Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration

Recently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain endophenotype in people with gender dysphoria (GD). However, despite mounting neuroimaging work, brain gender differences and effects of gender-affirming hormone therapy (GAHT) at the metabolite level remain understudied.

Thirty-one transgender men (TM) before and after testosterone administration (7.7 months ± 3.5 months), relative to 30 cisgender men (CM) and 35 cisgender women (CW) underwent magnetic resonance spectroscopy (¹H-MRS) at two time points. Two brain regions were assessed, i.e. the lateral parietal cortex and the amygdala/anterior hippocampus. Associated metabolites that were measured include N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), glutamate and glutamine (Glx), myo-inositol (mI), glycine (Gly) and their respective ratios.

A critical time by group interaction revealed an effect of GAHT in the lateral parietal cortex of TM. MI+Gly/Cr ratios decreased upon initiation of GAHT. In addition, NAA/Cr and Cho/Cr ratios were lower in CW when compared to CM in the lateral parietal cortex. Glx levels and Glx/Cr ratios in TM differed from those in CW in the amygdala/anterior hippocampus. Interestingly, pubertal age of onset of gender dysphoria (i.e. GD) in TM differentially affected testosterone-mediated effects on Cr concentration and NAA/Cr ratios when compared to childhood and adult GD onset in the amygdala/anterior hippocampus.

This ¹H-MRS study demonstrated that testosterone administration shifts mI+Gly/Cr ratios in the parietal cortex. In the amygdala/anterior hippocampus, modulation of metabolite concentrations by age of onset of GD is suggestive for a possible developmental trend.

This chapter reviews the effects of gender-affirming hormonal treatments (GAHT) in transgenders seeking hormonal treatment to develop desired secondary sex characteristics while preventing further development of undesired secondary sex characteristics. However, due to the scarce literature on the subject, the potential long-term effects of GAHT in transgenders are still unknown. With this understanding and considering that GAHT is a life-long hormonal treatment, this chapter begins by discussing the existing sex steroids treatments employed in virilization/feminization hormone therapies, their potential impact on health outcomes, and the organizational and activational effects of sex steroids on the brain during development. Next, MRI studies that include a longitudinal design with the aim of examining the effects of GAHT on brain structure and function are discussed. Finally, some evidence, gathered mainly from animal models, is discussed with the aim of explaining the effects of GAHT on the brain.

There are opportunities to improve neuroscience that include lesbian, gay, bisexual, and transgender (LGBT) people. In this review, we briefly describe how the history of LGBT people in psychiatry has influenced neuroimaging approaches; how these attitudes have shifted over time; and what we can do to ensure that our future work is rigorous, ethical, and in service of the LGBT community. We suggest ways to refine neuroimaging methodologies to improve our understanding of marginalization and stigma while shifting away from research that focuses solely on the “etiology” or origins of LGBT identities. We also offer suggestions for conducting representative research that is LGBT-inclusive, regardless of the population of interest.

Some transgender people desire a transition through gender-affirming hormone treatment (GAHT). To date, it is unknown how GAHT changes emotion perception in transgender people.

Thirty transgender men (TM), 30 cisgender men (CM), and 35 cisgender women (CW) underwent 3 Tesla functional magnetic resonance imaging (fMRI) while passively viewing emotional faces (happy, angry, surprised faces) at two timepoints (T0 and T1). At T0 all participants were hormone-naïve, while TM immediately commenced testosterone supplementation at T0. The second scanning session (T1) occurred after 6–10 months of GAHT in TM. All 3 groups completed both T0 and T1

GAHT in TM shifted the neural profile whilst processing emotions from a sex-assigned at birth pattern at T0 (similar to CW) to a consistent with gender identity pattern at T1 (similar to CM). Overall, the brain patterns stayed the same for the cis people at T0 and T1.

These findings document the impact of hormone treatment, and testosterone supplementation specifically, on emotion perception in TM.

It is well documented that childhood lead exposure is associated with long-term decreases in intelligence quotients (IQ). Lesser known is the relationship with neurobehavioral domains, especially in adolescence. This study sought to identify cross-sectional and longitudinal associations between lead exposure and adolescent executive and visual-motor functioning and examine sex-based differences. Participants were 681 children from Jintan, China who had their blood lead levels (BLLs) assessed at age 3–5 years and 12 years old and neurobehavioral functioning assessed through the University of Pennsylvania Computerized Neurocognitive Battery (PennCNB) platform http://www.med.upenn.edu/bbl at 12 years old. Mean BLLs were 6.41 mcg/dl at age 3–5 years and 3.10 mcg/dl at 12. BLLs at 3–5 years and 12 years were used as predictors for the individual neurobehavioral domains in general linear models while controlling for father and mother occupation and education, residence location, age, and adolescent IQ. Models were run separately for males and females. In adjusted models, males BLLs at 3–5 years were associated with increased time to correctly complete tasks in multiple domains including abstraction/flexibility (β = 19.90, 95% CI( 4.26, 35.54) and spatial processing (β = 96.00, 95% CI 6.18, 185.82) at 12 years. For females in adjusted models, BLLs at 3–5 years were associated with increasing time to correctly complete tasks on the episodic memory domain task (β = 34.59, 95% CI 5.33, 63.84) at 12 years. Two adolescent cross-sectional relationships remained in the adjusted models for males only, suggesting a positive association between BLLs and increasing time for correct responses on the attentional domain task (β = 15.08, 95% CI 0.65, 29.51) and decreasing time for correct responses on the episodic memory task (β = −73.49, 95% CI −138.91, −8.06) in males at 12 years. These associations remained with and without controlling for IQ. These results suggest that lead exposure is associated with overall deficits in male and female neurobehavioral functioning, though in different domains and different timing of exposure.

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals.

Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus).

Linear mixed models analysis revealed a significant measurement by gender identity effect (p_corr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (p_corr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men.

Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies.

Due to data protection laws processed data is available from the authors upon reasonable request. Please contact [email protected] with any questions or requests.