In 2017, New Zealand weightlifter Laurel Hubbard came out as transgender. Four years later, she competed in the Tokyo Olympics, where she was deemed to have a competitive advantage due to her genetically male gender. Hubbard met the guidelines set by the International Olympic Committee (IOC): Testosterone levels had been below the required limit for the previous 12 months.
The issue of transgender (or trans*identity) – identifying with a gender other than the one assigned at birth – is ubiquitous in today’s media, politics, and society. As in the case of Hubbard, a wide range of issues are being hotly debated: In which gender competition should trans people be allowed to compete in sports? Should they use women’s or men’s restrooms? And what pronouns should be used when talking about them?
As a neuroscientist, I am always asked the following question: Does the brain of someone who was assigned male at birth but identifies as female (or vice versa) have more masculine or more feminine characteristics? This is not an easy question to answer for several reasons. First, we would have to clarify what constitutes a male or female brain. For as we now know, the thought processes of the two sexes are much more similar to each other than has been assumed for a long time.
But there are trends: As we have found in various studies, men on average have a larger brain volume and a larger surface area of the cerebral cortex. Women, on the other hand, have slightly smaller and lighter brains, but compensate for this with thicker gray matter. This contains most of the nerve cell bodies, while their long extensions make up the white matter. We also see a slightly larger area in the frontal lobe in women and a proportionally larger hippocampus in men.
Despite these findings, one should not generalize. Rather, they indicate a simple tendency that cannot be applied to each individual brain (because each brain is demonstrably unique in its internal structure). And this is also true for trans* people.
The first study on the subject appeared in the journal Nature in 1995. The neurobiologist Dick Swaab and his team at the Netherlands Institute for Brain Research in Amsterdam had studied the brains of deceased trans* women – people who were considered to be male at birth, but who were later identified as female. The researchers paid particular attention to a small core region of the limbic system, which among other things controls sexual behavior and is generally larger in men than in women: the striae terminalis. As their measurements showed, the area in trans* women had an unusually small volume for men, more in line with the average for female brains. Swaab and his team speculated that it is primarily the interplay between the developing brain and sex hormones that shapes gender identity.
However, the study had several drawbacks: first, the sample was very small, with only six female subjects. In addition, the scientists had studied the brains of dead people – so the results cannot be easily extrapolated to living brains. And last but not least, some of the volunteers had already started gender reassignment hormone therapy. So it cannot be ruled out that the substances they took may have altered their brain structure.
But a lot has happened since then. Especially in the last ten years, several research groups around the world have been working on this topic. However, a general problem remains: there are relatively few subjects available. After all, the proportion of trans people in the population is not that high: it is estimated that 4.8 per 100,000 people come out and live openly trans in society. In addition, many researchers recruit from gender reassignment centers. Those who do not seek such treatment are therefore less likely to be included in studies, which skews study results. In order to find as large a homogeneous sample as possible, scientists from all over the world (including our own) have formed the ENIGMA Gender Studies Working Group. Its goal is to pool and analyze data already collected on the topic.
Using this database, we studied the brain structure of approximately 800 subjects. These included an equal number of cis females, cis males, trans females, and trans males, although the trans males had not yet received gender-affirming hormone treatment. Using imaging techniques, we compared, among other things, the volume of gray matter, the thickness of the cortex, and the size of its surface.
One thing quickly became clear: the brain structure of the trans people did not fit neatly into one gender or the other. As expected, many brain regions were larger on average in cis men than in cis women, such as the insula and the precentral gyrus. In trans women and men, however, the picture was much more varied: Some brain regions had a typically female volume, while others were more typically male. The other values, such as the size of the cortical surface, also varied between male and female, depending on the region. Do they perhaps have their own brain phenotype?
We investigated this question by looking closely at the brains of 23 trans men, trans women, cis men, and cis women. Again, the trans people had not yet started hormone treatment. The task of our subjects was simply to sit still and let their minds wander. The result was a resting state of the brain in which we could separately measure the activity of the default mode network. In this way, we were able to find out how different areas of the brain work together, i.e., how they are functionally connected.
We then fed the image data into a classification algorithm (a type of artificial intelligence). The program learned which activity patterns belonged to which of the four subject groups. After this learning phase, the algorithm was given new images to classify on its own. It did this with a hit rate of 64.4 percent. Although this may not seem like much, the probability of success was more than twice as high as the chance rate of 1 in 4, or 25 percent. So our study suggests that trans people do have a distinct brain phenotype. Finally, our algorithm did not simply assign the brain images of trans women and men to cisgender individuals.
The fact that the hit rate is still so far from 100 percent is probably due to several reasons. One of them is probably the great importance of individual factors in brain development: Every brain is shaped by genetic, hormonal, and other developmental biological influences, such as the abundance and distribution of certain receptors. In addition, the social environment and early childhood experiences influence the structure and function of individual brain areas.
Obviously, there are certain patterns that are related to gender identity. For example, some research groups have looked at the sensitivity of hormone receptors, particularly for testosterone and estrogen. It was found, for example, that the gene for the estrogen receptor shows certain variations more often in trans men than in cis women. Apparently, even the basic genetic makeup can be different in trans people and thus affect brain development.
The same may be true of the hormonal environment to which a fetus is exposed in the womb. One notable indicator of the amount of testosterone the future child received during pregnancy is the later ratio of the length of the ring finger to the length of the index finger. The more testosterone, the longer the ring finger in relation to the index finger. Women therefore tend to have a longer index finger and a shorter ring finger than men.
A team led by psychiatrist Johannes Kornhuber compared the height ratios of trans and cis people. They found that trans women on average had more typical female values, i.e. those of the identified gender. The control group of cis men, on the other hand, had a significantly lower length ratio. In the case of trans men, however, the researchers did not find a clear difference from cis women, the innate gender group. According to the medical researchers, a below-average testosterone concentration during pregnancy could influence the later gender identity of boys or men.
We believe that trans identity is also due to the fact that affected individuals have altered neural networks in the hypothalamus. This is like the control center for hormones and is involved in various sexual responses. To test this hypothesis, we scanned the brains of trans women and cis men. During the measurements, our subjects were allowed to sniff pheromone-like substances that mimicked either male or female sex hormones.
We were particularly interested in the activity of the hypothalamus – and discovered remarkable things: when trans women, like cis women, had the male odor in their nose, an area of the hypothalamus was more active. In cis men, on the other hand, this region was only stimulated when they sniffed the female scent. Another part of the hypothalamus also responded to the female scent in the trans women, so our results are not 100% conclusive. Nevertheless, we can conclude that transidentity is accompanied by reactions in certain brain circuits that are atypical for the innate sex. This is most likely due to the fact that nerve cells differentiate differently during brain development in the womb.
Currently, there is little research being done on and with transgender youth. One of the reasons for this is the small number of potential subjects. However, Sarah Burke and her colleagues at the VU University Medical Center Amsterdam managed to conduct the first study in the field of olfactory specificity with children and adolescents. The young participants identified with the opposite sex they were assigned at birth. The goal of Sarah and her team was clear: they wanted to find out how early in development foreign sex hormones are actively perceived and registered.
The result: Even before the onset of puberty, the children in the study showed altered neuronal activity in the hypothalamus when exposed to pheromone-like substances, beginning when they left infancy at the age of 6, i.e., when they had not yet been exposed to sex hormones. In the course of the study, they also found that the changes in the brain only become apparent with the onset of puberty. This means that even if transgender seven-year-olds have a sense of sex hormones, this is not yet reflected in the identified activity pattern in the brain.
As all the studies together suggest, puberty plays a crucial role in the sexual differentiation of the brain. However, all these measurements do not provide any information about how individuals perceive themselves and where gender identity is located in the brain. The latter usually corresponds to the sex assigned at birth. This is not the case for transsexuals. Which neural circuits are responsible for this discrepancy?
We wanted to explore this question further. To do this, we photographed the bodies of trans and cis people and then manipulated the photos with an image editing program. That is, we removed hands, feet, and the head, and in several stages made the body a little more masculine or a little more feminine. We then had the subjects look at the altered photos of their own bodies and measured their brain activity. As expected, the trans subjects were pleased with the change in their bodies to the opposite sex, which was reflected in increased activity of the hippocampus (the brain’s reward center) and increased release of dopamine (the so-called happiness hormone).
In general, then, when a person looks at images with which he or she can identify, activity increases in neural networks commonly involved in self-concept processing – including, for example, the dorsolateral cortex. This is true for all people. However, these brain regions do not become more excited when looking at the other body shapes. Thus, gender identity is anchored in the brain structures responsible for self-concept.
But back to the original question, which is: Does someone who is born male but identifies as female (and vice versa) now have a more masculine or a more feminine brain? Based on our now numerous studies in this area, we have to answer neither. Rather, transgender people have a distinct brain phenotype that, depending on brain regions and developmental influences, is more like that of one sex or the other.
There are some mental illnesses that affect women and men differently. For example, women are more likely to suffer from depression and anxiety, while men are more prone to alcohol abuse and behavioral problems. The causes are largely (still) unknown, but they are mostly due to divergent and deviating brain functions, and here in particular to neurotransmitter systems. So far, we do not know how transpersons fit into this dual risk profile, or even how to create a third one. With this knowledge (and that resulting from the following studies) we can better interpret early symptoms and take timely preventive measures.
Previous studies have mainly focused on trans people who clearly identify as either male or female. However, this need not be clear. Gender-diverse people who either have secondary characteristics of both sexes (e.g. an XY chromosome pair, but ovaries instead) or who do not identify with the binary gender system of the Western world are left behind and not included. This must change.