What has sex got to do with it? The role of hormones in the transgender brain

Abstract

Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

Biological sex classification with structural MRI data shows increased misclassification in transgender women

“…Our results imply that brain structure of TW (especially post CHT) does neither resemble a feminine nor masculine brain. In line with this idea, hormonal processes, brain-structural development and the development of gender identity are intertwined [21]. Intrauterine hormones (e.g.…”

Gender-Affirming Hormone Use in Transgender Individuals: Impact on Behavioral Health and Cognition

“…These people are cisgender (abbreviated cis ). Transgender (abbreviated trans ) is an umbrella term that describes those who do not have a gender identity, gender expression (i.e., the way one presents their gender to others), and/or behavior (i.e., how the person expresses their gender identity through actions) that matches their sex assigned at birth, as defined by the norms of a given culture [1••, 2]. …”

“…This “mosaic” of maleness and femaleness is present in all individuals, including both transgender and cisgender individuals [12••]. During puberty, gonadal steroids, life experiences, and genetics all influence the programmed brain to form a phenotype somewhere along the sex continuum and an identity somewhere along the gender continuum [1••, 2, 13, 14]. …”

“…Males tend to outperform females in spatial rotation tasks, and females outperform males in tasks requiring verbal fluency [16, 17]. In transgender individuals naive to GAHT, most cross-sectional neuroimaging research indicates that brain morphology, performance on cognitive tasks, and activation patterns at rest and during cognitive tasks are more congruent with gender identity than natal sex [1••, 18, 19•, 20–22, 23•, 24–29]. …”

The Link between Estradiol and Neuroplasticity in Transgender Women after Gender-Affirming Surgery: A Bimodal Hypothesis

“…In addition, we set out to examine possible links between changes in CTh and changes in memory performance due to CSHT with estradiol [25,26]. To the best of our knowledge and according to a recent neuroimaging review [27], this is the first longitudinal study evaluating the impact of CSHT on gray matter after GAS.…”