Navigating in the dark: Meta-synthesis of subjective experiences of gender dysphoria amongst transgender and gender non-conforming youth.

OBJECTIVE: We conducted a meta-synthesis of qualitative research on subjective experiences of gender dysphoria (GD) amongst transgender and gender non-conforming (TGNC) youth in order to improve clinical encounters, complement existing knowledge and potentially influence future research. METHODS: We systematically searched for qualitative studies on GD in English, German, Spanish and Scandinavian languages in seven databases. Starting with 2000 articles, we finally included 12 papers in the meta-synthesis, following Noblit and Hare's (1988) seven steps for qualitative meta-synthesis research. RESULTS: Through the consistent comparison of key concepts, we were able to cluster the findings from the 12 included studies into four meta-themes: (1) the emerging understanding and awareness of GD was described as navigation in the dark, (2) the importance of relationships and societal norms, (3) the role of the body and the exploration of one's own body and (4) sexuality and sexual impulses. The young person's relation with his or her own body and sexuality influences subjective experiences of GD. The experiences are always mediated in relation with other people and societal norms, and they are both long-lasting and changing. CONCLUSION: The phenomenological analysis indicated that GD is a complex phenomenon involving manifold factors that changes across time and place for each individual. GD is not a static phenomenon but an expression of continuous negotiation amongst the body, its impulses, sexual desire and the relationships in which each person participates. Therefore, clinicians who treat TGNC youth should help them to reflect on this developmental process over time as a complement to medical approaches.

Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-ß precursor protein (AßPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

Effects of inhibition of gonadotropin releasing hormone secretion on the response to novel objects in young male and female sheep.

This study investigated the actions of blocking the GnRH receptor using a specific agonist on the response of male and female sheep to a novel object placed in their pen. The study is part of a series performed on 46 same sex twin animals. One of the pair received a subcutaneous implant of the GnRH agonist Goserelin acetate every four weeks while the other remained untreated. Implantation began immediately prior to puberty; at 8 weeks in the males and 28 weeks in the females (as timing of puberty is sex specific). To determine the effects of agonist treatment on the reproductive axis blood samples were collected for measurement of testosterone in the males and progesterone in the females. In addition the volume of the scrotum was determined. The present study aimed to determine whether there are sexually differentiated behavioural responses to a novel object at different stages of brain development (8, 28 and 48 weeks of age) and whether these responses are altered by GnRHa treatment. Approach behaviour towards and interactions with the novel object were monitored as was the number of vocalisations per unit time during the test period. GnRHa treatment suppressed testosterone concentrations and testicular growth in the males and progesterone release in the females. Sheep vocalised significantly more prior to weaning (8 weeks of age) than post weaning (28 and 48 weeks of age) suggesting stress on separation from their dams. Our current study shows that males are more likely to leave their conspecifics to approach a novel object than females. As this behaviour was not altered by suppression of the reproductive axis we suggest that, although sex differences are more obviously expressed in the phenotype after puberty, these may be developed during adolescence but not primarily altered during puberty by sex hormones.

Peri-pubertal gonadotropin-releasing hormone agonist treatment affects sex biased gene expression of amygdala in sheep.

The nature of hormonal involvement in pubertal brain development has attracted wide interest. Structural changes within the brain that occur during pubertal development appear mainly in regions closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors, results in exaggerated sex-differences in cognitive executive function and emotional control, as well as sex and hemisphere specific patterns of expression of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explored effects of this treatment regime on the gene expression profile of the ovine amygdala. The study was conducted with 30 same-sex twin lambs (14 female and 16 male), half of which were treated with the GnRH agonist (GnRHa) goserelin acetate every 4th week, beginning before puberty, until approximately 50 weeks of age. Gene expression profiles of the left and right amygdala were measured using 8×15 K Agilent ovine microarrays. Differential expression of selected genes was confirmed by qRT-PCR (Quantitative real time PCR). Networking analyses and Gene Ontology (GO) Term analyses were performed with Ingenuity Pathway Analysis (IPA), version 7.5 and DAVID (Database for Annotation, Visualization and integrated Discovery) version 6.7 software packages, respectively. GnRHa treatment was associated with significant sex- and hemisphere-specific differential patterns of gene expression. GnRHa treatment was associated with differential expression of 432 (|logFC|>0.3, adj. p value <0.05) and 46 (p value <0.0.5) genes in the left and right amygdala, respectively, of female animals, relative to the reference sample which consisted of all a pooled sample from control and treated animals of both sexes. No genes were found to be differentially expressed as a result of GnRHa treatment in the male animals. The results indicated that GnRH may, directly and/or indirectly, be involved in the regulation of sex- and hemisphere-specific differential expression of genes in the amygdala. This finding should be considered when long-term peri-pubertal GnRHa treatment is used in children.

Effects of peripubertal gonadotropin-releasing hormone agonist on brain development in sheep--a magnetic resonance imaging study.

In many species sexual dimorphisms in brain structures and functions have been documented. In ovine model, we have previously demonstrated that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) action increased sex-differences of executive emotional behavior. The structural substrate of this behavioral alteration however is unknown. In this magnetic resonance image (MRI) study on the same animals, we investigated the effects of GnRH agonist (GnRHa) treatment on the volume of total brain, hippocampus and amygdala. In total 41 brains (17 treated; 10 females and 7 males, and 24 controls; 11 females and 13 males) were included in the MRI study. Image acquisition was performed with 3-T MRI scanner. Segmentation of the amygdala and the hippocampus was done by manual tracing and total gray and white matter volumes were estimated by means of automated brain volume segmentation of the individual T2-weighted MRI volumes. Statistical comparisons were performed with general linear models. Highly significant GnRHa treatment effects were found on the volume of left and right amygdala, indicating larger amygdalae in treated animals. Significant sex differences were found for total gray matter and right amygdala, indicating larger volumes in male compared to female animals. Additionally, we observed a significant interaction between sex and treatment on left amygdala volume, indicating stronger effects of treatment in female compared to male animals. The effects of GnRHa treatment on amygdala volumes indicate that increasing GnRH concentration during puberty may have an important impact on normal brain development in mammals. These novel findings substantiate the need for further studies investigating potential neurobiological side effects of GnRHa treatment on the brains of young animals and humans.

Sex-specific development of spatial orientation is independent of peripubertal gonadal steroids.

Prenatal exposure to androgens has been shown to modulate brain development, resulting in changed behavioral attitudes, sexual orientation and cognitive functions, including processing of spatial information. Whether later changes in gonadotropic hormones during puberty induce further organizational effects within the brain is still insufficiently understood. The purpose of this study was to assess development of spatial orientation before and after the time of normal pubertal development, in an ovine model where half of the animals did not undergo typical reproductive maturation due to the pharmacological blockade of gonadotropin releasing hormone receptor (GnRHR) signaling. The study formed part of a larger trial and utilized 46 pairs of same sex Scottish Mule Texel Cross twins (22 female and 24 male). One twin remained untreated throughout (control) while the other received a subcutaneous GnRH agonist (GnRHa: Goserelin-Acetate) implant every fourth week. GnRHa treatment began at eight and 28 weeks of age, in males and females respectively, because the timing of the pubertal transition is sexually differentiated in sheep as it is in humans. Spatial orientation was assessed at three different time points: eight weeks of age, before puberty and treatment in both sexes; 28 weeks of age, after 20 weeks GnRHa treatment in males and before puberty and GnRHa treatment in females; and at 48 weeks of age, which is after the normal time of the pubertal transition in both sexes. Spatial orientation was tested in a spatial maze with traverse time as the main outcome measure. GnRHa treatment did not affect spatial maze performance as no significant differences in traverse time between treated and untreated animals were observed at any time-point. Adolescent females (48 weeks of age) traversed the maze significantly faster than adolescent males, whereas no sex differences in traverse time were seen at earlier developmental stages (eight and 28 weeks). Development of sex differences in spatial orientation was independent of exposure to pubertal hormones since puberty-blocked and control animals both showed the same pattern of spatial maze performance. This result demonstrates the prenatal nature of spatial orientation development. Furthermore, the unexpected finding that female animals outperformed males in the spatial orientation task, underscores the importance of the testing context in spatial orientation experiments.

Peri-pubertal gonadotropin-releasing hormone analog treatment affects hippocampus gene expression without changing spatial orientation in young sheep.

BACKGROUND: Normal brain maturation is the result of molecular changes that can be modulated by endocrine variables associated with brain plasticity and results in sex- and age specific changes in cognitive performance. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors results in increased sex-differences in cognitive executive function and emotional control. In this study we explore effects of this treatment regime on hippocampal gene expression and spatial orientation. METHODS: The study was conducted with 30 same-sex twin lambs, half of which were treated with the GnRH analog (GnRHa) goserelin acetate every 4th week, beginning before puberty, until 50 weeks of age. Animals were tested in their spatial orientation ability at 48 weeks of age. Quantitative real time PCR analysis was conducted to examine effects of treatment on the expression of genes associated with synaptic plasticity and endocrine signaling. RESULTS: GnRHa treatment was associated with significant sex- and hemisphere specific changes in mRNA expression for some of the genes studied. The treatment had no significant effect on spatial orientation. However, there was a tendency that females performed better than males in spatial orientation. CONCLUSION: Our results indicate that GnRH directly and/or indirectly, is involved in the regulation of sex- and side-specific expression patterns of genes. Hence, these results should be considered when long-term peri-pubertal GnRHa treatment is used in children.

Development of psychophysiological motoric reactivity is influenced by peripubertal pharmacological inhibition of gonadotropin releasing hormone action--results of an ovine model.

This study reports the effects of peripubertal GnRH receptor inactivation on development of psychophysiological motoric reactivity (PMR; sometimes also called emotional reactivity), plasma cortisol concentrations and the relationship between plasma cortisol and PMR in male and female sheep. The study formed part of a larger trial and utilised 46 same sex twins. One twin remained untreated (control) while the other received a subcutaneous GnRH agonist (GnRHa Goserelin-Acetate) implant every 4th week, beginning at 8 and 28 weeks of age, in males and females, respectively (different, due to sex specific age of puberty). PMR, a measure of an animals' response to social isolation, was measured over a two minute period at 8, 28 and 48 weeks of age, using a three axis accelerometer. During the test period vocalisation rate was recorded. Cortisol was assayed in blood samples collected on a single day when animals were 40 weeks of age. PMR and vocalisation rate were significantly higher in females than males at all ages tested. At 28 weeks of age (20 weeks treatment) PMR was increased in treated males to the level seen in control females, by 48 weeks of age treated males' PMR was significantly less than controls. In females, 20 weeks of GnRHa treatment (28-48 weeks of age) was not associated with differences in PMR. Cortisol concentrations were significantly higher in females than males but were not affected by treatment. Plasma cortisol concentrations were positively correlated with PMR; this relationship being driven by the treated animals in both sexes. The results demonstrate that PMR is sexually dimorphic and cortisol dependent in sheep from at least 8 weeks of age. Importantly, they also demonstrate that long-term treatment of males with a GnRH agonist results in changes in age-dependent development of PMR.

Prepubertal gonadotropin-releasing hormone analog leads to exaggerated behavioral and emotional sex differences in sheep.

In mammals, sex specialization is reflected by differences in brain anatomy and function. Measurable differences are documented in reproductive behavior, cognition, and emotion. We hypothesized that gonadotropin-releasing hormone (GnRH) plays a crucial role in controlling the extent of the brain's sex specificity and that changes in GnRH action during critical periods of brain development, such as puberty, will result in altered sex-specific behavioral and physiological patterns. We blocked puberty in half of the 48 same-sex Scottish mule Texel cross sheep twins with GnRH analog (GnRHa) goserelin acetate every 3 weeks, beginning just before puberty. To determine the effects of GnRHa treatment on sex-specific behavior and emotion regulation in different social contexts, we employed the food acquisition task (FAT) and measurement of heart rate variability (HRV). ANOVA revealed significant sex and sex×treatment interaction effects, suggesting that treated males were more likely to leave their companions to acquire food than untreated, while the opposite effect was observed in females. Concordant results were seen in HRV; treated males displayed higher HRV than untreated, while the reverse pattern was found in females, as shown by significant sex and sex×treatment interaction effects. We conclude that long-term prepubertal GnRHa treatment significantly affected sex-specific brain development, which impacted emotion and behavior regulation in sheep. These results suggest that GnRH is a modulator of cognitive function in the developing brain and that the sexes are differentially affected by GnRH modulation.