AACE 25th Annual Scientific & Clinical Congress:

Transgender Research: The Role of Biology in Gender Identity Development

gender identity word cloudRecent studies provide evidence that biology plays a role in transgender identity development, explained Stephen M. Rosenthal, MD, at the American Association of Clinical Endocrinologists (AACE) 25th Annual Scientific & Clinical Congress, May 25-29, 2016 in Orlando, Florida.

"Compelling data now suggest that gender identity is not simply a psychosexual construct, but that it is influenced by biology, environmental, and cultural factors," explained Dr. Rosenthal, who is Professor of Pediatrics, Division of Pediatric Endocrinology, and Medical Director of the Child & Adolescent Gender Center at University of California in San Francisco. "The data that support a role of biology in gender identity development basically come from three different biomedical disciplines: from genetics, endocrinology, and brain studies."

The Genetics of Gender Identity
In a meta-analysis of twin studies, nearly 40% of identical twins were concordant for gender dysphoria in comparison with none of the non-identical twins.1 "That is very striking evidence. The non-identical twins who, just like the kids who are identical twins, grew up with the same parents in the same households. The only difference, obviously, is that the identical twins essentially share the same DNA," Dr. Rosenthal said.

"You might be thinking, if there really is a genetic component to this, why is the concordance only 39.1% among identical twins?," Dr. Rosenthal continued. "We know that epigenetic modifications of DNA affect gene expression, and we also know that people come out at all different ages. Some people come out at age 3 or 5 years, and some people come out in their 60s." He added that a limitation of all transgender studies is the degree of self-awareness among study subjects and their willingness to disclose this information.

Endocrinology and Gender Identity
Studies of endocrinology and gender identity are primarily based on research in people with disorders of sex development, which Dr. Rosenthal pointed out most transgender individuals do not have. He used congenital adrenal hyperplasia as an example as this condition—in addition to limiting the adrenal gland's ability to make cortisol, mineralocorticoids, often results in excess production of androgens—which can lead to masculinization of the external genitalia in affected women.

In a study of 250 genetic females with congenital adrenal hyperplasia who were raised as females, 95% identified as females in adulthood and 5% identified as males or with gender dysphoria, which is at least 10 to 20 times more frequent than in a control population for female-to-male transgenderism.2 "This suggests that prenatal and early postnatal androgens play some role in gender identity development," Dr. Rosenthal said.

Neurobiologic Basis for Transgender
Numerous gray and white matter studies suggest that some sexually dimorphic structures more closely align with gender identity than with physical sex, and that these brain structures more closely align with gender identity than physical sex characteristics in transgender individuals, even before they had received cross-sex hormones.3-5 "When people say, I have a female brain in a male body or vice versa, there is evidence to support that," Dr. Rosenthal said.  

Dr. Rosenthal highlighted a 2015 study by Joel et al in which the investigators examined more than 1,400 male and female brains from four datasets.6 Rather than supporting the notion of a sexually dimorphic view of the human brain, the vast majority of subjects had an overlap of structures commonly seen in men and structures commonly seen in women. The researchers concluded that human brains are a "mosaic" of features.  

"For the first time, there is a paper that I think is so compelling and exciting because I think it lends some scientific data and support and credibility to the whole notion of being non-binary. Their findings blow away the whole idea of a male and female brain."

The Importance of Transgender Research and Medicine
"Why do we do this work? Because we know if people are not acknowledged in who they are, there is a tremendous amount of suffering and risk," Dr. Rosenthal said. He pointed to a 2015 study by Reisner et al showing that people who are transgender have a two to three-fold increased risk for internalizing disorders such as depression, anxiety, suicidal ideation, and suicide attempts.7
"Now does this mean that kids are currently depressed if they are transgender? I don't think so at all," Dr. Rosenthal said. "I think it's important to acknowledge the fact that there is still a tremendous amount of misunderstanding and transphobia in our cultures, and that obviously has an impact on how people feel."

He stressed that study of the biologic underpinning of gender identity is not intended to provide a "litmus test" of transgender, but rather to increase knowledge and understanding in the community at large, which may lead to increased acceptance a positive impact on quality of life for people who don't fit stereotype gender norms.

1. Heylens G, De Cuypere G, Zucker KJ, et al. Gender identity disorder in twins: a review of the case report literature. J Sex Med. 2012;9(3):751-757.

2. Dessens AB, Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;34(4):389-397.

3. Luders E, Sánchez FJ, Gaser C, et al. Regional gray matter variation in male-to-female transsexualism. Neuroimage. 2009;46(4):904-907.

4. Rametti G, Carrillo B, Gómez-Gil E, et al. White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. J Psychiatr Res. 2011;45(2):199-204.

5. Hoekzema E, Schagen SE, Kreukels BP, et al. Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain. Psychoneuroendocrinology. 2015 May;55:59-71.

6. Joel D, Berman Z, Tavor I, et al. Sex beyond the genitalia: The human brain mosaic. Proc Natl Acad Sci U S A. 2015;112(50):15468-15473.

7. Reisner SL, Vetters R, Leclerc M, et al. Mental health of transgender youth in care at an adolescent urban community health center: a matched retrospective cohort study. J Adolesc Health. 2015;56(3):274-279.

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