Body-brain mismatch in transgender people may have a biological basis

Transidentity is a delicate subject, because the people who experience it have a relationship to their gender identity that is not necessarily in line with the sex that nature gave them at birth. A scientific study, the first of its kind, published in the journal Scientific Reports, believes to have identified biological evidence of the mismatch experienced by transgender people between the gender identity perceived by their brain and that developed by their body. To better understand this difference, researchers from the University of Augusta (United States) studied the genome of thirty transgender people, focusing in particular on the pathways of estrogen receptors in the brain.

A matter of hormones

The team of doctor John Graham Theisen, author of the study, gynecologist-obstetrician and researcher in women’s reproductive health at the National Institutes of Health at the University of Augusta (United States), identified 21 variants in 19 genes estrogen signaling pathways in the brain, essential for establishing whether the brain is male or female. These genes are involved in the massive sending of hormones to the brain, in particular estrogens, just before or after birth, which participate in the “masculinization” or “feminization” of the brain.

In the variants identified by the researchers, in men born male, these massive estrogen exposures do not occur, or the signaling pathway is altered, which does not “masculinize” the brain. Likewise, in women, estrogen exposure takes place when it shouldn’t, leading to masculinization.

These two phenomena lead to what is called gender dysphoria, a feeling of inadequacy between the internal and external sex of an individual. In other words, gender dysphoria characterizes the feeling of discomfort that some people may have who feel “stuck” in a gender in which they do not identify.

For John Graham Thiesen, the sexual identity to which the brain relates is immutable, and treatments, such as hormone therapy or surgery, aim to help the body correspond to the brain’s ideal.

For Dr. Lawrence Layman, chief of reproductive endocrinology, infertility and genetics at the Georgia College of Medicine, timing is everything. “It doesn’t matter what sex organs you have, what matters is whether estrogen and androgens, which are converted to estrogen in the brain, masculinize the brain during this critical time. We found gene variants that are important in some of these different areas of the brain.”

According to the researchers, although the critical period for brain masculinization may seem late, brain development continues long after birth. Pathways and receptors need to be established when estrogen arrives.

Timing of hormones

Researchers examined the DNA of 30 adult volunteers, who self-identify as transgender, and were diagnosed with gender dysphoria based on DSM-V criteria. Among them were 13 transgender men born female and transitioning to male, and 17 transgender women born male and transitioning to female.

The analysis of their complete genome, which consists of sequencing the protein-coding regions of a gene, was carried out at the Yale Genome Analysis Center. This analysis was then confirmed by Sanger sequencing, a method used to detect gene variants. The variants found were not present in a group of 88 control exome studies on non-transgender individuals that were also reviewed at Yale. Moreover, these variants were either absent or very rare in large control DNA databases.

For these researchers, one of the factors that could explain gender dysphoria could come from estradiol, a primary estrogen that we all produce very briefly during the perinatal phase (between the 22nd week of absence of the mother’s period and the infant’s first week of birth). During this phase, the brief release of estradiol would lead to two possibilities: either the signaling pathways would be activated by the estrogen receptors, resulting in a “male brain”, or — because the ovaries are quiescent in women pregnant — the absence of stimulation of estrogen receptors, would give rise to a “female brain”.

A biological basis for gender dysphoria

For Lawrence Layman, who has 20 years of experience in the care of transgender patients, there is a biological basis for gender dysphoria in the majority of cases. His colleague, John Graham Thiesen, agrees. “We certainly think that for the majority of people who suffer from gender dysphoria, there is a biological component. We want to understand what is the genetic component of gender identity.”

According to the researchers, although genetics has been identified as a factor in gender dysphoria, this has not been proven so far. Most of the genes or gene variants studied previously were associated with androgen receptors, which are the hormones traditionally linked to male traits, but which are also present in women, like estrogen for men.

Therefore, researchers focused on the little-known aspect of sex-specific brain development, which is an estrogen bath necessary early in life for brain masculinization, to identify potential sites of genetic variances. relevant. Initially, DNA testing revealed more than 120,000 variants, 21 of which were associated with estrogen-related brain pathways.

Animal studies have set the course

For their research, the team of scientists relied in part on a 2008 study on rats, which had made it possible to identify four areas of the brain whose pathways are associated with the development of a male or female brain. Based on these results, the researchers assumed that it could be the same in humans. Another study, conducted this time on primates going through puberty, also showed that disruption of these pathways leads to cross-sexual behavior. According to Lawrence Layman, many people report feelings of sex-related inadequacy as early as age five.

However, while sex-specific brain development has not been studied extensively in humans, the effects are still more pronounced during puberty. The increased sexual awareness at this stage makes gender dysphoria easier to express in adolescents. Similarly, previous studies have shown that exposure to sex hormones during the perinatal period can affect future sexual behavior. The preponderance of the data was obtained from research involving women with classic congenital adrenal hyperplasia from birth. This rare genetic disease resulting in abnormal production of hormones (in particular androgen) before birth, produces more or less significant external genital virilization. In these women, the rate of gender dysphoria reaches 3%, compared to 0.2% in unaffected women. On the other hand, the data available in men is insufficient to define a trend, which the scientists deplore.

For John Graham Theisen, genetic variants are responsible for our individual traits, such as eye color, and that similarly, gender is as unique and varied as other traits, most of which do not cause disease. For this reason, the researchers suggest changing the current classification system for variants (like that of the DSM) that do not suggest that they cause disease.

Increased stigma

In the United States, scientists consider that approximately 0.5 to 1.4% of people born male and 0.2 to 0.3% of people born female suffer from gender dysphoria. Identical (identical) twins are more prone to this condition than fraternal (fraternal) twins.

The lives of transgender people are often marked by sexual discrimination and violence, which can lead to depression, drug addiction and suicide attempts. In a 2010 US national study on discrimination against transgender people, 26% admit to using alcohol or drugs to cope, and 19% have been denied medical care. In that same report, 28% report instances of verbal harassment in a medical setting, or insurance companies not covering the cost of hormone therapy or gender-affirming surgical therapy. Finally, 41% of respondents say they have attempted suicide, compared to 1.6% for the general population. For the investigators, these discriminations are due to a lack of understanding of the biological basis of gender dysphoria.

The brain-body mismatch study was conducted on 30 people, and the researchers say they have data on another 30 people. Although the study, partly funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, appears to be the largest to date, the results of this study have been classified as preliminary.