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In recent years, US society has seen a sea change in the perception of transgender people, with celebrities such as Caitlyn Jenner and Laverne Cox becoming the recognizable faces of a marginalized population. Transgender rights have also become a mainstream political issue, and the idea that people should be referred to by the names and pronouns they find most fitting—whether or not these designations match those on their birth certificates, or align with the categories of male and female—is gaining acceptance.

Yet a biological understanding of the contrast between the natal sex and the gender identity of transgender people remains elusive. In recent years, techniques such as functional magnetic resonance imaging (fMRI) have begun to yield clues to possible biological underpinnings of the condition known as gender dysphoria. In particular, researchers are identifying similarities and differences between aspects of the structure and function of the brains of trans- and cisgender individuals that could help explain the conviction that one’s gender and natal sex don’t match.

Techniques such as functional MRI have begun to yield clues to possible biological underpinnings of gender.

The results may not have much effect on how gender dysphoria is diagnosed and treated, notes Baudewijntje Kreukels, who studies gender incongruence at VU University Medical Center in Amsterdam. “It’s really important that it will not be seen as, ‘When you see [gender dysphoria] in the brain, then it’s true.’” But the insights from such research could go a long way toward satisfying the desire of some transgender people to understand the roots of their condition, she adds. “In that way, it is good to find out if these differences between them and their sex assigned at birth are reflected by measures in the brain.”

A developmental mismatch between sex and gender?

One prominent hypothesis on the basis of gender dysphoria is that sexual differentiation of the genitals occurs separately from sexual differentiation of the brain in utero, making it possible that the body can veer in one direction and the mind in another.1 At the root of this idea is the notion that gender itself—the sense of which category one belongs in, as opposed to biological sex—is determined in the womb for humans. This hasn’t always been the scientific consensus. As recently as the 1980s, many researchers argued that social norms in how we raised our children solely dictated the behavioral differences that developed between girls and boys.

Perhaps the most famous proponent of this line of thinking was psychologist John Money, who went so far as to posit that a male baby with a congenital abnormality of the penis, or who had lost his penis in a surgical accident, could successfully be raised as a female following treatment with surgery and hormones. In at least one of Money’s cases, however, this course of action backfired dramatically: the subject reverted to living as a man during his teen years, and later committed suicide. Sex differences in the brain are now well documented, although the extent to which these arise from biological versus social factors is still hotly debated.

© ANA YAEL

The developmental mismatch idea draws support from two sets of findings. Animal studies demonstrated that the genitals and the brain acquire masculine or feminine traits at different stages of development in utero, setting up the potential for hormone fluctuations or other factors to put those organs on different tracks. (See “Sex Differences in the Brain,” The Scientist, October 2015.) And human studies have found that, in several regions, the brains of trans people bear a greater resemblance to those of cis people who share the trans subjects’ gender than to those of the same natal sex.

Dick Swaab of the Netherlands Institute for Neuroscience is a pioneer in the neuroscience underlying gender identity. In the mid-1990s, his group examined the postmortem brains of six transgender women and reported that the size of the central subdivision of the bed nucleus of the stria terminalis (BSTc or BNSTc), a sexually dimorphic area in the forebrain known to be important to sexual behavior, was closer to that of cisgender women than cisgender men.2 A follow-up study of autopsied brains also found similarities in the number of a certain class of neurons in the BSTc between transgender women and their cisgender counterparts—and between a transgender man and cisgender men.3 These differences did not appear to be attributable to the influence of endogenous sex hormone fluctuations or hormone treatment in adulthood. In another study published in 2008, Swaab and a coauthor examined the postmortem volume of the INAH3 subnucleus, an area of the hypothalamus previously linked to sexual orientation. The researchers found that this region was about twice as big in cisgender men as in women, whether trans- or cisgender.4

And it’s not just brain structure that appears to link transgender individuals more closely to people of their experienced gender than those of their natal sex. Functional similarities between transgender people and their cisgender counterparts were apparent in a study led by Julie Bakker of VU University Medical Center and the Netherlands Institute for Neuroscience in Amsterdam that examined neural activity during a spatial-reasoning task. Previous studies had indicated that the exercise engaged different brain areas in men and women. Bakker and colleagues found that trans boys (who had not been exposed to testosterone, but had had female pubertal hormones suppressed) as well as cisgender boys, displayed less activation than cisgender girls in frontal brain areas when they performed the task.5

Some studies have pinpointed characteristics of the transgender brain that fall in between what is typical for either sex.

Other studies have pinpointed characteristics of the transgender brain that fall in between what is typical for either sex—results that proponents of the developmental mismatch hypothesis generally see as support for their idea. In 2014, for example, Georg Kranz, a neuroscientist at the Medical University of Vienna, used diffusion MRI data to investigate differences in white matter microstructure among trans- and cisgender subjects. Cisgender women had the highest levels of a measure of a neural property known as mean diffusivity, cisgender men the lowest, and both transgender men and women fell in between—though it’s not fully understood what mean diffusivity may represent physiologically.6 “It seems that these transgender groups were at an intermediate stage,” Kranz says. Controlling for individuals’ hormone levels did not alter the differences between groups, leading the authors to suggest that white matter microstructure had instead been shaped by the hormonal environment before and soon after birth—though the possibility that later life experiences also play a role cannot be ruled out, he adds.

“All available evidence points towards a biologically determined identity,” Kranz says. “In [transgender] people you would say there was a mismatch in the testosterone milieu during the development of the body and then during development of the brain, so that the body was masculinized and the brain was feminized, or the other way around.”

Mixed results for studies of the transgender brain

It’s unlikely that gender identity has such a straightforward biological explanation, however, and some studies have identified features of the transgender brain that appear closer to the natal sex, casting doubt on the developmental mismatch hypothesis. In a 2015 study from the Netherlands Institute for Neuroscience, a comparison of the distribution of gray matter in 55 female-to-male and 38 male-to-female transgender adolescents with cisgender controls in the same age group found broad similarities in the hypothalami and the cerebellums of the transgender subjects and cisgender participants of the same natal sex.7 There were, however, some differences in specific subregions.

A 2013 study that focused on cortical thickness, which tends to be slightly greater in women than in men, also yielded mixed results. Led by Antonio Guillamon, a neuroscientist at the National Distance Education University in Spain, researchers analyzed the MRI scans of 94 subjects and found that the total cortical thickness of both transgender women and men was more similar to that of cis women than that of cis men. But this finding did not hold true across the entire brain: in a structure in the forebrain known as the right putamen, which is involved in motor tasks and learning, cortical thickness in transgender men was more similar to that in cisgender men, and transgender women showed no significant differences from either cisgender control group.8

“What we found is that, in several regions, cis women, male-to-female trans, and female-to-male trans have thicker cortex than cis males, but not in the same regions,” says Guillamon, who hypothesized in a 2016 review article that the brains of cisgender women, transgender women, transgender men, and cisgender men may each have a distinct phenotype.9 “The cortex is vital for gender.”

In another study that yielded mixed results with regard to the developmental mismatch hypothesis, researchers at RWTH Aachen University in Germany tested how cisgender people and transgender women discriminate between men’s and women’s voices. The team found that in some respects, such as the level of activation of a brain area called the right superior frontal gyrus, trans and cis women were similar, while cisgender men showed higher activity, possibly reflecting greater cognitive effort on the task.10 Despite similar levels of activation between trans and cis women, however, the transgender women were equally good at identifying male and female voices, while both cisgender groups found it easier to identify voices of the opposite sex.

“Overall, we see in some measures that [transgender people] actually do show these similarities with people [who] share their gender identity, but not for all measures,” says Kreukels. Researchers are “still trying to unravel” those similarities and differences in the brain, she says.

Gender identity: A complex phenomenon

Even if the prenatal environment can nudge the body and the brain in different directions, that’s probably only one facet of the forces underlying gender dysphoria, says Kreukels. The full picture, she explains, is likely to be “a combination between biological, psychological, and social factors—because we really think it’s a complex interplay between all these factors, and thus far research has not given a solution for that.”

Ivanka Savic, a neuroscientist at the Karolinska Institute in Sweden, also doubts the explanatory power of the developmental mismatch hypothesis. “It is not that simple that transgenderism is due to this disparity between the sex of the brain and the sex of the body,” she says. In 2011, for example, Savic and a colleague found that two brain regions, the thalamus and putamen, were smaller in transgender women than in cisgender controls, but overall gray matter volume was greater.11 These brain regions had been shown in previous studies to “mediate perception of the body,” Savic notes—for example, in fMRI studies where people were shown photographs of themselves and others. “The dysphoria is being unhappy with [one’s] own body, feeling every morning that ‘This body is mine, but it’s not me,’” she says.

In follow-up work, Savic’s group began exploring the brain’s neural networks, as revealed by fMRI, and found that “the connections between the networks mediating self and the networks mediating own body—my body—were weaker in transgender people,” she explains. Specifically, compared with cisgender individuals of both sexes, transgender men showed less connectivity among regions known as the anterior cingulate, posterior cingulate, and precuneus when they viewed images of themselves. But when the images were morphed to appear more male, connectivity between the anterior cingulate and the other two regions increased.12

One difficulty in interpreting the differences observed among groups is that it remains unclear when or why those differences developed, says Sven Müller, a psychologist at Ghent University in Belgium; and reported correlations may not reflect causal relationships. “I think the judgment is still out” about the extent to which gender incongruence has a biological cause, he says. “The brain is extremely plastic in adulthood,” he notes, so differences identified between transgender and cisgender people may or may not have been present from birth.

It is one of the pivotal points in biology, and the biology of humans.—Antonio Guillamon,

National Distance Education University, Spain

Additionally, logistical challenges confront scientists searching for a biological understanding of gender dysphoria. It is typically difficult to recruit enough transgender subjects to conduct studies with high statistical power. But some researchers are working to remedy that problem. In 2017, for example, the ENIGMA Consortium, which promotes networking and information-sharing among researchers working to detect modest gene effects on brain structure and function, launched a new, transgender-focused working group. And geneticist Lea Davis of Vanderbilt University is organizing a yet-to-be-funded effort to sequence and analyze the genomes of thousands of trans- and cisgender people in search of variations linked to gender identity.

Apart from the big mystery regarding the roots of gender identity, researchers in the field have a number of lingering questions. For example, for people who transition to identifying as a binary gender different from that assigned at birth, “we still also don’t know whether male-to-female and female-to-male transsexualism is actually the same phenomenon, or . . . [whether] you have an analogous outcome in both sexes but you have different mechanisms behind it,” says Elke Smith, a graduate student at RWTH Aachen University in Germany and author of a review on the transgender brain.13 Other outstanding questions include what, if any, differences there are in the brains of transgender people with different sexual orientations, and between those whose gender dysphoria manifests very early in life and those who begin to feel dysphoric during adolescence or adulthood, says Kreukels. Also still to be determined, adds Savic, is whether the brain differences that have been identified between cis and trans people persist after hormone treatment. (See “The Effect of Hormone Treatment on the Brain” below.)

More research could further clarify the basis not just of gender dysphoria, but also of gender itself, Guillamon suggests—with implications far beyond the pronouns with which we identify. “Phylogenetically, and with respect to evolution . . . it is important to know whether one is a male or a female,” and with whom to copulate, he says. “It is one of the pivotal points in biology, and the biology of humans.”

Savic says she hopes the results of studies on transgender people will help make gender identity a less-charged issue. “This is just part of the biology, the same way as I have black hair and somebody has red hair.”

For now, as is the case for many aspects of human experience, the neural mechanisms underlying gender remain largely mysterious. While researchers have documented some differences between cis- and transgender people’s brains, a definitive neural signature of gender has yet to be found—and perhaps it never will be. But with the availability of an increasingly powerful arsenal of neuroimaging, genomic, and other tools, researchers are bound to gain more insight into this fundamental facet of identity.

THE EFFECT OF HORMONE TREATMENT ON THE BRAIN

In order to avoid confounding effects, many studies comparing the brains of trans- and cisgender people only include transgender subjects who have not yet begun treatments to bring levels of key sex hormones in line with those of their experienced genders. But some groups are specifically exploring the effects that these treatments might have on the brain. “There is an ongoing debate over whether hormonal administration in adult individuals changes the brain or not,” says Sven Müller, a psychologist at Ghent University in Belgium. If cross-sex hormone treatment can shape the adult brain, he notes, it’s important to find out “what happens to the brain, and what are the implications for certain cognitive functions.” Only a handful of studies have addressed the question of how these hormone treatments affect the brain. In one led by Antonio Guillamon of National Distance Education University in Madrid, researchers found that testosterone thickened the cortex of transgender men, while six months or more of estrogen and antiandrogen treatment led to a thinning of the cortex in transgender women (J Sex Med, 11:1248-61, 2014). A Dutch study similarly concluded that the overall brain volumes of transgender women dropped as a result of treatment, while those of transgender men increased, particularly in the hypothalamus (Eur J Endocrinol, 155:S107-14, 2006). And last year, Karolinska Institute neuroscientist Ivanka Savic found that the brains of transgender men taking testosterone showed several changes, including increases in connectivity between the temporoparietal junction (involved in own-body perception) and other brain areas (Cereb Cortex, doi:10.1093/cercor/bhx054, 2017). In another study published last year, of 18 transgender men and 17 transgender women who’d undergone at least two years of hormone therapy, and 57 cisgender controls of both sexes, Müller and colleagues found indications that such hormone treatments might even affect regions the brain that are not commonly considered to be among those sensitive to sex steroids—specifically, the fusiform gyrus, involved in the recognition of faces and bodies, and the cerebellum, known in part for its role in motor control (Neuroendocrinology, 105:123-30, 2017). Moreover, he notes, the changes in the cerebellum were linked to treatment duration. “People might need to broaden the scope as to where in the brain they are looking for effects [of hormone treatments].” In addition to shedding light on the brain networks controlling gender perception and dysphoria, the results of these studies will add to what’s known about the effects of hormone treatment on transgender individuals, says Savic. “If we potentially provide treatment with sex hormones, which we should do for persons who need that, it is very important to know what sex hormones do to the brain.”

Correction (March 15): The original version of this article incorrectly stated that Lea Davis is organizing a study to look for genetic variants linked to gender dysphoria. We have corrected the article to reflect the fact that Davis is focused on understanding the genetic contribution to gender identity, not specifically gender dysphoria. The Scientist regrets the error.