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Copyright © 2011 Alexander, Skinner and Roselli.

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[Part Introduction] The early actions of sex steroids are imperative for the maturation and/or organization of several brain structures and neural circuits. The differentiated neural circuits are then responsible for sex-typical responses following puberty when sex steroids are synthesized at adult levels by the mature gonad. Thus, it is common to refer to the permanent developmental effects of sex steroids as “organizational,” while the reversible or transient effects observed during adulthood are referred to as “activational.”




Testosterone is unequivocally the primary gonadal steroid driving sexual differentiation and the development of sexual partner preference in male mammals. The effects of testosterone may be either direct and/or indirect, through its aromatase-derived estrogenic metabolites. However, there are several additional ways that hormone exposure may be responsible for atypical sexual partner preferences. Variations may relate to absolute levels of hormone, timing of exposure, metabolism to more or less active molecules, hormone receptor activity, availability of free as opposed to bound steroid, or some combination of these factors. Moreover, depending on the developmental timing of specific brain structures and their coincident exposure to the prevailing steroidal milieu, some brain structures may be demasculinized/defeminized, whereas others are not. In addition, the causes of variations could relate to individual genetic variability or exposure to environmental factors that suppress the reproductive axis (e.g., stress) or disrupt hormone actions (e.g., environmental endocrine disruptors; Ryan and Vandenbergh, 2002; Patisaul and Polston, 2008).


万恶睾酮论 。这个其实呃怎么说呢,应该算某种常识吧,哺乳动物的性别基础是偏女性的,是睾酮让雄性往雄性方向发展,无论是生理还是心理。


Development of female-directed partner preference in male rodents is independent of androgen receptor activation since both androgen insensitive rats (Tfm; Hamson et al., 2009) and androgen receptor knockout mice (Raskin et al., 2009) exhibit masculinized partner preference.



Sexual partner preferences are subject to activational effects of gonadal steroids in rodents. Intact females prefer males over females and intact males prefer estrous females over males (Hetta and Meyerson, 1978; Meyerson et al., 1980). In females, ovariectomy reduces sexual preference for a stimulus male which is restored by an injection of estradiol (Slob et al., 1987). In males, castration reduces sexual partner preference for an estrous female and either testosterone or estradiol restores it, but not dihydrotestosterone (DHT; Bakker et al., 1993).



The ineffectiveness of DHT indicates that, like for other aspects of masculine sexual behavior, estrogenic metabolites produced by brain aromatase mediate the activational effects of testosterone.



  1. 能把睾酮转换为雌激素 ↩︎



In humans, gender is traditionally assigned by the presence of testes in the male and the absence of testes (implying the presence of ovaries) in females, whereas gender identity and sexual orientation are neurological effects. Gender identity is defined as whether a person perceives themselves as male or female regardless of anatomy and should be considered separately from gender behavior. Accordingly, a person with female gender identity may have masculine gender behavior. Orientation is defined by who we desire sexually, not necessarily whom we have sex with. There is overwhelming evidence in all species that prenatal hormone exposure is the most critical factor determining anatomical sex. Over the past 50 years, animal models have provided seminal information on how hormones regulate sex-typical brain anatomy and behavior. Those studies framed the nature of questions that are currently being posed regarding the influence of hormones on sexual identity and orientation. Although animal models have provided some insight into sex-typical orientation, they will never yield information regarding gender identity. Moreover, as orientation is also not simply binary, animal models are unlikely to resolve whether all etiologies underlying homosexuality are common – e.g., do masculine and effeminate gay men develop similarly?

在人类中,性别传统上是由男性睾丸的存在和女性对睾丸的缺少(暗示卵巢的存在)来指派的,而性别认同和性取向是神经系统的的作用。性别认同被定义为一个人是否认为自己是男性或女性,无论解剖结构如何,都应该与性别表达分开考虑。因此,具有女性性别认同的人可能具有男性性别表达。性取向是由我们在性方面渴望的人来定义的,而不一定是我们与谁发生性关系。在所有物种中,有压倒性的证据表明,产前激素暴露是决定解剖性别的最关键因素。 在过去的 50 年里,动物模型提供了关于激素如何调节性别典型大脑解剖结构和行为的开创性信息。这些研究确定了目前提出的关于激素对性认同和性取向的影响的问题的性质。尽管动物模型提供了一些关于性别典型取向的见解,但它们永远不会产生有关性别认同的信息。此外,由于取向也不是简单的二元对立,动物模型不太可能确定同性恋的所有病因是否都是共同的——例如,男性和女性化的男同性恋者是否发展相似?

Theories behind human psychosexual development

Optimal-gender policy

John Money’s hypothesis that the human brain is gender neutral at birth and evolves thereafter under the influence of experience/learning and hormones was advanced from the 1950s to the 1990s (Money and Ehrhardt, 1972). This policy shaped decision making for the medical, surgical, and psychological management of sexual development and especially “disorders” thereof. This policy was seriously undermined with the discovery that some 46,XY individuals with penile agenesis, penile ablation, or cloacalextrophy who were raised female, reassigned themselves with their genetic sex or experience gender dysphoria later in life (see Meyer-Bahlburg, 2005 for review). In contrast, no such individuals raised male reassigned their gender. It should be noted, however, that for some persons who have not undergone “complete” masculinization/defeminization neonatally [e.g., partial androgen insensitivity (PAIS), congenital adrenal hyperplasia (CAH) – see below] there is some support for the contention that gender identity, but not behavior, may be shaped by experience/learning (Wisniewski et al., 2008). However, how much of individual sex identification is determined by a need to conform to an established identity is uncertain since changing gender is not readily accepted in most societies.


约翰·莫尼(John Money)的假设是,人类大脑在出生时是性别中立的,此后在经验/学习和性激素的影响下分化。这项理论从1950年代发展到1990年代(Money和Ehrhardt,1972)。
这项理论影响了性发育的医疗、外科和心理管理,特别是其中(将性别认同认为是)“障碍”的决策。这一理论最后破产,因为发现一些 46,XY 患有阴茎发育不全、消融营养不良的人类在作为女性长大后,改为认同了自己的遗传学性别(即男性),或在以后的生活中经历性别焦虑(参见 Meyer-Bahlburg,2005 年的评论)。相比之下,这些人作为男性养大后,不会认同自己的性别是女性。
然而,应该注意的是,对于一些没有经历过新生儿的“完全”男性化/去女性化过程的人[例如,部分性雄激素不敏感 (PAIS)、先天性肾上腺皮质增生症 (CAH)——见下文],有一些人支持性别认同而非性别表达可能由经验/学习塑造的论点(Wisniewski 等人,2008 年). 然而,由于大多数社会不容易接受性别变化,因此在多大程度上,个人的性别认同是由符合当前身份的需要塑造的,这是不确定的。

这个人就是臭名昭著的John Money了, 著名的 大卫·利马 就是在他的手术下被迫成为mtftm最终自杀。这件事也是最著名的,性别中立理论的破产导火索。

Genetics Studies on mammals (Carruth et al., 2002; Abel and Rissman, 2011) suggest that sex chromosome related genes contribute to sexual differentiation of the brain, but there is no evidence yet in humans to support a specific genetic component in the differentiation of gender identity. However, population studies and studies of identical twins support the hypothesis that at least some male and female homosexuality is a consequence of genetics (Bailey et al., 1991; Mustanski et al., 2005). Homosexuality runs in families (Bailey et al., 1991), and regions of the X chromosomes as well as chromosomes 7, 8, and 10 have been identified as sites of particular interest with respect to male homosexuality (Mustanski et al., 2005). However, candidate gene studies on the androgen receptor on Xq12 (Macke et al., 1993) or the enzyme aromatase on 15q21.2 (DuPree et al., 2004) have not demonstrated an association with male homosexuality. There is also evidence that birth order of boys may affect the potential of becoming gay with each additional older brother increasing the odds of becoming homosexual by approximately 33% (Cantor et al., 2002). A pivotal study by Bogaert (2006) demonstrated that the fraternal birth order operates during prenatal life since the effect was observed even when the biological older brother was reared in a separate household. Furthermore, non-biological siblings (adopted or step-brothers) had no effect on men’s sexual orientation (Bogaert, 2006). The most plausible, but not yet proven, explanation for this observation is that the mother develops an immune response that in some direct and/or indirect way, affects male fetal brain development during pregnancy. It is believed that this immune response is enhanced with each subsequent male pregnancy and increases the likelihood that some later born males will be sexually attracted to men as opposed to women (Bogaert and Skorska, 2011).


Human males and females express specific behavioral differences which, by definition, are neurologically mediated (Hines, 2011). Accordingly, there are numerous neuroanatomical differences (see Bao and Swaab, 2010 for review) among men and women: from cortical thickness, which is greater in women (Luders et al., 2006), to the suprachiasmatic nucleus, which is more elongated in women (Swaab et al., 1985). Testosterone has even been implicated in cerebral lateralization (Grimshaw et al., 1995). Indeed, there may be few neurological structures that are not sexually dimorphic.

It is noteworthy that several of these nuclei differ according to sexual orientation or in disorders of sexual development. The suprachiasmatic nucleus in homosexual men is more similar in gross structure to that of a woman (Swaab and Hofman, 1990). The interstitial nucleus of the anterior hypothalamus 3 (INAH-3) is larger in males than in females (Garcia-Falgueras and Swaab, 2008) and is also smaller in homosexual than heterosexual men (LeVay, 1991). In addition, the volume and number of neurons present in the INAH-3 in 46,XY transsexual (i.e., male to female) people is similar to that in XX women (Garcia-Falgueras and Swaab, 2008). The isthmus of the corpus callosum is larger in right handed homosexual men than heterosexual men (Witelson et al., 2008). An MRI study to identify corpus callosum shape at the midsagittal plane found that callosal shape reflected gender identity rather than genetic sex (Yokota et al., 2005). Women and 46,XY transsexual persons have a smaller central subregion of the bed nucleus of the stria terminalis (BNST) than men (Zhou et al., 1995), but the origin of this difference is controversial (Hines, 2011). Whether these neuroanatomically different sites actually play specific roles in gender identification and/or sexual orientation is not known. Indeed, they may simply reflect that, like the fingers, the brain has been exposed to a different endocrine milieu in utero .

人类男性和女性表现出特定的行为差异,根据定义,这些差异是神经介导的(Hines,2011)。因此,男性和女性之间存在许多神经解剖学差异(参见Bao和Swaab,2010年进行综述):从女性的皮质厚度更大(Luders等人,2006年)到女性的视交叉上核更加细长(Swaab等人,1985年)。睾酮甚至与大脑偏侧化有关(Grimshaw 等人,1995 年)。事实上,可能很少有神经结构不是性二态的。

值得注意的是,这些细胞核中的几个根据性取向或性发育障碍而有所不同。同性恋男性的视交叉上核在大体结构上与女性更相似(Swaab和Hofman,1990)。下丘脑前部 3 的间质核 (INAH-3) 在男性中比在女性中大(Garcia-Falgueras 和 Swaab,2008),在异性恋男性中比同性恋男性大(LeVay,1991)。 此外,46,XY 跨性别者(即MtF)的INAH-3中存在的神经元的数量和数量与XX女性相似(Garcia-Falgueras和Swaab,2008)。右撇子男同性恋者的胼胝体峡部比异性恋男性大(Witelson等人,2008)。一项用于识别矢状中平面胼胝体形状的 MRI 研究发现,胼胝体形状反映了性别认同而不是遗传性别(Yokota 等人,2005 年)。女性和46,XY 跨性别者的终纹(BNST)床核的中央亚区域比男性小(Zhou 等人,1995),但这种差异的起源是有争议的(Hines,2011)。 这些神经解剖学上不同的位点是否真的在性别认同和/或性取向中发挥特定作用尚不清楚。事实上,它们可能只是像手指一样反映出,大脑在子宫内暴露于不同的内分泌环境。



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Swyer syndrome

Probably the most compelling evidence that human neurological sexual differentiation is gonad dependent and independent of gene expression is provided by 46,XY persons with pure gonadal dysgenesis, or Swyer syndrome (Wisniewski et al., 2008). These individuals are externally female with streak gonads and, if untreated with estrogens, do not experience puberty. All reported cases identify as heterosexual females and experience no gender dysphoria. Since there is no MIH, the Müllerian duct structures develop into a rudimentary uterus and vagina so that 46,XY Swyer Syndrome women can maintain a pregnancy if treated hormonally.

Swyer综合征(注:46, XY 发育为女性表型,常与SRY基因有关)

46,XY患有单纯性腺发育不全或Swyer综合征的人可能提供了人类神经性别分化依赖于性腺且独立于基因表达的最令人信服的证据(Wisniewski等人,2008)。这些人外体为女性,有条纹性腺,如果不用雌激素治疗,则不会经历青春期。所有报告的病例均被确定为异性恋女性,没有性别焦虑。由于没有 MIH(苗勒管抑制激素),苗勒管结构发育成基本的子宫和阴道,因此如果接受激素治疗,46,XY Swyer 综合征女性可以妊娠。

Androgen insensitivity

In CAIS, a 46,XY person is unable to respond to androgens although MIH prevents development of the Müllerian ducts. Such individuals are infertile. Persons with CAIS identify as heterosexual females and do not experience gender dysphoria. CAIS provides evidence that, in humans, MIH does not play a central role in sexual differentiation.


在 CAIS(注:完全雄激素不敏感综合征,会使得 46, XY 发育为拥有睾丸但是是女性表型) 中,尽管 MIH 阻止了苗勒管发育(为子宫和阴道),但雄激素对这些 46,XY 的人完全无效。这样的人是不育的。CAIS患者认同是异性恋女性,不会出现性别焦虑症。CAIS提供的证据表明,在人类中,MIH在性别分化中不起核心作用。

From a societal acceptance perspective, 46,XY women with Swyer syndrome or CAIS conform to the binary stereotype, i.e., male vs. female. In contrast, with 46,XY PAIS, the degree of anatomical and neurological differentiation depends on the extent of retained androgen sensitivity. Although attempts are made to raise persons as male or female, gender dysphoria is not uncommon (Wisniewski et al., 2008) and it is arguable that either category is appropriate.

从社会接受度的角度来看,患有Swyer综合征或CAIS的46,XY女性符合二元性别刻板印象,即性别要么是男性要么女性。相比之下,对于 46,XY PAIS(部分性雄激素不敏感综合征),解剖学和神经学分化的程度取决于对雄激素敏感性的程度。虽然多种尝试试图将这些人按男性或女性养大,但性别焦虑并不少见(Wisniewski et al., 2008),并且是否要将其划为男女二者中的一类存在争议。

46,XY congenital estrogen deficiency
There are very few reported cases of 46,XY estrogen deficiency caused by either estrogen insensitivity or aromatase deficiency (Rochira et al., 2001). Although there are some reproductive anomalies, all individuals identify as heterosexual males (Rochira et al., 2001). Although the numbers are limited, this evidence is persuasive that estrogen plays little role in human male-typical sexual differentiation.




If there is masculinization/defeminization of the genitalia, but not the brain, it would be hypothesized that a 46,XY transgendered person develops. Studies by Savic and Arver (2011) support this hypothesis, but the number of individuals studied is very small. In some societies, most notably Independent Samoa, 46,XY transgendered persons indentify as a third gender, fafafine, which is feminine and there is no societal stigmatization associated with this gender. Fa’fafine are indentified at a very early age and seminal studies by Vasey et al. (2011) suggest that their psychosocial development is similar to girls, supporting the hypothesis that their brains have not undergone masculinization/defeminization. It is of note that fraternal birth order has been associated with the probability of a fa’fafine being born (VanderLaan and Vasey, 2011).


如果生殖器有男性化/去女性化,但大脑没有,就会发育成一个 46,XY 的跨性别者。Savic 和 Arver (2011) 的研究支持这一假设,但研究的个体数量非常少。在一些社会中,尤其是Independent Samoa,46,XY的跨性别者被认定为第三性别, fa’fafine,被算作是女性,并且没有与这种性别相关的社会污名化。Fa’fafine在很小的时候就被识别出来,Vasey等人(2011)的开创性研究表明,她们的心理社会发育与女孩相似,支持了她们的大脑没有经历过男性化/去化化的假设。值得注意的是,兄弟出生顺序与fa’fafine出生的概率有关(VanderLaan和Vasey,2011)。

Diethylstilbestrol and other xeno- and phyto-steroids
Diethylstilbestrol, a synthetic estrogen, was first synthesized in 1938 but, like several other xeno- and phyto-estrogens, it has affinity for the androgen receptor (Wang et al., 2010). Between 1940 and 1970, DES was used as a gestation facilitator and approximately 2 million US babies were exposed in utero although the duration and dose of DES were variable. Interestingly, there is a higher incidence of homosexuality in women exposed to DES as fetuses (Ehrhardt et al., 1985). Anecdotal evidence (Swaab, 2007) also suggested a higher incidence of DES exposure in 46,XY transgendered persons. There are numerous reports of an association between xeno- and phyto-estrogens and impaired sexual differentiation although most have focused on the effects on sexual anatomy and, by inference, the brain. For example, exposure to high levels of genistein or fungicides, which may act as xenosteroids, are associated with a higher incidence of hypospadias in men. Methoxyacetic acid, the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis, and causes testicular atrophy was shown to affect androgen sensitive HOX genes (Bagchi et al., 2011).

己烯雌酚 (DES) 是一种合成雌激素,于 1938 年首次合成,但与其他几种变种和植物雌激素一样,它对雄激素受体具有亲和力(Wang 等人,2010 年)。1940 年至 1970 年间,DES 被用作妊娠促进剂,大约 200 万美国婴儿在子宫内 暴露,尽管 DES 的持续时间和剂量各不相同。有趣的是,在胎儿时期暴露于DES的妇女中,同性恋的发生率更高(Ehrhardt等人,1985)。轶事证据(Swaab,2007 年)还表明,在 46,XY 跨性别者中,DES 暴露的发生率更高。有许多关于异种雌激素和植物雌激素与性别分化受损之间关联的报道,尽管大多数报告都集中在对性解剖学的影响上,并通过推断对大脑的影响。例如,暴露于高水平的染料木黄酮或杀菌剂(可能充当异种类固醇)与男性尿道下裂的发病率较高有关。甲氧基乙酸是工业化学品乙二醇单甲醚的主要活性代谢产物,破坏精子发生,并导致睾丸萎缩,被证明会影响雄激素敏感的HOX基因(Bagchi等人,2011)。