但是对于跨性别者出生性别和性别认定相差异的生物学意义上的理解仍然不得而知。近年来诸如功能性磁共振成像【functional magnetic resonance imaging (fMRI)】一类的技术已经开始得出一些对于这种被称为性别焦虑的状态在生物学上可能的构成基础的线索，特别是研究者们正在鉴定的跨性别和顺性别个体的大脑在结构及功能的不同层面的相似性和差异性，可能对解释一个人所认定的性别与其出生时的性别并不相配的坚定信念会有所助益。
诸如功能性磁共振成像【functional magnetic resonance imaging (fMRI)】一类的技术已经开始得出一些对于性别在生物学上可能的构成基础的线索
这些结果可能对于如何诊断及治疗性别焦虑并不会产生多大影响，在阿姆斯特丹自由大学医学院（VU University Medical Center in Amsterdam）研究性别不一致的 Baudewijntje Kreukels 说明道，“很重要的一点是不能被看作这样，‘当你在大脑里看见了「性别焦虑」，那就是真的。’”但是来自于这些研究的深刻见解可能对于满足一些跨性别者理解自身状态的根源的愿望会有很大助益，她补充道，“如此一来，能够发现他们与出生时被指定性别的差异是否是其大脑中什么度量的反映就太好了。”
荷兰神经科学院（Netherlands Institute for Neuroscience）的Dick Swaab 是一位在性别认定所潜在的神经科学方面的先驱者。1990年代中期他的团队检查了六位跨性别女性死后的大脑并且报告说，纹状体床核【bed nucleus of the stria terminalis (BSTc or BNSTc)】——前脑上一个在性方面具双相性且已知对性行为很重要的区域——中心区的大小与顺性别女性比与顺性别男性更为接近。2一个尸检大脑的后续研究也发现在纹状体床核的某类特定神经元的数目，跨性别女性与其顺性别对应者——以及一个跨性别男性与顺性别男性——之间的相似性。3这些差异看起来并不能归咎于内分泌的性激素功能或是成年后的激素治疗的影响。在发表于2008年的另一项研究中，Swaab和一位合作者在尸检中检查了INAH3亚核——下丘脑中生前与性取向相关联的一个区域——的容量，这些研究者们发现顺性别男性的该区域大约是无论跨性别还是顺性别女性的两倍。4
另外一些研究已经确定跨性别者大脑的特征处于两种性别的典型性特征之间——这些结果一般都被发育性不相配假说的倡导者视作对其观点的支持。比如在2014年，维也纳医科大学（Medical University of Vienna）的神经学家 Georg Kranz运用漫射式磁共振成像（diffusion MRI）的数据来调查跨性别和顺性别实验者的白质微结构。一种被称作平均扩散率（mean diffusivity）的对神经性属性的度量，顺性别女性水平最高，顺性别男性最低，跨性别男性和女性居于二者之间——虽然平均扩散率在生理学意义上代表着什么还未被完全理解。6“看起来似乎这些跨性别群体属于一种中间状态，” Kranz说道。对个体激素水平的控制并未改变群体之间的差异，导致作者们建议白质微结构其实在出生前及出生之初就已经被所处的激素环境决定了——虽然之后的生活经历也扮演了一个角色的可能性并不能被排除，他补充说道。
2013年一项集中于皮质厚度——女性倾向于稍大于男性——的研究也给出了不统一结果。由西班牙国家远程教育大学（National Distance Education University in Spain）的神经学家 Antonio Guillamon领军，研究者们对94位实验者的磁共振成像进行了分析，发现跨性别女性和男性总的的皮质厚度都更接近于顺性别女性甚于顺性别男性。但此项发现并非对整个大脑都如此：在前脑一个参与肌肉运动和学习、被称作右壳核的结构里，跨性别男性的皮质厚度与顺性别男性的更相似，而跨性别女性与两个顺性别对照组都未显示出明显的差别。8
在与发育性不相配假说相关的另一项给出不统一结果的研究中，德国亚琛工业大学（RWTH Aachen University in Germany）的研究者们测试了顺性别者与跨性别女性如何分辨男性和女性声音。这个团队发现在某些方面，比如一个被称作右额上回的大脑区域的激活水准，跨性别和顺性别女性相似，而顺性别男性显示出更高的活力——可能反应出其在此项任务上所作的感知努力。10仅管在激活水准上跨性别和顺性别女性相似，但跨性别女性在辨别男性和女性的声音上同样擅长，而两种顺性别者都发现辨别相反性别的声音更容易。
在解读所观察到的这些不同群组之间差异时的一个困难是，什么时候或为什么这些差异会发生仍不清楚，比利时根特大学（Ghent University in Belgium）心理学家 Sven Müller说道，并且报告说相互关联也许反应的并非随意的关系。关于性别不一致多大程度上具有生物性起因“我认为判决仍未定，”他说道。“大脑在成年时期可塑性极强，”他说明道，所以跨性别者和顺性别者之间被鉴定出的那些差异可能是、也可能不是从出生时就具有了。
另外，那些探索性别焦虑生物学解释的科学家们还面临着后勤方面的挑战。要征集到足够多的跨性别实验者来进行具有高效统计意义的研究通常都很困难，但有些研究者正在努力补救此问题。比如在2017年，通过整合分析增进神经系统成像遗传学联合会（Enhancing Neuro Imaging Genetics through Meta Analysis, ENIGMA Consortium）——该组织致力于促进检测对大脑结构及功能产生适中基因影响的研究者们建立联系及分享信息——启动了一个新的、专注于跨性别现象的工作团队。范德堡大学（Vanderbilt University）遗传学家Lea Davis 正在组织一项尚待资助的努力，对上千位跨性别者和顺性别者进行基因组排序和分析，以寻找与性别认定相关联的变异。
除了关于性别认定的根源这个巨大的谜团之外，此领域的研究者们长期以来还有几个问题，比如对于那些经历变性过程，认定自身的二元化性别与其出生时的指定性别不同的人们，“我们仍然不知道男-变-女和女-变-男的变性欲是否属于同一种现象，或者「是否」你从两种性别出来一个相似的结果但其背后却有两种不同的机制，”一名德国亚琛工业大学的研究生以及一篇关于跨性别者大脑评论性文章的作者 Elke Smith说道。13另外一些出色的问题还包括，那些性取向不同的跨性别者，以及那些其性别焦虑在人生的早期就显示出来和那些在青少年或成年时才开始感觉焦虑的人们，他们的大脑有哪些——假如有任何的话——差别，Kreukels说道。另外还需确定的是，Savic补充道，那些在顺性别者和跨性别者之间已被确定的大脑上的差异是否在激素治疗之后仍然持续。（参见以下“激素治疗对大脑的影响”）
A.-M. Bao, D.F. Swaab, “Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders,” Front Neuroendocrin, 32:214-26, 2011.
J.-N. Zhou et al., “A sex difference in the human brain and its relation to transsexuality,” Nature, 378:68-70, 1995.
F.P. Kruijver, “Male-to-female transsexuals have female neuron numbers in a limbic nucleus,” J Clin Endocrinol Metab, 85:2034-41, 2000.
A. Garcia-Falgueras, D. Swaab, “A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity,” Brain, 131:3132-46, 2008.
S.M. Burke et al., “Male-typical visuospatial functioning in gynephilic girls with gender dysphoria—organizational and activational effects of testosterone,” J Psychiatry Neurosci, 41:395-404, 2016.
G.S. Kranz et al., “White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging,” J Neurosci, 34:15466-75, 2014.
E. Hoekzema et al., “Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain,” Psychoneuroendocrino, 55:59-71, 2015.
L. Zubiaurre-Elorza et al., “Cortical thickness in untreated transsexuals,” Cereb Cortex, 23:2855-62, 2013.
A. Guillamon et al., “A review of the status of brain structure research in transsexualism,” Arch Sex Behav, 45:1615-48, 2016.
J. Junger et al., “More than just two sexes: the neural correlates of voice gender perception in gender dysphoria,” PLOS ONE, 9:e111672, 2014.
I. Savic, S. Arver, “Sex dimorphism of the brain in male-to-female transsexuals,” Cereb Cortex, 21:2525-33, 2011.
J.D. Feusner et al., “Intrinsic network connectivity and own body perception in gender dysphoria,” Brain Imaging Behav, 11:964-76, 2017.
E.S. Smith et al., “The transsexual brain—A review of findings on the neural basis of transsexualism,” Neurosci Biobehav R, 59:251-66, 2015.
Transgender (trans) women (TW) were assigned male at birth but have a female gender identity or gender expression. The literature on management and health outcomes of TW has grown recently with more publication of research. This has coincided with…
The brain and cognition
Recent studies have investigated baseline differences between the brains of trans versus cis individuals as well as the effect of GAHT on the brain and cognition. The white matter microstructure of TW prior to initiation of GAHT has been characterized by diffusion tensor imaging to be between control females and control males.222–225 Hahn and colleagues226 also described different structural connectivity networks in 21 TW prior to initiating GAHT compared with control females and males. Seiger and colleagues227 analyzed brain MRIs of 14 TW (mean age 26.9 ± 6.1 years) at baseline and after at least 4 months (169 days ± SD 38 days) of continuous oral or transdermal oestradiol and anti-androgens (cyproterone acetate ± GnRHa ± finasteride) and found decreases in the hippocampal region, increases in the ventricles and a correlation between progesterone levels and changes in grey matter structure. Mueller and colleagues228 found neuroanatomical volume differences in the amygdala, putamen and corpus callosum in TW compared with cis women but not cis men, suggesting the possibility of localized influence of sex hormones on neuroanatomy. These studies suggest there are hormonal influences on cortical and subcortical structures related to cognition, memory and emotional processing. Reviews stress that additional short- and long-term studies are needed to better understand the role of sex hormones on the adult human brain structure and function and how they relate to psychological differences between females and males.229,230
Brain-derived neurotrophic factor (BDNF) is involved in neurogenesis, neuronal maturation and synaptogenesis, influencing brain plasticity. A study of 10 TW from Belgium showed a significant decrease in BDNF levels after 12 months of GAHT (p = 0.014) independent of age, weight, BMI, total fat mass, total lean mass, LH, FSH, oestradiol, testosterone, cortisol, physical activity or smoking.231 Therefore, it was concluded that the decreased BDNF in TW after GAHT resulted from the GAHT rather than as a consequence of or risk factor for gender identity.231
Nguyen and colleagues232 published a recent review of cross-sectional and longitudinal studies from the last 5 years, nearly all from European cohorts, and summarized fewer depressive symptoms, anxiety, problems with socialization and interpersonal functioning, global functional impairment, interpersonal sensitivity and hostility in TW on GAHT compared with baseline. They also summarized the general findings above that GAHT is correlated with changes in global and regional brain volumes, white matter microstructure and in cognitive performance on sex-biased tasks requiring verbal and visual memory in the direction of gender identity rather than assigned sex.232 However, no studies have examined how GAHT influences executive function and cognitive domains used for daily living, and additional research will provide valuable data on these and other brain processes.
Several studies have found a correlation between gender identity and brain structure. A first-of-its-kind study by Zhou et al. (1995) found that in a region of the brain called the bed nucleus of the stria terminalis (BSTc), a region which is known for sex and anxiety responses (and which is affected by prenatal androgens), cadavers of six persons who were described as having been male-to-female transsexual or transgender persons in life had female-normal BSTc size, similar to the study’s c In a …
Brain structure
General
Several studies have found a correlation between gender identity and brain structure.[8] A first-of-its-kind study by Zhou et al. (1995) found that in a region of the brain called the bed nucleus of the stria terminalis (BSTc), a region which is known for sex and anxiety responses (and which is affected by prenatal androgens),[9] cadavers of six persons who were described as having been male-to-female transsexual or transgender persons in life had female-normal BSTc size, similar to the study’s cadavers of cisgender women. While those identified as transsexual had taken hormones, this was accounted for by including cadavers of non-transsexual male and female controls who, for a variety of medical reasons, had experienced hormone reversal. The controls still had sizes typical for their gender. No relationship to sexual orientation was found.[10]
In a follow-up study, Kruijver et al. (2000) looked at the number of neurons in BSTc instead of volumes. They found the same results as Zhou et al. (1995), but with even more dramatic differences. One MtF subject, who had never gone on hormones, was also included and matched up with the female neuron counts nonetheless.[11]
In 2002, a follow-up study by Chung et al. found that significant sexual dimorphism (variation between sexes) in BSTc did not become established until adulthood. Chung et al. theorized that either changes in fetal hormone levels produce changes in BSTc synaptic density, neuronal activity, or neurochemical content which later lead to size and neuron count changes in BSTc, or that the size of BSTc is affected by the generation of a gender identity inconsistent with one’s assigned sex.[12]
It has been suggested that the BSTc differences may be due to the effects of hormone replacement therapy. It has also been suggested that because pedophilic offenders have also been found to have a reduced BSTc, a feminine BSTc may be a marker for paraphilias rather than transsexuality.[2]
In a review of the evidence in 2006, Gooren considered the earlier research as supporting the concept of transsexuality as a sexual differentiation disorder of the sex dimorphic brain.[13]Dick Swaab (2004) concurs.[14]
In 2008, a new region with properties similar to that of BSTc in regards to transsexuality was found by Garcia-Falgueras and Swaab: the interstitial nucleus of the anterior hypothalamus (INAH3), part of the hypothalamic uncinate nucleus. The same method of controlling for hormone usage was used as in Zhou et al. (1995) and Kruijver et al. (2000). The differences were even more pronounced than with BSTc; control males averaged 1.9 times the volume and 2.3 times the neurons as control females, yet regardless of hormone exposure, MtF transsexuals were within the female range and the FtM transsexual within the male range.[15]
A 2009 MRI study by Luders et al. of 24 MtF transsexuals not yet treated with cross-sex hormones found that regional gray matter concentrations were more similar to those of cisgender men than to those of cisgender women, but there was a significantly larger volume of gray matter in the right putamen compared to cisgender men. Like earlier studies, it concluded that transsexuality was associated with a distinct cerebral pattern.[16] (MRI allows easier study of larger brain structures, but independent nuclei are not visible due to lack of contrast between different neurological tissue types, hence other studies on e.g. BSTc were done by dissecting brains post-mortem.)
An additional feature was studied comparing 18 female-to-male transsexuals who had not yet received cross-sex hormones with 24 cisgender male and 19 female gynephilic controls, using an MRI technique called diffusion tensor imaging or DTI.[17] DTI is a specialized technique for visualizing white matter of the brain, and white matter structure is one of the differences in neuroanatomy between men and women. The study took into account fractional anisotropy values for white matter in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Rametti et al. (2010) discovered that, “Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract.”[17] The white matter pattern in female-to-male transsexuals was found to be shifted in the direction of biological males.
Hulshoff Pol et al. (2006) studied the gross brain volume of 8 male-to-female transsexuals and in six female-to-male transsexuals undergoing hormone treatment. They found that hormones changed the sizes of the hypothalamus in a gender consistent manner: treatment with male hormones shifted the hypothalamus towards the male direction in the same way as in male controls, and treatment with female hormones shifted the hypothalamus towards the female direction in the same way as female controls. They concluded: “The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain.”[18]
A 2016 review agreed with the other reviews when considering androphilic trans women and gynephilic trans men. It reported that hormone treatment may have large effects on the brain, and that cortical thickness, which is generally thicker in cisgender women’s brains than in cisgender men’s brains, may also be thicker in trans women’s brains, but is present in a different location to cisgender women’s brains.[2] It also stated that for both trans women and trans men, “cross-sex hormone treatment affects the gross morphology as well as the white matter microstructure of the brain. Changes are to be expected when hormones reach the brain in pharmacological doses. Consequently, one cannot take hormone-treated transsexual brain patterns as evidence of the transsexual brain phenotype because the treatment alters brain morphology and obscures the pre-treatment brain pattern.”[2]
Androphilic male-to-female transsexuals
Studies have shown that androphilic male-to-female transsexuals show a shift towards the female direction in brain anatomy. In 2009, a German team of radiologists led by Gizewski compared 12 androphilic transsexuals with 12 cisgender males and 12 cisgender females. Using functional magnetic resonance imaging (fMRI), they found that when shown erotica, the cisgender men responded in several brain regions that the cisgender women did not, and that the sample of androphilic transsexuals was shifted towards the female direction in brain responses.[19]
In another study, Rametti and colleagues used diffusion tensor imaging (DTI) to compare 18 androphilic male-to-female transsexuals with 19 gynephilic males and 19 androphilic cisgender females. The androphilic transsexuals differed from both control groups in multiple brain areas, including the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract. The study authors concluded that androphilic transsexuals were halfway between the patterns exhibited by male and female controls.[20]
A 2016 review reported that early-onset androphilic transgender women have a brain structure similar to cisgender women’s and unlike cisgender men’s, but that they have their own brain phenotype.[2]
Gynephilic male-to-female transsexuals
Research on gynephilic trans women is considerably limited.[2] While MRI taken on gynephilic male-to-female transsexuals have likewise shown differences in the brain from non-transsexuals, no feminization of the brain’s structure have been identified.[2] Neuroscientists Ivanka Savic and Stefan Arver at the Karolinska Institute used MRI to compare 24 gynephilic male-to-female transsexuals with 24 cisgender male and 24 cisgender female controls. None of the study participants were on hormone treatment. The researchers found sex-typical differentiation between the MtF transsexuals and cisgender males, and the cisgender females; but the gynephilic transsexuals “displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus”.[21]
The researchers concluded that:
Contrary to the primary hypothesis, no sex-atypical features with signs of ‘feminization’ were detected in the transsexual group … The present study does not support the dogma that [male-to-female transsexuals] have atypical sex dimorphism in the brain but confirms the previously reported sex differences. The observed differences between MtF-TR and controls raise the question as to whether gender dysphoria may be associated with changes in multiple structures and involve a network (rather than a single nodal area).[21]
Berglund et al. (2008) tested the response of gynephilic MtF transsexuals to two steroids hypothesized to be sex pheromones: the progestin-like 4,16-androstadien-3-one (AND) and the estrogen-like 1,3,5(10),16-tetraen-3-ol (EST). Despite the difference in sexual orientation, the MtFs’ hypothalamic networks activated in response to the AND pheromone, like the androphilic female control groups. Both groups experienced amygdala activation in response to EST. Gynephilic male control groups experienced hypothalamic activation in response to EST. However, the MtF subjects also experienced limited hypothalamic activation to EST. The researchers concluded that in terms of pheromone activation, MtFs occupy an intermediate position with predominantly female features.[22] The MtF transsexual subjects had not undergone any hormonal treatment at the time of the study, according to their own declaration beforehand, and confirmed by repeated tests of hormonal levels.[22]
A 2016 review reported that gynephilic trans women differ from both cisgender male and female controls in non-dimorphic brain areas.[2]
Gynephilic female-to-male transsexuals
Fewer studies have been performed on the brain structure of transgender men than on transgender women.[2] A team of neuroscientists, led by Nawata in Japan, used a technique called single-photon emission computed tomography (SPECT) to compare the regional cerebral blood flow (rCBF) of 11 gynephilic FtM transsexuals with that of 9 androphilic cis females. Although the study did not include a sample of biological males so that a conclusion of “male shift” could be made, the study did reveal that the gynephilic FtM transsexuals showed significant decrease in blood flow in the left anterior cingulate cortex and a significant increase in the right insula, two brain regions known to respond during sexual arousal.[23]
A 2016 review reported that the brain structure of early-onset gynephilic trans men generally corresponds to their assigned sex, but that they have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure, especially in the right hemisphere.[2] Morphological increments observed in the brains of trans men might be due to the anabolic effects of testosterone.[2]
Prenatal androgen exposure
Prenatal androgen exposure, the lack thereof, or poor sensitivity to prenatal androgens are commonly cited mechanisms to explain the above discoveries. To test this, studies have examined the differences between transsexual and cisgender individuals in digit ratio (a generally accepted marker for prenatal androgen exposure). A meta-analysis concluded that the effect sizes for this association were small or nonexistent.[24]
Congenital adrenal hyperplasia in persons with XX sex chromosomes results in what is considered to be excess exposure to prenatal androgens, resulting in masculinization of the genitalia and, typically, controversial prenatal hormone treatment[25] and postnatal surgical interventions.[26] Individuals with CAH are usually raised as girls and tend to have similar cognitive abilities to the typical female, including spatial ability, verbal ability, language lateralization, handedness and aggression. Research has shown that people with CAH and XX chromosomes will be more likely to be same sex attracted,[25] and at least 5.2% of these individuals develop serious gender dysphoria.[27]
In males with 5-alpha-reductase deficiency, conversion of testosterone to dihydrotestosterone is disrupted, decreasing the masculinization of genitalia. Individuals with this condition are typically raised as females due to their feminine appearance at a young age. However, more than half of males with this condition raised as females become males later in their life. Scientists speculate that the definition of masculine characteristics during puberty and the increased social status afforded to men are two possible motivations for a female-to-male transition.[27]
Contrary to the primary hypothesis, no sex-atypical features with signs of ‘feminization’ were detected in the transsexual group … The present study does not support the dogma that [male-to-female transsexuals] have atypical sex dimorphism in the brain but confirms the previously reported sex differences. The observed differences between MtF-TR and controls raise the question as to whether gender dysphoria may be associated with changes in multiple structures and involve a network (rather than a single nodal area).
