Augusta University: Gender Dysphoria in Transsexual People Has Biological Basis

The Gender dysphoria that occurs in some transgender persons can be explained by the concentration of a basic hormone that the brain receives in the uterus and during the first years of life.



Trangenderism is a sensitive issue because people who experience it have a connection to their sexual identity that does not necessarily correspond to the sex that nature has given them. A study, the first of its kind published in the journal Scientific Reports, believes it has identified biological evidence of a discrepancy between the sexual identity perceived by the brain and that developed by the body in transgender people. To better understand this difference, researchers from the University of Augusta have studied the genomes of 30 transgender individuals, focusing on the pathways of estrogen receptors in the brain.

The hormone issue

The team of the research author, Dr. John Graham Theisen, gynecologist and obstetrician and researcher in women’s reproductive health at the National Institutes of Health at the Augusta  University, has identified 21 variants in 19 genes in the estrogenic signaling pathways of the brain that are necessary to determine whether the brain is male or female. These genes are involved in the mass release of hormones, including estrogens, into the brain shortly before or after birth, which contribute to the “masculinization” or “feminization” of the brain.

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In the variants identified by the researchers, these estrogen exposures do not occur in male-born men, or the signaling pathway is altered, which does not “masculinize” the brain. Similarly, in women, if estrogen exposure occurs when it should not, could lead to masculinization.

Both phenomena would lead to so-called sexual dysphoria, a feeling of inadequacy between the inner and outer sex of the individual. In other words, sexual dysphoria is characterized by a feeling of discomfort that some people may experience when they feel “trapped” in a gender they cannot identify with.

For Thiesen, the gender identity to which the brain refers is unchanged, and treatments such as hormone therapy or surgery are designed to help the body adapt to the brain’s ideal.

For Dr. Lawrence Layman, head of the Department of Reproductive Endocrinology, Infertility and Genetics at Georgia College of Medicine, time is of the essence. “It doesn’t matter what genitals you have, it’s important that estrogen and androgens, which are converted to estrogen in the brain, masculinize the brain at this critical time. We have found genes that are important in some of these different areas of the brain”.

Scientists say that although the critical period for brain masculinization may seem late, the development of the brain continues long after birth. When estrogen arrives, pathways and receptors must be established.

The researchers examined the DNA of 30 adult volunteers who identified themselves as transsexual and diagnosed sexual dysphoria based on the DSM-V criteria. These included 13 transgender men born as women and in transition to men and 17 transgender women born as men and in transition to women.

The Yale Genome Analysis Center performed an analysis of their entire genome by sequencing the protein coding regions of the gene. This analysis was then confirmed by Sanger sequencing, the method used to detect gene variants. The variants found did not occur in the group of 88 control tests on non-transgender individuals that were also examined at Yale. In addition, these variants were missing or very rare in large control DNA databases.

For these researchers, one of the factors that could explain sexual dysphoria could be estradiol, the basic estrogen that we all produce very briefly in the perinatal phase (between the 22nd week of the missing maternal menstrual period and the first week of childbirth). In this phase, the short-term release of estradiol would lead to two possibilities: Either the signaling pathways would be activated by estrogen receptors, resulting in a “male brain”, or – since the ovaries are at rest in pregnant women – a lack of estrogen receptor stimulation would result in a “female brain”.

The biological basis of sexual dysphoria

For Lawrence Layman, who has 20 years of experience in dealing with transgender patients, there is a biological basis for sexual dysphoria in most cases. His colleague, John Graham Thiesen, agrees. “We certainly believe that for most people suffering from sexual dysphoria there is a biological component. We want to understand what the genetic component of sexual identity is”.

According to the researchers, although genetics has been identified as a factor in sexual dysphoria, it has not yet been proven. Most of the genes or gene variants studied earlier were related to androgen receptors, i.e. hormones traditionally associated with male characteristics but also present in women, such as estrogen in men.

Therefore, the scientists focused on the little-known aspect of gender-specific brain development, namely the estrogen bath required by the brain in the early stages of life in order to identify potential sites of significant genetic variation. Initially, DNA tests revealed over 120,000 variants, 21 of which were associated with estrogenic pathways.

Animal testing

The team of scientists based their investigations partly on a 2008 rat study, which identified four brain areas whose developmental pathways are related to the development of the male or female brain. Based on these findings, the scientists assumed that it could be the same in humans. Other studies, this time on primates during adolescence, also showed that disruption of these pathways leads to trans behavior. According to Lawrence Layman, many people report feelings of gender inadequacy as early as five years of age.

While gender-specific brain development in men has not been studied in detail, the effects are more pronounced in adolescence. Increased sexual awareness at this stage makes it easier to express sexual dysphoria in adolescents. Similarly, previous studies have shown that perinatal exposure to sex hormones can influence future sexual behavior. The majority of the data are from studies in women with classic congenital adrenal hyperplasia from birth. This rare genetic disorder, which causes abnormal production of hormones (especially androgens) before birth, leads to varying degrees of external virilization of the genitals. In these women the rate of sexual dysphoria reaches 3%, compared to 0.2% in women who are not affected by the disease. On the other hand, the data available for men are not sufficient to determine the trend, which the scientists deplore.

According to John Graham Theisen, genetic variations are responsible for our individual characteristics, such as eye color, and gender is as unique and diverse as other characteristics, which usually do not cause disease.

Increasing stigma

In the United States, researchers estimate that about 0.5-1.4% of men and 0.2-0.3% of women are born with sexual dysphoria. True” (identical) twins are more prone to this condition than “fraternal” twins.

The lives of transsexual people are often marked by discrimination and sexual violence, which can lead to depression, drug addiction and suicide. In a 2010 U.S. national survey on discrimination against transgender people, 26% of transgender people admitted to drinking or using alcohol or drugs, and 19% refused medical care. In the same report, 28% of respondents reported verbal harassment in the medical community or at insurance companies that do not cover the cost of hormone therapy or affirmative-action surgery. Finally, 41% of respondents reported that they tried to commit suicide, compared to 1.6% of the total population. For researchers, this discrimination is due to a lack of understanding of the biological basis of sexual dysphoria.

A study on body-brain mismatch was conducted on 30 people, and researchers say they have data on another 30 people. Although the study, which is partly funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, appears to be the largest to date, its findings were considered preliminary.


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