earlier, we defined intersex individuals as those whose genetic, gonadal, hormonal, and genital sex characteristics do not perfectly match. Because there is so much individual variability among brains and brain regions, essentially the brain is more “intersex” than distinctly male or female [6]. The brains of transgender individuals (even before hormone treatment) have been shown via several measures of brain structure to lie somewhere in between those of cisgender males and females [reviewed in 7] – evidence not only of a non-binary sex spectrum in the brain, but also biological validation of transgender identity. 

Sex differences in the brain are complex and multi-faceted, and this might arise in part from the different roles that genetic and hormonal aspects of biology have on different brain characteristics. There is a fascinating case study that gives insight into this complexity. It comes with several disclaimers. First, the study was done in birds, not humans. It is also a case study, which means that it is largely the study of one single bird. It is in no way related to transgender identity – I bring it up solely because it illustrates the complex and mosaic nature of the brain with respect to sex-based differences. 

Researchers studied a zebra finch that was half male and half female [8]. I do not mean that the bird had a mix of male and female characteristics, but rather that the right half of the bird was male in appearance, gonads, and cellular genetics (in birds, males are ZZ and females are ZW), while the left half of the bird was female (Figure 3). While cellularly the bird was half male and half female, hormones circulate in the bloodstream and thus cannot be restricted to only one half of the body. Studying this rare bird allowed the researchers to understand which sex differences in the bird brain are driven by genetics and which are driven by hormonal signals. There was, perhaps unsurprisingly, a mix of both genetic and hormonal influences, even among the same brain circuits. For instance, the birdsong circuitry on the right (male) side of the brain was more masculine than the same circuit on the left, suggesting a genetic component in determining sex differences. However, this circuitry in the left (female) half of the brain was still more masculine than typical female song circuitry, suggesting that circulating hormones also influence the differentiation of these song regions [8]. In terms of behavior, the bird produced a birdsong indistinguishable from that of a typical male.

Sorry, J.K. Rowling, but biological sex – in the body and in the brain – is more complex, nuanced, and non-binary than you might want to believe. 

“That is Between You and the Book”

My research grandfather (the research advisor of my advisor), Dr. Ben Barres, was a transgender man who fought tirelessly for the rights of those underrepresented and/or facing harassment in science. He also happened to love Harry Potter – Ben identified strongly with young Harry’s sense that he was somehow “different” and misunderstood. I imagine that many others struggling with their identities felt the same kinship to Harry. 

Ben died from pancreatic cancer in 2017 before he could be hurt by J.K. Rowling’s words. But I hope children and adults who feel betrayed by the author of a series that boosted their sense of self find peace in Daniel Radcliffe’s public statement:

“Transgender women are women. Any statement to the contrary erases the identity and dignity of transgender people and goes against all advice given by professional health care associations […] If these books taught you that love is the strongest force in the universe, capable of overcoming anything; if they taught you that strength is found in diversity, and that dogmatic ideas of pureness lead to the oppression of vulnerable groups; if you believe that a particular character is trans, nonbinary, or gender fluid, or that they are gay or bisexual; if you found anything in these stories that resonated with you and helped you at any time in your life — then that is between you and the book that you read, and it is sacred. And in my opinion nobody can touch that.”

References

1. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature. 1991;351(6322):117-121. doi:10.1038/351117a0
2. Blackless M, Charuvastra A, Derryck A, Fausto-Sterling A, Lauzanne K, Lee E. How sexually dimorphic are we? Review and synthesis. Am J Hum Biol. 2000;12(2):151-166. doi:10.1002/(SICI)1520-6300(200003/04)12:2<151::AID-AJHB1>3.0.CO;2-F
3. Keevil BG, Clifton S, Tanton C, et al. Distribution of Salivary Testosterone in Men and Women in a British General Population-Based Sample: The Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). J Endocr Soc. 2017;1(1):14-25. Published 2017 Jan 12. doi:10.1210/js.2016-1029
4. Lin Y, Ter Horst GJ, Wichmann R, et al. Sex differences in the effects of acute and chronic stress and recovery after long-term stress on stress-related brain regions of rats. Cereb Cortex. 2009;19(9):1978-1989. doi:10.1093/cercor/bhn225
5. Tebbens M, Nota NM, Liberton NPTJ, et al. Gender-Affirming Hormone Treatment Induces Facial Feminization in Transwomen and Masculinization in Transmen: Quantification by 3D Scanning and Patient-Reported Outcome Measures. J Sex Med. 2019;16(5):746-754. doi:10.1016/j.jsxm.2019.02.011
6. Joel D. Male or Female? Brains are Intersex. Front Integr Neurosci. 2011;5:57. Published 2011 Sep 20. doi:10.3389/fnint.2011.00057
7. Guillamon A, Junque C, Gómez-Gil E. A Review of the Status of Brain Structure Research in Transsexualism. Arch Sex Behav. 2016;45(7):1615-1648. doi:10.1007/s10508-016-0768-5
8. Agate RJ, Grisham W, Wade J, et al. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. Proc Natl Acad Sci U S A. 2003;100(8):4873-4878. doi:10.1073/pnas.0636925100