Estradiol Replacement as a Potential Enhancer of Working Memory and Neuroplasticity in Hypogonadal Trans Women.

INTRODUCTION: The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. METHODS: Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. RESULTS: Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. DISCUSSION: These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.

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

For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available on the impact of CSHT on the brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness (CTh) and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at 2 time points: on the last day of the washout (t1) and on the last day of the 2-month CSHT period (t2). Between these 2 time points, CTh increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, these findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in CTh. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus, and the right pars opercularis. Although there was an improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and CTh. Altogether, these findings suggest that there is a link between estradiol and CTh.

Effects of Estradiol Therapy on Resting-State Functional Connectivity of Transgender Women After Gender-Affirming Related Gonadectomy.

An extreme incongruence between sex and gender identity leads individuals with gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-affirming surgery (GAS). Although few studies have investigated the effects of CSHT on the brain prior to GAS, no studies in the extant literature have evaluated its impact during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex (SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-to-female) participants underwent functional magnetic resonance imaging (fMRI) and neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout; t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed, while the SMC and the dorsolateral striatum were targets for seed-based functional connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel exploratory analysis again using the thalamus as a seed. A final complementary data-driven approach using multivoxel pattern analysis (MVPA) was conducted to identify a potential seed for further sbFC analyses. An increase in the rs-FC between the left thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within the subcallosal cortex (SubCalC) representing the highest variation in peak activation between time points. Setting the SubCalC as a seed, whole-brain analysis showed a decoupling between the SubCalC and the medial frontal cortex during CSHT. These results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged in cognitive, emotional, and sensorimotor processes.

Psychological distress among transgender people in Brazil: frequency, intensity and social causation - an ICD-11 field study

Objective: To describe self-reported experiences of gender incongruence related to discomfort and body changes to be more congruent to the desired gender, and to examine whether experiences of psychological distress related to gender identity were more strongly related to the experience of gender incongruence per se or to experiences of social rejection. Methods: This field study used a structured interview design in a purposive sample of transgender adults (aged >18 years or older) receiving health-care services in two main reference centers in Brazil. Results: A high proportion of participants (90.3%, n=93) reported experiencing psychological distress related to their gender identity and report having experienced social rejection related to their gender identity during the interview index period and that rejection by friends was the only significant predictor for psychological distress. Conclusions: Gender incongruence variables were not significant predictors of distress. This result supports the recent changes proposed by the Word Health Organization in ICD-11 to move transgender conditions from the Mental and Behavioral Disorders chapter to a new chapter on Sexual Disorders and Conditions Related to Sexual Health.

Psychological distress among transgender people in Brazil: frequency, intensity and social causation - an ICD-11 field study.

OBJECTIVE: To describe self-reported experiences of gender incongruence related to discomfort and body changes to be more congruent to the desired gender, and to examine whether experiences of psychological distress related to gender identity were more strongly related to the experience of gender incongruence per se or to experiences of social rejection. METHODS: This field study used a structured interview design in a purposive sample of transgender adults (aged >18 years or older) receiving health-care services in two main reference centers in Brazil. RESULTS: A high proportion of participants (90.3%, n=93) reported experiencing psychological distress related to their gender identity and report having experienced social rejection related to their gender identity during the interview index period and that rejection by friends was the only significant predictor for psychological distress. CONCLUSIONS: Gender incongruence variables were not significant predictors of distress. This result supports the recent changes proposed by the Word Health Organization in ICD-11 to move transgender conditions from the Mental and Behavioral Disorders chapter to a new chapter on Sexual Disorders and Conditions Related to Sexual Health.

Brain Maturation, Cognition and Voice Pattern in a Gender Dysphoria Case under Pubertal Suppression.

Introduction: Gender dysphoria (GD) (DMS-5) is a condition marked by increasing psychological suffering that accompanies the incongruence between one's experienced or expressed gender and one's assigned gender. Manifestation of GD can be seen early on during childhood and adolescence. During this period, the development of undesirable sexual characteristics marks an acute suffering of being opposite to the sex of birth. Pubertal suppression with gonadotropin releasing hormone analogs (GnRHa) has been proposed for these individuals as a reversible treatment for postponing the pubertal development and attenuating psychological suffering. Recently, increased interest has been observed on the impact of this treatment on brain maturation, cognition and psychological performance. Objectives: The aim of this clinical report is to review the effects of puberty suppression on the brain white matter (WM) during adolescence. WM Fractional anisotropy, voice and cognitive functions were assessed before and during the treatment. MRI scans were acquired before, and after 22 and 28 months of hormonal suppression. Methods: We performed a longitudinal evaluation of a pubertal transgender girl undergoing hormonal treatment with GnRH analog. Three longitudinal magnetic resonance imaging (MRI) scans were performed for diffusion tensor imaging (DTI), regarding Fractional Anisotropy (FA) for regions of interest analysis. In parallel, voice samples for acoustic analysis as well as executive functioning with the Wechsler Intelligence Scale (WISC-IV) were performed. Results: During the follow-up, white matter fractional anisotropy did not increase, compared to normal male puberty effects on the brain. After 22 months of pubertal suppression, operational memory dropped 9 points and remained stable after 28 months of follow-up. The fundamental frequency of voice varied during the first year; however, it remained in the female range. Conclusion: Brain white matter fractional anisotropy remained unchanged in the GD girl during pubertal suppression with GnRHa for 28 months, which may be related to the reduced serum testosterone levels and/or to the patient's baseline low average cognitive performance.Global performance on the Weschler scale was slightly lower during pubertal suppression compared to baseline, predominantly due to a reduction in operational memory. Either a baseline of low average cognition or the hormonal status could play a role in cognitive performance during pubertal suppression. The voice pattern during the follow-up seemed to reflect testosterone levels under suppression by GnRHa treatment.

Association of the gene encoding neurogranin with schizophrenia in males.

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.

Transthyretin: no association between serum levels or gene variants and schizophrenia.

It has been proposed that schizophrenia results from an environmental insult in genetically predisposed individuals. Environmental factors capable of modulating transcriptional activity and their carriers could link the genetic and environmental components of schizophrenia. Among these is transthyretin (TTR), a major carrier of thyroid hormones and retinol-binding protein (RBP). Retinoids and thyroid hormones regulate the expression of several genes, both during development and in the adult brain. Decreased TTR levels have been reported in the cerebrospinal fluid of patients with depression and Alzheimer's disease, and the absence of TTR influences behavior in mice. DNA variants capable of altering TTR ability to carry its ligands, either due to reduced transcription of the gene or to structural modifications of the protein, may influence development of the central nervous system and behavior. In the present study we searched for variants in the regulatory and coding regions of the TTR gene, and measured circulating levels of TTR and RBP. We found a novel single nucleotide polymorphism (SNP), ss46566417, 18 bp upstream of exon 4. Neither this SNP nor the previously described rs1800458 were found associated with schizophrenia. In addition, serum TTR and RBP levels did not differ between mentally healthy and schizophrenic individuals. In conclusion, our data does not support an involvement of the TTR gene in the pathophysiology of schizophrenia.